Natural Substances and Botanicals as Modulators in Major Depressive Disease: Focus on BDNF - A Review

Erhan Yarar^*
*Correspondence: Dr. Erhan Yarar, Translational Medical Expert and Co-President of the Epigenetics and Nutrigenetic Society, Istanbul, Turkey, Email:

Keywords

Major depressive disease • Epigenetics • Brain • Epigenome

Introduction

MDD is a public health issue of utmost importance that is associated with grave consequences in terms of excessive mortality, disability, and secondary morbidity. Therefore, it is now clear that current research on the health impact of depression should go beyond estimating its prevalence, symptoms severity, and complications. MDD patients have quality of life deficits that are directly attributable to the mood disturbance, the degree of the decrement in BDNF is proportional to the severity of depressive symptoms, the negative relation between depression and BDNF is as great as worse than that observed in other chronic medical disorders and the adequate combo treatment of depression and other related medical conditions is mostly associated with a significant improvements. Once BDNF levels in these patients are increased with satisfaction results via translational medicine approach such as standard drugs and natural substances a combo treatment MDD seems get better than before.

Depressions effect on brain derived neurotrophic factor (BDNF) and theoretical aspects

MDD is a psychological issue described by in any event of low state of mind that is seen across most situations. Pharmacological and nonpharmacological medications have moderate effect for the current treatment of depression and come also with adverse/side effects. MDD is a heterogeneous issue, for the most part analyzed based on symptomatic measures alone. It would be of extraordinary assistance when explicit biomarkers for different subtypes and indication groups of depression become accessible to aid conclusion and subtyping of MDD and low BDNF levels, and to empower checking and anticipation of treatment reaction. Be that as it may, presently available biomarkers don’t arrive at adequate affectability and explicitness, and frequently the connection to basic pathophysiology is muddled. Decreased BDNF is known to be related with depression. Research recommends that expanding BDNF can switch a few manifestations of MDD.

MDD is disease of imbalances and dysregulation in structural and synaptic plasticity. BDNF restores neurons and in synaptic plasticity. BDNF is decreased in MDD and antidepressants come up short in elevating BDNF and with long term adverse effects such as insomnia, type 2 diabetes mellitus, weight gain, sexual dysfunction, movement disorders, hypertension, myocardial infarction, stroke, hepatotoxicity etc. and unpredictable relapse and remission phases of MDD therefore making CBD as an attractive choice for treating MDD. BDNF is present in nearly all brain regions and has utmost importance in regulation of neuroprotection, synaptogenesis, memory and cognition.

BDNF has been appeared to advance the turn of events, capacity, and expression of serotonergic neurons. Because increasingly dynamic serotonin brings about progressively positive moods, antidepressants work to build serotonin levels to a satisfying level but cannot succeed in preserving that level in long term after cessation and many side and adverse effects accompany such as bone fractures, hyperlipidemia, and suppression of bone marrow and endocrinology issues. Taken together, it is thought that a decrease in the hippocampal BDNF action may be straightforwardly identified with the pathophysiology of MDD, a stress related disease and this action has been broadly contemplated. Numerous investigations and meta-examinations have demonstrated that serum and plasma BDNF levels are diminished in depressed patients. It is recommended that the decrease in BDNF levels in depression is most likely because of expanded corticosteroids, since enactment of the Glucocorticoid Receptors (GRs) contrarily influences the BDNF quality. In such manner, there is no distinction between bipolar confusion and MDD, in spite of the fact that serum BDNF levels are lower in bipolar depression contrasted with MDD. The nutrition, including polyphenol, flavonoid compounds, and cruciferous vegetables possess multiple beneficial effects, and some can simultaneously change the DNA methylation, histone modifications and expression of microRNA (miRNA) [1].

BDNF is not a sole candidate in diagnosing the MDD because it is also low in other diseases such as schizophrenia OCD Alzheimer’s and Huntington’s disease dementia aging and some other depressive conditions making it a target candidate for medications [2-6]. Diagnosis of MDD is entirely based on observation and there is no biomarker so far apart from some strong indications for BDNF and imaging techniques such as MRI and CT. Using BDNF as a biomarker for MDD is still open to debate but recent data indicates that BDNF can be thought of as a marker that relates to the emergence and/or progression of the MDD symptoms that are common to many pathological conditions such as deficits in cognitive brain parts in MDD patients [7]. For example that BDNF expression is higher in the hippocampus and the amygdala shows its role in MDD. Conclusions from animal models and clinical and human studies suggest that decayed and imbalanced BDNF signaling might play an important role in the etiology of the MDD [8].

Numerous patients are persistant to the accessible helpful medications, which for the most part act by expanding the degrees of the monoamines serotonin and noradrenaline in the synaptic separated. Indeed, even in the cases antidepressants are powerful, it is typically watched a deferral of half a month between the beginning of treatment and decrease of the clinical manifestations. Moreover, a considerable amount of these patients who show reduction with high treatment present a relapse of wretchedness upon treatment discontinuance. Both fundamental and clinical evidence shows that downturn is related with a few auxiliary and neurochemical changes where the degrees of neurotrophins, especially of BDNF, are modified. Antidepressants, just as other helpful systems, appear to reestablish these levels. Neuronal decay, for the most part recognized in limbic structures that control state of brain and insight, similar to the hippocampus, is seen in depressed patients and in human social standards for gloom.

There are some pathophysiological speculations how really MDD as a disease emerge for which a summary of them here should have been referenced.

The monoamine theory depicts that MDD is an aftereffect of a distorted monoamine synapse framework, especially; serotonin, noradrenaline, adrenaline and dopamine, bringing about diminished extracellular monoamines complexes and neurotransmission. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-Derived Neurotrophic Factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are two seemingly distinct signaling systems that play regulatory roles in many neuronal functions including survival, neurogenesis, and synaptic plasticity. A common feature of the two systems is their ability to regulate the development and plasticity of neural circuits involved in mood disorders such as depression and anxiety. BDNF promotes the survival and differentiation of 5-HT neurons. Conversely, administration of antidepressant Selective Serotonin Reuptake Inhibitors (SSRIs) enhances BDNF gene expression. There is also evidence for synergism between the two systems in affective behaviors and genetic epitasis between BDNF and the serotonin transporter genes [9].

Stress-related alterations in BDNF levels occur in key limbic structures which is a causative factor of the pathogenic process in MDD [10]. In accordance of this theory neurotrophins are growth factors shaping formation and plasticity of neuronal networks and any dysregulation in BDNF might cause MDD [11]. MDD exhibits region-specific alterations in the level and functioning of BDNF. Upregulation of BDNF occurs in the amygdala and nucleus accumbens in MDD and downregulation in the hippocampus and medial prefrontal cortex (mPFC) and low levels of BDNF causes dysfunction in these regions of brain and in astrocytes and microglia in MDD circuits [12,13]. Abnormalities in BDNF and its cognate receptor tropomycin receptor kinase B (TrkB) and splice variant (TrkB. T1) are also observed in MDD. Epigenetic modulation of the Bdnf and Trkb genes may contribute to their altered expression and for example cannabidiol regulates and affects this procedure Tyrosine kinase-coupled receptor (TrkB) is the primary signal transduction receptor for BDNF [14]. BDNF and TrkB expression have been shown to decrease in the hippocampus of depression patients.

The activation of the BDNF-TrkB pathway is important in the development and the growth of neurons. Elevated plasma levels of corticosterone suppress the BDNF-TrkB protection pathway in the hippocampus, which is associated with a corresponding change in nanoscale structural disorder in the hippocampus. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation [15].

On the other hand BDNF and serotonin (5-hydroxytryptamine, 5-HT) are two seemingly distinct signaling systems that play regulatory roles in many neuronal functions including survival, neurogenesis, and synaptic plasticity. A common feature of the two systems is their ability to regulate the development and plasticity of neural circuits involved in mood disorders such as depression and anxiety. BDNF promotes the survival and differentiation of 5-HT neurons. Conversely, administration of antidepressant selective serotonin reuptake inhibitors (SSRIs) enhances BDNF gene expression. There is also evidence for synergism between the two systems in affective behaviors and genetic epitasis between BDNF and the serotonin transporter genes [9] 5-HT1A and 5-HT2A receptor agonists upregulates BDNF protein and mRNA expression in various brain regions in the rat model of post stress, whereas the 5-HT1A and 5-HT2A receptor antagonists downregulates expression of the neurotrophin indicating serotonins regulation of the expression. Same is true for dopamine. In fact the dopaminergic system serves as the reward system of the brain and therefore plays a central role in the MDD too. BDNF, also, has been implicated in the actions of various reward systems too including a satisfying mood level. Dopamine D1 receptor signaling can contribute to increase BDNF protein synthesis, which could potentially initiate BDNF/TrkB activity. This bridge shows implicaitons for the selective role of D1-like receptor signaling and of BDNF in regulating dopamine-mediated behaviors such as reward, cognition, and motor activity, mood, sleep and energy. Dopamine-BDNF signaling could lead to the uncovering of biomarkers such as BDNF and reflect the MDD level therefore the adjuvant medication profile of exogenous and/or endogenous substances [16]. When the monoamine systems of serotonin (5-HT; 5-hydroxytryptamine), norepinephrine and dopamine dysfunctions it might cause abnormalities in production and functioning of MDD (Figures 1 and 2).

Since BDNF is related with expanded neural versatility and endurance and diminished atrophy, exposing to continues pressure was recognized to diminish BDNF levels and converse such attributes in guinea pigs. Single nucleotide polymorphism Val66Met on the BDNF quality has been recognized to be liable for unfolded movement subordinate discharge of BDNF and resultantly expanded depression highlights. Higher groupings of cholecystokinin receptors and cholecystokinin B receptors have been accounted for in people who died by suicide [17]. The diminishing in monoamine neurotransmission results either from too little synapses discharged by presynaptic neurons, or from quickly reabsorbed/manipulated synapses or a lessening in postsynaptic receptors but also observed in other psychiatric conditions not making it a sole player in MDD. Studies have conflicting results and despite any positive observations monoamine theory is still being very much open to debate.

Literature Review

Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis HPA axis has been also questioned in the etiology of MDD; it activates neuroendocrine components for example in cannabis-like brain cells and so energizes them to higher activity reaching and affecting the amygdala and forebrain which viable the HPA axis. The amygdala invigorates the nerve center which thusly energizes the HPA axis which by expanding blood cortisol complexes follows up on a positive way component to affect the amygdala. Over-excitation of the HPA axis is hindered with a negative examination instrument by the hippocampus which restrains the HPA axis activity dysfunction caused by dysregulation of HPA axis has been also questioned as one of the etiology of MDD. Studies show raised cortisol, adrenocorticotrophic hormone ACTH and corticotrophin releasing hormone CRH levels in patients with MDD and raised glucocorticoid complexes seem to cause restraint of average prefrontal cortex excitation in MDD. Low blood BDNF levels are observed significantly in MDD [18]. Hypothalamic-Pituitary-Adrenal Axis HPA axis activation of neuroendocrine frameworks is an essential physiological reaction to push, chiefly by HPA axis. Enthusiastic upgrades arrive at the amygdala and forebrain which viable the HPA axis. The amygdala invigorates the nerve center which thusly energizes the HPA axis which by expanding blood cortisol complexes follows up on a positive way component to additionally affect the amygdala. Over-excitation of the HPA axis is hindered with a negative examination instrument by the hippocampus which restrains the HPA axis activity. Raised glucocorticoid complexes have been acclaimed to cause restraint of average prefrontal cortex excitation in MDD. Low blood BDNF levels have been recognized to happen in significant depression which standardize during decrease [17].

One study finds out that there are no significant relationships between cortisol levels and sBDNF levels yet low BDNF might contribute to the neurobiology of psychiatric conditions and also burnout syndrome [19]. Although several studies indicate a strong connection in-between BDNF and MDD and HPA axis this theory of HPA axis is also open to debate and cannot be considered as a sole contender. Also involvement of HPA axis dysregulations and BDNF in the pathogenesis of antidepressant treatments is also open to debate but hormonal challenge tests showed elevated HPA activity (hypercortisolism) in MDD patients although hypocortisolism is also seen in other psychiatric and stressful events making it not a reliable sole candidate.

Decreased degrees of interleukins in MDD are also questioned. Elevated CRP and IL-6 were discovered in people with MDD and depression was related with higher CRP levels in MDD. Similarly, higher CRP and IL-6 levels are related with psychological indications of MDD [20]. It is essential that peripheral cytokines aid inflammatory processes and the immune system to form coordinated responses to infection, which are produced by a broad range of cells including macrophages, B lymphocytes, T lymphocytes and mast cells, endothelial cells, fibroblasts, and various stromal cells [21]. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis, neurotoxicity and neuroinflammation in the brain of MDD patients. There is significant relationship between failed treatment trials and tumor necrosis factor (TNF), soluble TNF receptor 2 (sTNF-R2) and interleukin (IL)-6. Checking inflammatory markers and targeting inflammation or its downstream mediators via diverse treatment options may be relevant for MDD patients. Increased Interleukin-1, interleukin-6 and diminished I-4 and I-10 are considered causing MDD and so MDD is accompanied by an immune response with an increased production of pro-inflammatory cytokines. Inflammatory markers do decrease BDNF articulation yet in resistant MDD patients both IL-1β plasma concentrations are increased making them as candidates to identifying MDD. It is obvious that cytokines induce behavioral effects by activating inflammatory signaling pathways in the brain, leading to the reduction of growth factors such as BDNF and the expression of BDNF is affected by immune cells and the immune factors they secrete. The immunomodulatory process also needs the regulation of BDNF-mediated signaling pathways. How BDNF participates in the regulation of the neuroimmune axis in MDD is still unclear [22].

For the present with center around epigenetics BDNF appears as a promising contender for diagnosing and treatment of MDD. BDNF is accepted to be one of the most significant of the “development factors” (trophic components or neurotrophins) that impact how the brain creates, develops, and changes its associations after some time. Other major neurotrophins incorporate NGF (nerve development factor), GDNF (glial cell-determined neurotrophic factor), CNTF (ciliary neurotrophic factor), and NT-3 (neurotrophin-3).

The newly arisen neuroplasticity theory of MDD is also an approach to explain the pathogenesis of MDD [23]. Neuroplasticity is considered to be one of the vital characteristics of the nervous tissue which manifests in reversible changes which is called functional plasticity. It seems to modulate the expression of genotype into phenotype by continuous adaptation and thus bring about long-lasting effects which are essential for MDD. Neuroplasticity is brain’s capability to form new connections and change to rewire circuits. Neurogenesis is the ability of the brain to grow new neurons. In both cases natural compounds such as Cannabidiol (CBD) exhibits an increase in the hippocampal BDNF protein levels and stimulates neurogenesis and promotes dendritic restructuring neurons in the hippocampus [24]. CBD’s effects were associated with increased release BDNF in limbic brain regions that are often associated with depression development. BDNF is recognized for promoting brain neuroplasticity, such as new synaptic formation and cell proliferation, which are process required for the antidepressant effect. CBD increases AEA concentrations moderately, stimulate to decrease FAAH levels and the neurotransmitter glutamate, thereby relieving stress. CBD seems to interfere with stress-induced synaptic remodeling. The evidence indicates CBD interacts with 5HT1A-mediated neurotransmission, TRPV1 receptors, and inhibition of anandamide metabolism, and plastic changes take place over time and contribute to CBD-induced behavioral effects in response to chronic treatment. CBD’s chronic effects are still sparse, it is clear that no single mechanism will explain the remarkable pharmacological profile of CBD. The effects of plasticity can cause either positive or negative changes during evolutionary plasticity, reactive plasticity, adaptational plasticity, and during functional or structural recovery of damaged neuronal circuits (reparation plasticity) and thereby causing MDD lead either to negative or positive avenues. As a member of BDNF of the growth factor family BNDF is involved in promoting synaptic efficacy, neuronal connectivity and neuroplasticity. BDNF seems to be a key mediator of synaptic plasticity, neuronal connectivity and dendritic assistance. CBD in conjunction with neuroplastic mechanisms help repair and restore the neuronal circuitry damaged by MDD [25].

Neurotrophic factors such as BDNF are compounds can bind to common tyrosine kinase receptors and in case of MDD the expression of BDNF and its receptor TrkB was decreased along with impaired hippocampal neurogenesis and dendritic arborization, and neuroinflammatory response which leads into deeper MDD symptoms [26]. Abnormalities in neuroplasticity may be related to changes in levels of neurotrophic factors, especially BDNF, which plays a key role in neuroplasticity. The synthesis and secretion of BDNF are activitydependent, a phenomenon related to neuronal plasticity [27]. As CBD is shown to enhance BDNF expression it indirectly leads to the form new connections by activating the BDNF-TrkB signaling pathway. Because CBD’s effect is blocked when BDNF signaling is hindered in the brain, CBD starts to establish rapid neurochemical and neuroplastic effects in limbic brain regions favoring stress coping strategies and resilience to MDD development.

Although all factors related to these theories are considered playing roles in MDD none of them could be accepted as sole candidates and there is no “unified theory” to explain the cause the MDD in terms of BDNF and other mechanisms but almost all studies underline the effects of CBD and indicate cannabidiol as a safe option for applying as alone or in combination with conventional drugs as an adjuvant medication in MDD. Therefore natural compounds along with translational medicine and with conventional medications’s roles should be underlined. The nutrition, including polyphenol, flavonoid compounds, and cruciferous vegetables possess multiple beneficial effects, and some can simultaneously change the DNA methylation, histone modifications and expression of microRNA (miRNA). This review mainly summarizes the information of epigenetic agents of DNMTs and HDACs inhibitors, miRNA mimics and antimiRs, as well as the natural nutrition. Some future perspectives related to the epigenetic therapy with respect to natural endogenous substances are also included. Successful antidepressants incorporate SSRIs, SNRIs, and a developing number of different kinds of present day antidepressants, (for example, bupropion and mirtazapine), TCA and MAOI antidepressants, ECT and an assortment of psychotherapies [28]. These are current treatment options (Figures 1 and 2).

Natural substances and their epigenetic influence on BDNF

The high number of articles disseminated (more than one hundred compounds for 14 botanicals) supports the creating excitement for the use of standard things as BDNF modulators. Evaluations organized support the speculation that botanicals might be viewed as critical modulators of BDNF in central nerve system CNS diseases, without high responses.

Further clinical evaluations are necessary to state botanicals as preventive pros or as steady adjuvant to the pharmacological treatment. From the start, considering the multifaceted thought of the BDNF structure intelligently refined appraisal of the various parts both at understanding and translational levels is necessary actually, not very many assessments report the BDNF isoform or the structure evaluated, and, every so often, the particles pile of the band researched doesn’t relate to either the create or the predecessor structure.

Most examinations contrasted the impact of botanicals and the impacts got from a reference tranquilize, demonstrating comparative adequacy. Many natural compounds exert antidepressant-like effects compared to the conventional medications in therapy. However, most of the clinical studies do not pay attention to the side effects following botanical treatment. Although promising results have been found on natural compounds and BDNF modulation, the number of studies of these botanicals is too low for drawing conclusive results. Considering the complexity of the BDNF system, as briefly described in the introduction, a progressively refined investigation of the various components both at interpretation and translational levels is compulsory. Without a doubt, not many investigations report the BDNF isoform or the structure estimated and, the sub-atomic load of the band analyzed doesn’t relate to either the mature or the antecedent structure. All in all, considering the key role of the marker in various pathological conditions influencing the central nervous system such as in MDD, BDNF may represent to a significant to balance these conditions. Botanicals might be viewed as valuable contender to balance in vivo BDNF. On the off chance that clinical examinations affirm this proof, these regular items might be utilized for forestalling CNS dysfunction or as a helpful adjuvant to the pharmacological treatment [29].

Here it will be elaborated some of the components to increase BDNF levels and decrease depressive symptoms and serve as adjuvant treatment options. Evidences for them derive mainly from traditional applications. Since these compound’s effects are mainly observed in animal models there is an urgent need for human clinical trials. The greater part of the investigations exhibited that treatment with botanicals may forestall or potentially standardize the adjustments of BDNF.

Melatonin (N-acetyl-5-methoxytryptamine) has been found as a hormone secreted by the pineal gland, in spite of the way that it is moreover incorporated in various organs, tissues, and cells. The circadian musicality of melatonin is normally used as a pointer stage position since it is an inside and out portrayed, high-amplitude beat compelled by the hypothalamic suprachiasmatic nuclei. Melatonin, the essential indoleamine hormone of the mammalian pineal gland, is known to have a plenty of neuroregulatory, neuroprotective and different properties. Melatonergic signalling is intervened by its two GPCRs, MT1 and MT2, which are generally communicated in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes [30]. Melatonin definitely promotes BDNF expression and that is shown in several studies. Melatonin and resveratrol ameliorates the BDNF expression of hippocampal protein [31].

Tanshinone IIA (TSA) is the for the most part dynamic constituent of Salvia miltiorrhiza and has various organic impacts, anti-inflammatory and antioxidant effects and significant neuroprotective effects against cerebral ischemia and Alzheimer’s disease. One study explored the stimulant impacts and the component of TSA by looking at the BDNF expression in the hippocampus of depressed mice. The Tail Suspension Test (TST) and constrained swim test (FST) demonstrated that TSA can fundamentally lessen the fixed status time of mice. Ceaseless organization of TSA expanded p-ERK and p-CREB, BDNF proteins in mice hippocampus. TSA essentially expanded the declaration of p-ERK, p-CREB and BDNF proteins in dexamethasone-treated PC12 cells, and this upgrade was stifled by pretreatment with the extracellular sign directed kinase (ERK) inhibitor SL327. The SL327 treatment uniquely stifled the expanded degrees of p-ERK, p-CREB and BDNF in mice hippocampus initiated by TSA, forestalling the stimulant impacts of TSA. Antidepressantlike effects of TSA were intervened by ERK-CREB-BDNF pathway in mice hippocampus [32].

Palmitoylethanolamide (PEA) is a lipid lipid mediator utilized in the clinic for its neuroprotective, anti-neuroinflammatory and pain relieving properties. Pretreatment with PEA signicantly lessens iNOS, glial brillary acidic protein expression and apoptosis, and reestablishes neuronal NO synthase just as BDNF; PEA invigorates the statement of BDNF [33]. PEA increases the expression of BDNF, a representative neurotrophic factor in the central nervous system, in the hippocampal dentate gyrus, and most BDNF-positive cells were also stained with anti-glial fibrillary acidic protein one of the major intermediate filament proteins of mature astrocytes [34]. One study found out that PEA induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP Response Element-Binding protein (CREB) in the hippocampus after ischemia; PEA increased the expression of BDNFin the hippocampal dentate gyrus, and most BDNF-positive cells were also stained with anti-glial fibrillary acidic protein (one of the major intermediate filament proteins of mature astrocytes) and PEA increased doublecortin positive neuronal precursor cells in the dentate gyrus subventricular zone or subgranular zone. Besides, PEA can reestablish hippocampal BDNF signalling pathway, and improve mitochondrial dysfunction, both pathological aspects, known to be consistently associated with ASDs. Furthermore, PEA reduces the overall inflammatory state of BTBR mice, reducing the expression of proinflammatory cytokines at hippocampal, serum, and colonic level. PEA effects on gut microbiota composition suggest an involvement of microbiota-gut-brain axis. So it has pleiotropic mechanism of action, supporting neuroprotection, anti-inflammatory effects, and the modulation of gut-brain axis [35].

The epigenetic agent acetyl-L-carnitine (LAC) has rapid and enduring antidepressant-like effects in LAC-deficient rodents. LAC levels were decreased in patients with MDD versus age- and sex-matched healthy controls in two independent study centers. The degree of LAC deficiency reflected both the severity and age of onset of MDD. The lowest LAC levels were found in patients with treatment-resistant depression, whereby history of emotional neglect and being female predicted decreased LAC levels [36]. The LAC may serve as a candidate biomarker to help the diagnosis of a clinical endophenotype of MDD that supplementation of LAC exerts rapid antidepressant actions, at least in part, by acetylating histones to regulate the expression of key genes important for synaptic plasticity, increasing the proneurogenic molecule BDNF to high levels and a critical regulator of synaptic glutamate release, the metabotropic glutamate receptor of class-2, mGlu2. LAC levels were diminished in patients with MDD versus age-and sex-matched health controls in two independant study centres. The level of LAC lack reflected both the seriousness and time of beginning of MDD. The most reduced LAC levels were found in patients with treatment-safe depression, whereby history of enthusiastic disregard and being female anticipated diminished LAC levels [36]. The LAC may fill in as an applicant biomarker to help the analysis of a clinical endophenotype of MDD that supplementation of LAC applies quick upper activities, in any event to some degree, by acetylating histones to manage the statement of key qualities significant for synaptic versatility, expanding the proneurogenic atom BDNF to elevated levels and a basic controller of synaptic glutamate discharge, the metabotropic glutamate receptor of class-2, mGlu2.

Zinc deficiency has been implicated in the endocrine pathway of depression. Zn inadequacy was related with epigenetic imperfections, for example, the diminished methylation levels of DNA and histones, and these debilitations were reestablished by dietary methyl donor supplementation. Zinc supplement can shield cells against oxidative damage from different ecological upgrades including heat pressure. Dietary supplementation with Zn expanded mRNA and protein expressions of tissue metallothionein (MT) as free extreme foragers. Zn lack expands MT2 advertiser DNA methylation and histone acetylation levels [37]. A zinc-lacking eating regimen actuated significant levels of serum cortisol fixation in rodents. Industriously elevated levels of cortisol have been embroiled in the advancement of wretchedness by means of hyperactivity of the hypothalamic–pituitary–adrenal (HPA) pivot. Expanded plasma cortisol levels could, in this way, possibly intercede the connection between zinc deficiency and depression. In conclusion, the potential energizer properties of zinc might be identified with its capacity as an opponent of the (NMDA) receptor and contribution in the l-arginine–nitric oxide (NO) pathway as an inhibitor. NMDA has been restoratively focused in clinical and preclinical evidence supports the presence of disrupted glutamate homeostasis and neurotransmission in depressed subjects [38]. Zn is largely present in the CNS, stored within synaptic vesicles at several glutamatergic nerve terminals, and synaptically released upon neuronal activity. Zinc affects neuronal processes as well as BDNF signaling [39].

The coffee plant, a woody enduring tree developing at higher elevations. Notwithstanding the way that beans are particularly well off in caffeine, various constituents are accessible in a huge aggregate, including tocopherols and acid subsidiaries, for example, chlorogenic acid [29]. Three assessments investigated the in vitro effect of caffeine on BDNF. In particular, caffeine upregulated the BDNF protein levels in mouse hippocampal cuts (100 μM for 5 minutes) extended the BDNF release in hippocampal neurons, and capably viabled the BDNF isoform I and IV explanation inside seeing KCl (10?mM) in cortical neurons Caffeine changes CREB-subordinate quality verbalization in making cortical neurons. Late epidemiological assessments demonstrated that step by step coffee usage is connected with a lower danger for a couple of neurological issue, for instance, Alzheimer’s and Parkinson’s disease; in any case, the molecular instruments at risk for the protective effect of coffee against neurological messes have not been clarified. As BDNF propels neuronal continuance and guarantees against neuronal damage. One examination found that mixed coffee applied an inhibitory effect on the auto phosphorylation of tropomyosin receptor kinase B (TrkB), a BDNF receptor. Additionally, coffee lessened the phosphorylation of Akt in BDNF-treated SHSY5Y cells. Treatment with coffee didn’t impact the TrkB receptor on the cell surface. The significant constituents of espresso, for example, caffeine, caffeic acid, chlorogenic acid, and trigonelline had no impact on TrkB phosphorylation initiated by BDNF. Furthermore, espresso decreased the BDNF-initiated increment in BDNF quality expression and the neurite outgrowth advanced by BDNF. Several data propose that the defensive impact of espresso detailed in epidemiological examinations against neurological clutters may not be related with BDNF motioning through TrkB [40].

Withania somnifera (L.) Dunal, additionally called Ashwagandha or Indian ginseng (Solanaceae), is a standard Ayurvedic fix presumed to be useful as an antistress and memory enhancer. Pretreatment with a an alcoholic concentrate of Ashwagandha leaves (100mg, 200mg, and 300 mg/kg for 7 days) from a general point of view hindered the effects thinking about the scopolamine treatment (3 mg/kg, for instance, the diminishing of the mRNA explanation of BDNF transcript assortment 1 and of proBDNF and mBDNF protein expression at all the focuses endeavored. To be sure, posttreatment at 200 mg/kg was unfit. Animals dealt with when hypobaric hypoxia with 200 mg/kg of the concentrate exhibited a comprehensive explanation of BDNF and a colossal decrease in lethargy and course length in the MWM test [41].

Rhodiola rosea L. (Crassulaceae) (Salidroside (SA)) has a long history of utilization as a supportive plant in two or three traditional medications. All around 140 blends were isolated from roots and rhizome - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic dangerous subordinates. One in vitro assessment surveyed the effect of SA on BDNF indicating that the unadulterated compound prompted mesenchymal undifferentiated cells to restrict into dopaminergic neurons. SA treatment (100 μg/mL) for 1–6 days on a very major level widened the BDNF mRNA levels while at 12 days, an opposite effect was found. In a sudden manner, the effect on the BDNF mRNA levels was extensively progressively tough since it was so far present after 12 days [29]. In vivo, the treatment for 5 days (12 and 24 mg/kg, per os) with SA or fluoxetine hindered the improvement of the downturn like direct and of the downregulation of BDNF protein levels in the hippocampus incited by a solitary imbuement of LPS [42]. Taking everything into account, Rhodiola rosea has conventional and pharmacological verification of usage in depletion, and rising confirmation supporting acumen and mentality [43].

Ginseng radix contains the whole or cut dried extract of Panax ginseng C.A. Meyer and contains at any rate 0.4% of the total of ginsenosides (Rg1) and (Rb1). Ginsenosides are triterpenoid saponins which are the standard in peril for the trademark activities of ginseng clears. Panax ginseng remove or unadulterated blends applied a helpful result in like way on the scopolamine animal model. If all else fails, wild ginseng (WG) roots (200 mg/ kg, i.p.) normalized the mRNA level of BDNF in the rat hippocampus of the scopolamine-treated assembling, additionally as lessening the flight inaction in the MWM test. In like way, pretreatment with ginsenosides (Rg5) and (Rh3) (5, 10, and 20 mg/kg, per os) quelled the abatement of mBDNF protein expression started by scopolamine implantation (1 mg/kg, i.p.) and decreased the lethargy time in MWM.

The potential neuroprotective effect of express constituents of green tea leaves, including catechins, was investigated in two in vitro evaluations. L-Theanine pretreatment (500 μM) applied an observed effect by on a basic level stifling the downregulation of BDNF protein as a result of the treatment with two tainting related neurotoxicants (rotenone and dieldrin) in the human cell line SH-SY5Y. Moreover, pretreatment with GT catechins, for instance, epicatechin (EC) and (+)- catechin, captured the abatement of mBDNF and the development in the precursor structure prompted by the unsafe HIV (human immunodeficiency disease) protein Tat. [44].

Ginkgo biloba is an old Chinese tree having a spot with the collaboration of Ginkgoaceae, made for its flourishing moving properties. Despite the way that the two leaves and seeds are beginning at now utilized as homemade tranquilizer sedative in China, in different nations, leaves are viewed as the uncommon wellspring of dynamic checks and dried green leaves are utilized for giving pharmaceutical definitions or as areas of food supplements. Ginkgo biloba and its constituents were examined on BDNF in three in vitro, eight in vivo, and one clinical assessment. Ginkgo biloba leaf clear (EGb761, 100 μg/ mL) reestablished the degrees of BDNF protein (both genius and structure) in cells stimulated with certified medium composed to enact amyloid ß-peptide Aß clarification. Relationship of individual EGb761 constituents, unequivocally, ginkgolides A (GA), B (GB), C (GC), and J (GJ) and 10 μg/mL bilobalide, broadened the degrees of BDNF by following a relative model [29].

As necessities be, flavonol-moved concentrate containing quercetin, kaempferol, and isorhamnetin (50 μg/mL) on an exceptionally fundamental level reestablished BDNF protein verbalization in twofold transgenic APP/PS1 essential neurons. Moreover, 100 mg/mL of YY162, an approved condition including terpenoid-fortified Ginkgo biloba and ginsenoside Rg3, blocked the decrease of BDNF levels induced by 48h of Aroclor 1254 in SH-SY5Y neuroblastoma cell line.

Crocus sativus L. has a place with the Iridaceae family; for the most part known as saffron and is broadly advanced in Iran and utilized presently and customary prescriptions. The shade of saffron is all things considered an immediate consequence of the carotenoid named crocin, which is considered among the dynamic standards for the most part responsible for neuroprotective activity. Two in vivo appraisals investigated the impact of Crocus sativus on BDNF expression. Crocin affiliation (12.5 mg/kg, i.p.) for 21 days to clueless male Wistar rodents applied an energizer sway and essentially expanded the expression of BDNF in the hippocampus [45]. Similarly, consistent treatment with C. sativus watery concentrate (40, 80, or 160 mg/kg/day, i.p.), updated the quality and protein levels of BDNF in the rat hippocampus. Furthermore at 40 and 160 mg/kg/day, and stimulation was comparably seen [46].

Magnesium has a strong relationship with BDNF unequivocally the threonate structure. Expressly (10, 15, and 20 mg/kg) decreased hyperactivity in the open field test in rodents in the olfactory bulbectomy (OB) model of depression. Since the widely inclusive hyperactivity in the open field test is seen as a result of pressure also as anxiety, these results appear to strengthen the general speculation that underpins both the high and anxiolytic activities of magnesium [47,48]. The assessments demonstrated that tireless relationship of magnesium was associated with advancement in the BDNF and GluN2B subunit levels in the hippocampus, which shows changes that join forces with improved neuroplasticity [49]. Along these lines, extended BDNF and GluN2B subunit levels in the amygdala may show the revamping of synaptic affiliations negatively affected by bulbectomy and the normalization of neural transmission between the amygdala and other cerebrum structures [47]. Magnesium might apply stimulant impacts through its job in serotonergic, noradrenergic and dopaminergic neurotransmission, expanded expression of BDNF and balance of the rest wake cycle through increase of the biosynthesis of melatonin [50]. Magnesium l-threonate was explicitly made to cross the the brain’s protective filter, the blood-brain barrier.

Bacopa monnieri (L.) (BM) is an enduring, crawling herb which is broadly utilized in conventional ayurvedic medication as a neural tonic to improve insight and memory. Examination into the organic impacts of this plant has expanded lately, encouraging its neuroprotective and memory boosting capacity among others. In this specific situation, a broad writing study permits an understanding into the investment of various flagging pathways and oxidative instrument engaged with the relief of oxidative worry, alongside other circuitous systems regulated by bioactive particles of BM to improve the intellectual activity by their synergistic potential and cell assortment component [51]. Bacopa monnieri in PC12 cells, pretreatment with a hydroalcoholic separate completely hindered the diminishing of BDNF mRNA levels related with cell hurt provoked by scopolamine or sodium nitroprusside [52].

Several important studies and trials have indicated that Vitamin D is basic for ordinary mental health and capacity, and Vitamin D insufficiency has been connected with neurological disorders, including depression. Vitamin D is likewise associated with the underlying biosynthetic phases of serotonin, a neurotransmitter which has been implicated in both depression and the mechanism of action of antidepressant drugs. A study found diminished hippocampal levels of BDNF in a preclinical model of discouragement, and these were standardized by Vitamin D organization. Then again, different strides in require magnesium as a cofactor, including Vitamin D official to Vitamin D restricting protein, 25 (OH)D blend, 1,25 (OH)2D union, 25-hydroxylase combination, and Vitamin D receptor expression. Likewise, serum 1, 25 (OH) 2D levels stay low in people with magnesium lack in any event, following Vitamin D admission. Magnesium lack has additionally been found to lessen parathyroid hormone production and the quantity of Vitamin D receptors in target cells [53]. Critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1a-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation [54].

The impact of the gut microbiota on has been convincingly shown in rodents and also in humas. There the basic step is gut-brain axis. Without gut microbes, the focal expression of BDNF, and N-methyl-d-aspartate receptor (NMDAR) subunits are diminished, though, oral probiotics increment BDNF, and confer noteworthy anxiolytic impacts. The prebiotic-interceded multiplication of gut microbiota in rodents, similar to probiotics, expands brain BDNF expression, potentially through the association of gut hormones. The impact of GOS on segments of focal NMDAR flagging was more prominent than FOS, and may mirror the proliferative strength of GOS on microbiota. It would seem that that prebiotics probiotics and Fructo-oligosaccharides (FOS), Galacto-oligosaccharides (GOS) give a sound premise to additionally examine the utility of prebiotics in the upkeep of mind wellbeing and adjunctive treatment of neuropsychiatric issue [55]. Augmentation of SSRI treatment with probiotic microscopic organisms Lactobacillus Plantarum 299v improves psychological execution and diminished KYN fixation in MDD patients. Another study found out that from baseline to 12 weeks, synbiotic supplementation resulted in a significant decrease in depressive symptom and serum BDNF increased significantly in the synbiotic group when compared to the placebo A rather simple way to increase BDNF levels is through butyrate, a short chain fatty acid (SCFA) that acts as a histone deacetylase inhibitor (HDACi), therefore relaxes chromatin and enhances BDNF expression in the hippocampus. Butyrate may also suppress pro-inflammatory cytokines production by inhibiting nuclear factor-kappa beta (NF-kß) activation [56]. Additionally, butyrate can build the expression of catalysts associated with the amalgamation of glutathione (GSH), which is cell reinforcement chemical responsible for lessening hydrogen peroxide and lipid hydroperoxide, in this manner diminishing oxidative stress, another neurodegenerative factor [57]. Intestinal microbiota produces a significant extent of the short cahin unsaturated fat SCFA. During maturing, happens a change in microbiota (dysbiosis) with a huge increment in obsessive microorganisms (Proteobacterium) to the detriment of advantageous ones (Bifidobacterium); this prompts a diminished creation of SCFA. These changes have been identified with ceaseless foundational aggravation and subsequently neuroinflammation [58].

Discussion

In the most recent years, proof in respects of the connection among microbiota and the mind has proposed that the earlier may impact distinctive MCI pathophysiological pathways. Subsequently, supplementation with prebiotics and probiotics may reestablish harmful impacts saw on the mind because of maturing by diminishing aggravation and oxidative pressure, while expanding neurotrophic factors and neuronal versatility [59]. Butyrate is a piece of a notable class of epigenetic substances known as histone deacetylase inhibitors (HDACi). Adjustment of histone acetylation and deacetylation through ecological elements and utilization butyrate in cases or for instance cold potatos may forestall ailments and look after wellbeing. In a more extensive setting, there is a developing interest for dietary HDACi, specifically butyrate in light of the fact that its effect on epigenetic components will prompt increasingly explicit and effectual restorative systems in the anticipation and treatment of various diseases [60].

Omega-3 unsaturated fats (i.e., EPA and DHA) direct sign transduction and quality expression, and shield neurons from death. It is apparent that BDNF empowers synaptic transmission and learning limit by tweaking synapsin I and CREB. Supplementation of omega-3 unsaturated fats in the eating routine murdered the total of the investigated impacts of FPI, that is, standardized degrees of BDNF and related synapsin I and CREB, decreased oxidative harm, and balanced learning handicap [61]. It is known that intellectual processes, for example, learning and memory, are influenced in depression. Several authors have described histone deacetylase (HDAC) inhibitors as a class of medications that improves long haul memory development. Taking into account that neurotrophic factors has been pointed as a key occasion engaged with cognition and depressive disorder, levels of neurotrophic factors (BDNF, NGF and GDNF) were additionally researched. MD and CMS initiated depression like conduct in the constrained swimming test (FST) memory impairment in the Object Recognition (OR) test, without altering locomotor activity of rats. In addition, SB was able to reverse the stress-induced neurotrophic factors decrease and reversed memory impairment. The results indicate that the stress both at early and later stage of life may induce cognitive impairment in animals and neurotrophic factors (BDNF, NGF and GDNF) levels decrease [62].

Curcumin, as another part from the histone deacetylase inhibitors, can control the expression of class I HDACs (HDAC1, HDAC3, and HDAC8), and can manufacture the expression of Ac-histone H4 in Raji cells. Curcumin owns a noteworthy effort in coordinating B-NHL cell line Raji cell extension and apoptosis. Curcumin is the main curcuminoid found in turmeric (Curcuma longa), a flavor as frequently as conceivable used in Asian countries. Given its alleviating and malignancy anticipation specialist properties, it has been guessed that curcumin might be feasible in treating signs of a combination of neuropsychiatric issue, for instance, incapacitation. Different Meta-examines exhibited the sufficiency of the joined use of curcumin with antidepressants in the treatment of wretchedness. The arrangement of action of curcumin, similarly as the opportunities for its further use is thought of [63]. Curcumin intervenes its neuroprotective impacts not just in neurotraumatic clutters (stroke, spinal line injury, awful cerebrum injury, and epilepsy), yet additionally in Parkinson infection, Huntington illness, and Prion maladies. What’s more, curcumin additionally advance its advantageous impacts in neuropsychological scatters (discouragement, bipolar clutters, and tardive dyskinesia). The instrument related with neuroprotective activity of curcumin isn’t completely comprehended. Be that as it may, it is turning out to be progressively clear that mitigating and cell reinforcement properties of curcumin might be answerable for neuroprotective impacts. At the sub-atomic level, neuroprotective impacts of curcumin and fundamental segment curcuminoids are joined by downregulating exercises of phospholipases, lipooxygenase, cyclooxygenase-2, which lead to low degrees of leukotrienes, thromboxanes, prostaglandins. What’s more, curcumin likewise hinders the statement of TNF-an, IL-12, MCP-1, and interferon-inducible protein. Moreover, curcumin likewise adjusts different synapse levels in the cerebrum [64]. Effects of curcumin on BDNF and extracellular sign directed kinase (ERK) levels in the hippocampus were likewise inspected. Interminable treatment with curcumin fundamentally switched the CUS-incited social and intellectual parameters (decreased sucrose inclination and weakened learning and memory work) in focused on rodents. Also, CUS diminished hippocampal BDNF and ERK levels, while curcumin viably turned around these modifications. The energizer like impacts of curcumin in CUS rodents are identified with its inclination to advance BDNF and ERK in the hippocampus [65].

The stimulant dynamic elements of Traditional Chinese Medication (TCM), distinguished can be commonly separated into saponins, flavonoids, alkaloids, polysaccharides and others. Albiflorin, Baicalein, Berberine chloride, beta- Asarone, cannabidiol, Curcumin, Daidzein, Echinocystic corrosive (EA), Emodin, Ferulic corrosive, Gastrodin, Genistein, Ginsenoside Rb1, Ginsenoside Rg1, Ginsenoside Rg3, Hederagenin, Hesperidin, Honokiol, Hyperoside, Icariin, Isoliquiritin, Kaempferol, Liquiritin, L-theanine, Magnolol, Paeoniflorin, Piperine, Proanthocyanidin, Puerarin, Quercetin, Resveratrol (trans), Rosmarinic corrosive, Saikosaponin A, Senegenin, Tetrahydroxystilbene glucoside and Vanillic corrosive are promising contender to find a medication to treat MDD and other neurologic and mental sicknesses and scatters. Extraordinary compared to other case of TCM concerning expanding BDNF levels is Yue; an ethanol concentrate of Yueju pill, a Traditional Chinese Medicine home grown equation broadly used to treat state of mind issue, shows fast upper impacts like ketamine, likely by means of moment improvement of cerebrum inferred neurotrophic factor (BDNF) articulation in the hippocampus. One of five individual constituent herbs of Yueju, Gardenia jasminoides Ellis (GJ) shows a critical impact. The energizer reaction begins at 2 hours after GJ organization. Like Yueju and ketamine, a solitary organization of GJ fundamentally lessens the quantity of break disappointments in the scholarly defenselessness test. Besides, GJ diminishes inactivity of food utilization in the oddity smothered taking care of test. GJ has fast upper impacts, which are related with the raised articulation of BDNF in the hippocampus [66].

Japanese traditional medicine Kampo has potential as medications for the treatment of MDD that the concentrates have mending impacts for Major Depressive Disease and other despondency related disarranges. One of them is Sansonito and one examination discovered that sansoninto (SAT) separate applied solid impacts and its oral organization enhances the pathologies of some social debilitations. SAT separate applies hostile to melancholy like impacts interceded by the up-directed articulation of BDNF in the hippocampus and by the upgraded phosphorylation of the cAMP reaction component restricting protein (CREB) through the mitogen-initiated protein kinase (MAPK) course and Ca2+/calmodulin-subordinate protein kinase II (CaMK II) course, a downstream flagging course of the N-methyl-D-aspartate (NMDA) receptor. SAT has potential as another healing medication in the treatment of melancholy like conduct [67]. One other tried and affirmed compound of Kampo is Kami-shoyo-san (KSS) a conventional medication utilized in Japan to treat pressure related neuropsychiatric issue, for example, despondency or tension particularly for Major Depressive Syndrome and burdensome disorder and side effects. KSS is a consolidated planning of Paeoniae radix, Bupleuri radix, Atractylodis macrocephalae rhizoma, Liriopis tuber, Angelicae gigantis radix, Hoelen, Menthae folium, Glycyrrhizae radix, and Zingiberis rhizoma produces energizer like impacts at both the social and atomic levels [68]. Bupleuri radix and Angelicae radix, significant segments of KSS, are accounted for to have a coupling partiality for 5-HT1AR and treatment with Bupleuri radix extricate essentially expanded p-CREB and BDNF articulation in refined SH-SY5Y cells [69]. Studies propose the likelihood that the upregulation of p-CREB and BDNF articulation after treatment with Bupleuri Radix concentrate may be a result of 5-HT1AR regulation. P-CREB incites BDNF translation in the hippocampus, which is significant for energizer impacts [10]. KSS is by all accounts interceded through up-guideline of CREB and BDNF instigated by Bupleuri Radix. BDNF ties its tyrosine kinase B (TrkB) receptor and initiates PI3K/Akt flagging, bringing about the phosphorylation and restraint of glycogen synthase kinase-3 GSK-3. Bupleuri radix has liking for both dopamine D2 and 5-HT1A receptors, which might be liable for its stimulant like impacts. CREBTF (CREB, cAMP reaction component restricting protein) is a cell interpretation factor. It ties to certain DNA groupings called cAMP reaction components (CRE), in this way expanding or diminishing the interpretation of the qualities. Treatment with Bupleuri Radix essentially expands CREB phosphorylation and lifts BDNF levels in SH-SY5Y cells. BR separate expands phosphorylation of Akt and glycogen synthase kinase-3 (GSK-3). BR may apply its impacts through activities on CREB and BDNF actuation, prompting incitement of the PI3K/Akt/GSK-3 flagging pathway [70]. BR has stimulant like impacts in any event to a limited extent, through up-guideline of CREB and BDNF, in this manner enacting the PI3K/Akt/GSK-3 flagging pathway by means of the TrkB receptor [71] (Figures 1 and 2).

There is a growing interest and extensive work with respect to cannabinoid use in psychiatric patients suffering from MDD and cannabis-BDNF interactions. The grown-up mammalian brain can create new neurons in a procedure called grown-up neurogenesis, which happens chiefly in the subventricular zone (SVZ) and in the hippocampal dentate gyrus (DG). BDNF expression and docking capacities and cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been appeared to autonomously regulate neurogenesis, yet how they may associate is obscure. A growing body of significant research suggests CBD oil can function as a strong component of a natural plan to alleviate anxiety. Strong preclinical evidence suggests positive mental health benefits of CBD oil that include decreased feelings of social isolation, improved autistic tendencies, and a lessening of posttraumatic stress disorder (PTSD) symptoms. Cannabidiol (CBD) is a low tetrahydrocannabinol (THC) product manufactured from Cannabis sativa. CBD is popular for its medicinal benefits. After Tetrahydrocannabinol (THC), CBD is the second-most-abundant component of cannabis. Cannabis has been used for psychiatric issues for almost thousand years. It is generally considered safe for application and in fact has been used for decades. Medicinally use of cannabis has history dating back centuries. The most abundant compound in cannabis, THC is also a cannabinoid and possesses negative psychoactive effects. A cannabis plant has different amounts of CBD and THC depending on the strain and thus provides different medicinal effects. Cannabidiol and related compounds including specific terpenes offer promising treatment options. CBD indirectly affects the CB1 receptors by halting the enzymatic breakdown of anandamide, enhancing anandamide, permitting it to remain in the system longer and provide medical benefits. Cannabidiol works through a variety of complex pharmacological actions, such as inhibition of endocannabinoid reuptake, transient receptor potential vanilloid 1 and G protein–coupled receptor 55 activation, and increasing the activity of serotonin 5-HT1A receptors and cannabidiol’s minimal agonism of the CB receptors likely accounts for its negligible psychoactivity when compared with THC.

There are some evidences of CBD’s modulatory effects on dopamine activity within the mesolimbic pathway, functional interactions with the serotonin 5-HT1A receptor system, and their downstream molecular signaling effects relieves the symptoms in MDD [72]. The inhibitory action of cannabinoids on catecholamine secretion at the level of the adrenal medulla is also observed [73]. CBD improves and restores 5-HT and BDNF levels via 5HT1A receptor activation [74]. There are CB1 receptors located in hippocampus and amygdala and any stress and anxiety is a result of the bed nucleus of the stria terminalis coordinating a stress-based response in conjunction with the amygdala. CBD produces its anxiolytic effects via activation of the 5HT- 1a receptor associated with serotonin, as well as affecting positively the amygdala. The acute anxiolytic and antidepressive activities of intense CBD are proposed to be interceded by serotonin 5HT1A receptors. The crosstalk among cannabinoids and serotoninergic signaling is unpredictable. In rodents, CBD administration into the dorsal portions of periaqueductal gray matter (dPAG) produces against aversive impacts in the elevated plus maze and flight-induced by local electric stimulation. These impacts were prevented by WAY-100635, a 5HT1A opponent (Campos and Guimarães) Other cerebrum areas, for example, the basal ganglia, the bed nucleus of stria terminallis, the prelimbic PFC and the dorsal raphe core likewise appear to intervene CBD impacts through 5HT1A receptors [75]. The molecular mechanism by which CBD encourages 5HT1A receptor activation is still obscure. Evidence proposes that it might include allosteric regulation of this receptor, advancing 5HT1A agonist-related situmulation of [35S] GTPγS binding increment in 5-HT discharge or potentially reuptake inhibiton or the circuitous development of heterodimers comprising of 5HT1A and different receptors, for example, CB1 [76]. CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNFTrkB signaling pathway. The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug [25].

The pre-clinical and clinical studies available so far indicate that CBD has a good safety record. Cannabidiol doses up to 300 mg/d have been used safely for up to 6 months and doses of 1200 to 1500 mg/d were used in a study for up to 4 weeks. In another trial CBD doses up to 300 mg/d have been used without any adverse effects for up to 6 months and doses of 1200 to 1500 mg/d were used in a study for up to 4 weeks [77,78]. There are some concerns regarding the metabolic interaction. For example the enzymes etabolizing escitaloprame are CYP3A4, CYP2D6, and CYP2C19. Escitaloprame and CBD share many of the same enzymatic pathways and, therefore, have a strong chance of interacting such as CBD may elevate the effect of convential drugs yet it looks like it does not decrease it either. (Culpepper) The CYP450 pathway also metabolizes CBD in the liver. CBD inhibits catalytic activity of human CYP3A enzymes (CYP3A4 and CYP3A5) at utmost level [79]. Escitaloprame and CBD use many of the same enzymatic pathways at the same time and therefore clinician should pay attention to a possible interaction and dosages should be calculated accordingly and attention to tapering of the doses of escitaloprame and increasing CBD should be given.

Therefore physicians should not disregard patients’ interest in cannabidiol as treatment option and continue to educate both patients and themselves about alternative therapies with the assistance and guidance of translational medicine experts that combinations of CBD and exogenous/endogenous compounds are of utmost importance and needed as necessary as patient’s unique medical conditions such as endocrinology, cardiology and other related health problems. The principle finding of studies and practices is that CBD alongside conventional prescriptions and enhancements can be a successful compound to diminish Major Depressive Disease and General Anxiety Disorder and other related issue as showed in a critical or analytical summing up especially of a medical case history of several patients. Further investigation should be directed to decide the permanency of patient’s certain practices and to what extent they should keep taking the CBD. There is not a sensible establishment to suggest dosing from the logical writing. Be that as it may, in accordance of several studies and practices this enhancement given 30mg gradually increasing the doses up to 100 mg a day seems to appear to provide relief of key symptoms with minimal side effects. Almost none of the patients voice any complaints or discomfort from the utilization of CBD. Personally I believe in existential psychotherapy and that and further evaluations should continue as needed both by physicians and patients. In spite of the fact that CBD is viewed as commonly safe the drawn out impacts are yet to be considered. The ultimate goal is to gradually taper the use of conventional drugs and transition patients into CBD 10 to 100mg a day until symptoms are dissolved to an acceptable degree and patients should be encouraged lifelong coping strategies such as exercise, massage, yoga, meditation, and various other therapeutic activities such as skull acupuncture what patients can easily do at home. There is an urgent need that any psychiatrist should also collaborate with general physicians and especially translational medicine experts regarding patient’s full medical evaluation and treatment options as needed [80-95].

Conclusion

Antidepressants frequently come up short since patients show late relapses and short-remissions and with diverse adverse and side effects breaking up all metabolisms. Since there is no specific targeted medicinal drug to build the degree of BDNF one should seriously think about to embed a few botanicals, unsaturated fats, minerals, substance components, probiotics, prebiotics, flavonoids into treatment instruments as for MDD due to their pleiotropic effect to increase the levels of BDNF. In spite of the fact that standardization of the botanicals and natural endogenous and exogenous substances is as yet problematic the characteristic supply offers some effective plants and even some endogenous items might be utilized for forestalling CNS distortion or as a helpful adjuvant to the pharmacological treatment regarding so far unsolved issue called MDD. Combo drug and natural substances treatment options should not be ignored for improving quality of life as shown in the various studies but one of the most important need deriving from this review is that psychiatrist should collaborate with translational medicine experts and physicians as needed for patients other medical conditions causing or contributing to disease development. Conventional medications and standard clinical approachment to MDD seem to miss the mark so translational medication appears as a significant and ground breaking treatment option along with conventional medicine in surveying and treating patients. This review aimed to promote normal substance’s application as an apparatus of translational medicine. In this regard translational medication assists with expanding BDNF levels too without causing side and antagonistic impacts. Therapists and translational medicine specialists should cooperate for MDD and other psychiatric conditions.

References

1. Polyakova, Maryna, Katharina Stuke, Katharina Schuemberg and Karsten Mueller, et al. "BDNF as a Biomarker for Successful Treatment of Mood Disorders: A Systematic & Quantitative Meta-Analysis." J Affective Disord 174 (2015): 432-440.
2. Xiu, Mei Hong, Li Hui, Yu Feng Dang and Tian De Hou, et al. "Decreased Serum BDNF levels in Chronic Institutionalized Schizophrenia on Long-Term Treatment with Typical and Atypical Antipsychotics." Progress Neuro-Psychopharmacol Biolog Psych 33 (2009): 1508-1512.
3. Maina, Giuseppe, Gianluca Rosso, Roberta Zanardini and Filippo Bogetto, et al. "Serum Levels of Brain-Derived Neurotrophic Factor in Drug-Naive Obsessive-Compulsive Patients: A Case-Control Study." J Affective Disord 122 (2010): 174-178.
4. Zajac, MS, TYC Pang, N Wong and B Weinrich, et al. "Wheel Running and Environmental Enrichment Differentially Modify Exon‐Specific BDNF Expression in the Hippocampus of Wild‐Type and Pre‐Motor Symptomatic Male and Female Huntington's Disease Mice." Hippocampus 20 (2010): 621-636.
5. Arancio, Ottavio and Moses V Chao "Neurotrophins, Synaptic Plasticity and Dementia." Curr Opinion Neurobiol 17 (2007): 325-330.
6. Tapia-Arancibia, Lucia, Esteban Aliaga, Michelle Silhol and Sandor Arancibia. "New Insights into Brain BDNF Function in Normal Aging and Alzheimer Disease." Brain Res Rev 59 (2008): 201-220.
7. Miranda, Magdalena, Juan Facundo Morici, María Belén Zanoni and Pedro Bekinschtein. "Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain." Frontiers Cellular Neurosci 13 (2019): 363.
8. Nieto, Rodrigo, Manuel Kukuljan, and Hernan Silva. "BDNF and Schizophrenia: From Neurodevelopment to Neuronal Plasticity, Learning, and Memory." Frontiers Psych 4 (2013): 45.
9. Martinowich, Keri and Bai Lu. "Interaction between BDNF and Serotonin: Role in Mood Disorders." Neuropsychopharmacol 33 (2008): 73-83.
10. Duman, Ronald S and Bhavya Voleti. "Signaling Pathways Underlying the Pathophysiology and Treatment of Depression: Novel Mechanisms for Rapid-Acting Agents." Trends in Neurosci 35 (2012): 47-56.
11. Huang, Eric J and Louis F Reichardt. "Trk Receptors: Roles in Neuronal Signal Transduction." Annual Rev Biochem 72 (2003): 609-642.
12. Autry, Anita E and Lisa M Monteggia. "Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders." Pharmacol Rev 64 (2012): 238-258.
13. Rial, Daniel, Cristina Lemos, Helena Pinheiro and Joana M Duarte, et al. "Depression as a Glial-Based Synaptic Dysfunction." Frontiers Cellular Neurosci 9 (2016): 521.
14. Dwivedi, Yogesh. "Brain-derived neurotrophic factor: Role in Depression and Suicide." Neuropsych DisTreatm (2009): 2-4.
15. Bhandari, Shiva, Pradeep K Shukla, Huda M Almabadi and Peeyush Sahay. "Optical Study of Stress Hormone‐Induced Nanoscale Structural Alteration in Brain Using Partial Wave Spectroscopic Microscopy." J Biophotonics 12 (2019): e201800002.
16. Küppers, Eva and Cordian Beyer. "Dopamine Regulates Brain-Derived Neurotrophic Factor (BDNF) Expression in Cultured Embryonic Mouse Striatal Cells." Neuroreport 12 (2001): 1175-1179.
17. Karege, Félicien, Guido Bondolfi, Nicola Gervasoni and Michèle Schwald, et al. "Low Brain-Derived Neurotrophic Factor (BDNF) Levels in Serum Of Depressed Patients Probably Results from Lowered Platelet BDNF Release Unrelated to Platelet Reactivity." Biological Psych 57 (2005): 1068-1072.
18. Galea, Roberto and David Cassar. "Brain-Derived Neurotrophic Factor—Major Depressive Disorder and Suicide." Open Access Library J 6 (2019): 1-16.
19. Sertoz, Ozen Onen, Ibrahim Tolga Binbay, Ersin Koylu and Aysin Noyan, et al. "The Role of BDNF and HPA axis in the Neurobiology of Burnout Syndrome." Progress Neuro-Psychopharmacol Biolog Psych 32 (2008): 1459-1465.
20. Gimeno, David, Mika Kivimäki, Eric J Brunner and Marko Elovainio, et al. "Associations of C - reactive protein and Interleukin-6 with Cognitive Symptoms of Depression: 12-year follow-up of the Whitehall II study." Psycholog Med 39 (2009): 413.
21. Barton, Gregory M and Jonathan C Kagan. "A Cell Biological View of Toll-like Receptor Function: Regulation through Compartmentalization." Nature Rev Immunol 9 (2009): 535-542.
22. Jin, Yang, Li Hua Sun, Wei Yang and Ran Ji Cui, et al. "The Role of BDNF in the Neuroimmune Axis Regulation of Mood Disorders." Frontiers Neurol 10 (2019): 515.
23. Liu, Bangshan, Jin Liu, Mi Wang and Yan Zhang, et al. "From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder." Frontiers Cellular Neurosc 11 (2017): 305.
24. Mori, Marco Aurélio, Erika Meyer, Ligia Mendes Soares and Humberto Milani, et al. "Cannabidiol Reduces Neuroinflammation and Promotes Neuroplasticity and Functional Recovery after Brain Ischemia." Progress Neuro-Psychopharmacol Biological Psych 75 (2017): 94-105.
25. Sales, Amanda J, Manoela V Fogaça, Ariandra G Sartim and Vitor S Pereira, et al. "Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex." Mol Neurobiol 56 (2019): 1070-1081.
26. Guilloux, Jean-Philippe, Gaelle Douillard-Guilloux, Rama Kota and Xingbin Wang, et al. "Molecular Evidence for BDNF-and GABA-Related Dysfunctions in the Amygdala of Female Subjects with Major Depression." Mol Psych 17 (2012): 1130-1142.
27. Caldeira, Margarida V, Carlos V Melo, Daniela B Pereira and Ricardo Carvalho, et al. "Brain-Derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery ofα-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons." J Biol Chem 282 (2007): 12619-12628.
28. Bondolfi, Guido, Françoise Jermann, Martial Van der Linden and Marianne Gex-Fabry, et al. "Depression Relapse Prophylaxis with Mindfulness-Based Cognitive Therapy: Replication and Extension in the Swiss Health Care System." J Affective Disord 122 (2010): 224-231.
29. Sangiovanni, Enrico, Paola Brivio, Mario Dell’Agli and Francesca Calabrese. "Botanicals as Modulators of Neuroplasticity: Focus on BDNF." Neural Plasticity 2 (2017): 2-4.
30. Bahna, Sarra G and Lennard P Niles. "Epigenetic Regulation of Melatonin Receptors in Neuropsychiatric Disorders." British J Pharmacol 175 (2018): 3209-3219.
31. Shen, Ting, Yuyi You, Chitra Joseph and Mehdi Mirzaei Alexander Klistorner, et al. "BDNF polymorphism: A Review of its Diagnostic and Clinical Relevance in Neurodegenerative Disorders." Aging Disease 9 (2018): 523.
32. Lu, Jiaqi, Hang Zhou, Danyang Meng and Junjun Zhang, et al. "Tanshinone IIA Improves Depression-like Behavior in Mice by Activating the ERK-CREB-BDNF Signaling Pathway." Neuroscience 430 (2020): 1-11.
33. Impellizzeri, Daniela, Giuseppe Bruschetta, Marika Cordaro and Rosalia Crupi, et al. "Micronized/Ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model Of Inflammatory Pain." J Neuroinflammat 11 (2014): 1-9.
34. Cuzzocrea, Salvatore, Rosalia Crupi, Irene Paterniti and Daniela Impellizzeri, et al. "Palmitoylethanolamide Enhances Brain-Derived Neurotrophic Factor Production and Neurogenesis in the Hippocampus Following Ischemic Brain Injury." (2013):1177-1213.
35. Cristiano, Claudia, Claudio Pirozzi, Lorena Coretti and Gina Cavaliere, et al. "Palmitoylethanolamide Counteracts Autistic-Like Behaviours in BTBR T+ tf/J mice: Contribution of Central and Peripheral Mechanisms." Brain Behav Immun 74 (2018): 166-175.
36. Nasca, Carla, Benedetta Bigio, Francis S Lee and Sarah P Young, et al. "Acetyl-l-carnitine Deficiency in Patients with Major Depressive Disorder." Proc National Acad Sci 115 (2018): 8627-8632.
37. Zhu, Yongwen, Xiudong Liao, Lin Lu and Wenxiang Li, et al. "Maternal Dietary Zinc Supplementation Enhances the Epigenetic-Activated Antioxidant Ability of Chick Embryos from Maternal Normal and High Temperatures." Oncotarget 8 (2017): 19814.
38. Wang, Xiaoxi and Bing Zhou. "Dietary Zinc Absorption: A Play of Zips and ZnTs in the Gut." IUBMB life 62 (2010): 176-182.
39. Frazzini, Valerio, Alberto Granzotto, Manuela Bomba and Noemi Massetti, et al. "The Pharmacological Perturbation of Brain Zinc Impairs BDNF-Related Signaling and the Cognitive Performances of Young Mice." Scient Rep 8 (2018): 1-12.
40. Kakio, Shota, Yosuke Nakazawa, Megumi Funakoshi-Tago and Hiroomi Tamura. "Coffee Modulates the Function of Brain-Derived Neurotrophic Factor (BDNF) in Human Neuroblastoma SH-SY5Y Cells." Neurosci Med 6 (2015): 165.
41. Jain, V, I Baitharu, D Prasad and G Ilavazhagan. "Enriched Environment Provides Neuroprotection Via Activation Of Bdnf Mediated PI3 Kinase Pathway." J Neurochem 115 (2010): 53-53.
42. Zhao, Hong-Bin, Hui Ma, Xiao‐Qin Ha and Ping Zheng, et al. "Salidroside Induces Rat Mesenchymal Stem Cells to Differentiate into Dopaminergic Neurons." Cell Biol International 38 (2014): 462-471.
43. Panossian, Alexander, G Wikman and Jerome Sarris. "Rosenroot (Rhodiola rosea): Traditional Use, Chemical Composition, Pharmacology and Clinical Efficacy." Phytomed 17 (2010): 481-493.
44. Nath, Samir, Muznabanu Bachani, Deepti Harshavardhana and Joseph P. Steiner. "Catechins Protect Neurons against Mitochondrial Toxins and HIV Proteins via Activation of the BDNF Pathway." J Neurovirol 18 (2012): 445-455.
45. Hassani, Faezeh Vahdati, Vahideh Naseri, Bibi Marjan Razavi and Soghra Mehri, et al. "Antidepressant Effects of Crocin and its Effects on Transcript and Protein Levels of CREB, BDNF, and VGF in Rat Hippocampus." DARU J Pharmac Sci 22 (2014): 16.
46. Ghasemi, T, K Abnous, F Vahdati and S Mehri, et al. "Antidepressant Effect of Crocus sativus Aqueous Extract and its effect on CREB, BDNF, and VGF Transcript and Protein Levels in Rat Hippocampus." Drug Res 65 (2015): 337-343.
47. Harkin, Andrew, John P Kelly and Brian E Leonard. "A Review of the Relevance and Validity of Olfactory Bulbectomy as a Model of Depression." Clin Neurosci Res 3 (2003): 253-262.
48. Poleszak, Ewa, Bernadeta Szewczyk, Ewa Kędzierska and Piotr Wlaź, et al. "Antidepressant-and Anxiolytic-Like Activity of Magnesium in Mice." Pharmacol Biochem Behavior 78 (2004): 7-12.
49. Slutsky, Inna, Nashat Abumaria, Long-Jun Wu and Chao Huang, et al. "Enhancement of Learning and Memory by Elevating Brain Magnesium." Neuron 65 (2010): 165-177.
50. Pochwat, Bartlomiej, Magdalena Sowa-Kucma, Katarzyna Kotarska and Paulina Misztak, et al. "Antidepressant-Like Activity of Magnesium in the Olfactory Bulbectomy Model is Associated with the AMPA/BDNF Pathway." Psychopharmacol 232 (2015): 355-367.
51. Sukumaran, Nimisha Pulikkal, Augustine Amalraj, and Sreeraj Gopi. "Neuropharmacological and Cognitive Effects of Bacopa monnieri (L.) Wettst–A review on its Mechanistic Aspects." Compl Therap Med 44 (2019): 68-82.
52. Pandareesh MD and T Anand. "Neuroprotective and Anti-Apoptotic Propensity of Bacopa monniera Extract against Sodium Nitroprusside Induced Activation of iNOS, Heat Shock Proteins and Apoptotic Markers in PC12 Cells." Neurochem Res 39 (2014): 800-814.
53. Abiri, Behnaz and Mohammadreza Vafa. "Effects of Vitamin D and/or Magnesium Supplementation on Mood, Serum Levels of BDNF, Inflammatory Biomarkers, and SIRT1 in Obese Women: A Study Protocol for a Double-Blind, Randomized, Placebo-Controlled Trial." Trials 21 (2020): 1-7.
54. Fetahu IS, Höbaus J and Kállay E (2015) Vit D; the epigenome. Front Physiol 5: 164.
55. Savignac, Helene M, Giulia Corona, Henrietta Mills and Li Chen, et al. "Prebiotic Feeding Elevates Central Brain Derived Neurotrophic Factor, N-methyl-D-aspartate Receptor Subunits and D-serine." Neurochem Int 63 (2013): 756-764.
56. Haghighat, Neda, Majid Mohammadshahi, Shokouh Shayanpour, and Mohammad Hossein Haghighizadeh. "Effect of Synbiotic and Probiotic Supplementation on Serum Levels of Endothelial Cell Adhesion Molecules in Hemodialysis Patients: A Randomized Control Study." Probiotics Antimicrobial Proteins 11 (2019): 1210-1218.
57. Hamer, Henrike M, Daisy MAE Jonkers, Aalt Bast and Steven ALW Vanhoutvin, et al. "Butyrate Modulates Oxidative Stress in the Colonic Mucosa of Healthy Humans." Clin Nutrition 28 (2009): 88-93.
58. Caracciolo, Barbara, Weili Xu, Stephen Collins, and Laura Fratiglioni. "Cognitive Decline, Dietary Factors and Gut–Brain Interactions." Mech Ageing Develop 136 (2014): 59-69.
59. Franco-Robles, Elena and Mercedes G López. "Implication of Fructans in Health: Immunomodulatory and Antioxidant Mechanisms." The Scient World J 2 (2015): 2-4.
60. Canani, Roberto Berni, Margherita Di Costanzo, and Ludovica Leone. "The Epigenetic Effects of Butyrate: Potential Therapeutic Implications for Clinical Practice." Clin Epigenet 4 (2012): 1-7.
61. Wu, Aiguo, Zhe Ying and Fernando Gomez-Pinilla. "Dietary Omega-3 Fatty Acids Normalize BDNF Levels, Reduce Oxidative Damage, and Counteract Learning Disability after Traumatic Brain Injury in Rats." J Neurotrauma 21 (2004): 1457-1467.
62. Silva, Valvassori S, Bitencourt Varela R, Orlandi Arent C and Colombo Dal-Pont G, et al. Sodium Butyrate Functions as an Antidepressant And Improves Cognition with Enhanced Neurotrophic Expression in Models of Maternal Deprivation and Chronic Mild Stress. Curr Neurovas Res 11 (2014): 359-366.
63. Katasonov, AB. "Curcumin as an Ajuvant Treatment of Depression: Mechanisms of Action and Application Prospects." Zhurnal Nevrologii i Psikhiatrii Imeni SS Korsakova 120 (2020): 125-131.
64. Farooqui, Akhlaq A. "Therapeutic Importance of Curcumin in Neurological Disorders other than Alzheimer Disease." In Therapeutic Potentials Curcumin Alzheimer Dis 2: 297-334.
65. Liu, Dexiang, Zhen Wang, Ze Gao and Kai Xie, et al. "Effects of Curcumin on Learning and Memory Deficits, BDNF, and ERK Protein Expression in Rats Exposed to Chronic Unpredictable Stress." Behav Brain Res 271 (2014): 116-121.
66. Zhang, Xiang Yang, Wu-Fang Zhang, Dong-Feng Zhou and Mei Hong Xiu, et al. "Brain-Derived Neurotrophic Factor Levels and its Val66Met Gene Polymorphism Predict Tardive Dyskinesia Treatment Response to Ginkgo biloba." Biolog Psych 72 (2012): 700-706.
67. Sawamoto, Atsushi, Satoshi Okuyama, Yoshiaki Amakura and Rie Yamada, et al. "Sansoninto as Evidence-Based Remedial Medicine for Depression-Like Behavior." J Nat Med 72 (2018): 118-126.
68. Terauchi, Masakazu, Shiro Hiramitsu, Mihoko Akiyoshi and Yoko Owa, et al. "Effects of Three Kampo Formulae: Tokishakuyakusan (TJ-23), Kamishoyosan (TJ-24), and Keishibukuryogan (TJ-25) on Japanese Peri-And Postmenopausal Women with Sleep Disturbances." Arch Gynecol Obstetr 284 (2011): 913-921.
69. Liao, JF, YM Jan, SY Huang and HH Wang, et al. "Evaluation with Receptor Binding Assay on the Water Extracts of Ten CNS-Active Chinese Herbal Drugs." Proc National Sci Council 19 (1995): 151-158.
70. Mantani, Naoki, Akito Hisanaga, Toshiaki Kogure and Toshiaki Kita, et al. "Four Cases of Panic Disorder Successfully Treated with Kampo (Japanese Herbal) Medicines: Kami‐shoyo‐san and Hange‐koboku‐to." Psych Clin Neurosci 56 (2002): 617-620.
71. Seo, Mi Kyoung, Jae Chun Song, Sun Jung Lee and Kyung Ah Koo, et al. "Antidepressant-like effects of Bupleuri Radix extract." Eur J Integ Med 4 (2012): e392-e399.
72. Renard, Justine, Christopher Norris, Walter Rushlow and Steven R Laviolette. "Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments." Neurosci Biobehav Rev 75 (2017): 157-165.
73. Niederhoffer, Nathalie, Henrik H Hansen, Javier J Fernandez‐Ruiz and Bela Szabo. "Effects of Cannabinoids on Adrenaline Release from Adrenal Medullary Cells." British J Pharmacol 134 (2001): 1319-1327.
74. Magen I, Y Avraham, Z Ackerman and L Vorobiev, et al. "Cannabidiol Ameliorates Cognitive and Motor Impairments in Bile‐Duct Ligated Mice via 5‐HT1A Receptor Activation." British J Pharmacol 159 (2010): 950-957.
75. Fogaça, Manoela V, FMCV Reis, AC Campos and FS Guimaraes. "Effects of Intra-Prelimbic Prefrontal Cortex Injection of Cannabidiol on Anxiety-Like Behavior: Involvement of 5HT1A Receptors and Previous Stressful Experience." Eur Neuropsychopharmacol 24 (2014): 410-419.
76. Russo, Ethan B, Andrea Burnett, Brian Hall and Keith K Parker. "Agonistic Properties of Cannabidiol at 5-HT1A Receptors." Neurochem Res 30 (2005): 1037-1043.
77. Trembly B and M Sherman. "Double-Blind Clinical Study of Cannabidiol as a Secondary Anticonvulsant, presented at: Marijuana’90 International Conference on Cannabis and Cannabinoids, Kolymbari, Crete." International Association for Cannabinoid Medicines (1990).
78. Zuardi, Antônio Waldo, JAS Crippa, SM Dursun and SL Morais, et al. "Cannabidiol was Ineffective for Manic Episode of Bipolar Affective Disorder." J Psychopharmacol 24 (2010): 135-137.
79. Campos, AC and FS Guimaraes. "Cannabidiol Injected into the Dorsolateral Periaqueductal Grey Produces Anxiolytic-Like Effects." Behav Pharmacol 18: S16-S17.
80. Chen, Wen G, Qiang Chang, Yingxi Lin and Alexander Meissner, et al. "Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2." Sci 302 (2003): 885-889.
81. Culpepper, Larry. "Escitalopram: A New SSRI for the Treatment of Depression in Primary Care." Primary Care Compan J Clin Psych 4 (2002): 209.
82. Lima-Ojeda, Juan M, Rainer Rupprecht and Thomas C Baghai. "Neurobiology of Depression: a Neurodevelopmental Approach." World J Biolog Psych 19 (2018): 349-359.
83. Kim, Eun-Jin, Il-Hoon Jung, Thi Kim Van Le and Jin-Ju Jeong, et al. "Ginsenosides Rg5 and Rh3 Protect Scopolamine-Induced Memory Deficits in Mice." J Ethnopharmacol 146 (2013): 294-299.
84. Konar, Arpita, Navjot Shah, Rumani Singh and Nishant Saxena, et al. "Protective Role of Ashwagandha Leaf Extract and its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells." PloS one 6 (2011): e27265.
85. Kowiański, Przemysław, Grażyna Lietzau, Ewelina Czuba and Monika Waśkow, et al. "BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity." Cellul Mol Neurobiol 38 (2018): 579-593.
86. Lener, Marc S, Mark J Niciu, Elizabeth D Ballard and Minkyung Park, et al. "Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine." Biolog Psych 81 (2017): 886-897.
87. Rudzki, Leszek, Lucyna Ostrowska, Dariusz Pawlak and Aleksandra Małus, et al. "Probiotic Lactobacillus plantarum 299v Decreases Kynurenine Concentration and Improves Cognitive Functions in Patients with Major Depression: A Double-Blind, Randomized, and Placebo Controlled Study." Psychoneuroendocrinol 100 (2019): 213-222.
88. Liester, Mitchell B and Erin E Sullivan. "A Review of Epigenetics in Human Consciousness." Cogent Psychol 6 (2019): 1668222.
89. Mlyniec, Katarzyna. "Zinc in the Glutamatergic Theory of Depression." Current Neuropharmacol 13 (2015): 505-513.
90. Pruunsild, Priit, Anna Kazantseva, Tamara Aid and Kaia Palm, et al. "Dissecting the Human BDNF Locus: bidirectional transcription, complex splicing, and Multiple Promoters." Genomics 90 (2007): 397-406.
91. Sánchez-Villegas, Almudena, Cecilia Galbete, Miguel Ángel Martinez-González and J Alfredo Martinez, et al. "The Effect of the Mediterranean Diet on Plasma Brain-Derived Neurotrophic Factor (BDNF) Levels: The Predimed-Navarra Randomized Trial." Nutri Neurosci 14 (2011): 195-201.
92. Weaver, IC, D’Alessio AC, Brown SE and Hellstrom IC, et al.”The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes”. J Neurosci 2 (2007): 27.
93. Wu, Feifei, Huaqiang Li, Liangzhong Zhao and Xiaoyu Li, et al. "Protective effects of Aqueous Extract from Acanthopanax senticosus against Corticosterone-Induced Neurotoxicity in PC12 Cells." J Ethnopharmacol 148 (2013): 861-868.
94. https://www.eposavje.com/ostale-novice/koronavirus-zbirne-informacije-torek-21-april-2020
95. Zhang, Xiang Yang, Dong Feng Zhou, Jian Min Su, and Pei Yan Zhang. "The effect of Extract of Ginkgo biloba added to Haloperidol on superoxide dismutase in in-patients with Chronic Schizophrenia." J Clin Psychopharmacol 21 (2001): 85-88.