Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles.
Biomedicines March 7, 2023 Hans O Kalkman 16 citations
Depression involves an infection-like inflammation in the brain driven by activation of microglial Toll-like receptors and the enzyme glycogen synthase kinase-3β (GSK3β). GSK3β shifts the balance between the pro-inflammatory transcription factor NFκB and the neuroprotective, anti-inflammatory transcription factor NRF2. Tricyclic antidepressants work by activating GS-coupled microglial receptors, raising cAMP, and activating protein kinase A, which inhibits GSK3β. Other antidepressant principles—cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine, and vagus nerve stimulation—also inhibit GSK3β. Screening for NRF2 activation in microglial cells with TLR-activated GSK3β activity could accelerate discovery of novel antidepressants.