Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response

Joint Webinar : 32^nd world congress on Neurology and Therapeutics & 33^rd International Conference on Neurology and Cognitive Neuroscience

January 25-26, 2023 | Webinar

Mohamed H. Yousef, Mohamed Salama, Hassan A. N. El-Fawal and Anwar Abdelnaser

The American University in Cairo, Egypt

Scientific Tracks Abstracts: J Neurol Disord

Abstract :

Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with nuclear factor kappa B (NF-κB). GSK3 is also a suppressor of nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies. Furthermore; we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition. The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess posttreatment expression levels of pro-inflammatory markers and antioxidant genes; pro - inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2- dependent, DsiRNA-mediated knockdown of Nrf2 was attempted. Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3β- selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence use of selective GSK3β inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition is not Nrf2 dependent. Keywords: GSK3; Paralog selectivity; Microglia; Neuroinflammation; Neurodegenerative diseases; Oxidative stress; Nrf2; NF-κB.
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Biography :

Mohamed H. Yousef currently working in the School of Sciences and Engineering, Biotechnology Graduate Program, The American University in Cairo, Cairo, Egypt.