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 DOI: 10.3390/biomedicines11030806 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Psilocybin |
| Keywords | 5-ht2b Gs-coupled receptor Gsk3β Nrf2 Cannabinoid cbr2 Depression risk factor Microglia Toll-like receptor Neuroinflammation Antidepressants |
| Citations | 16 |
| Key findings | Inhibiting GSK3β in microglial cells to shift the balance from NFκB to NRF2 is a common mechanism for current and experimental antidepressants, and screening for NRF2 activation may identify new antidepressant principles. |
Abstract
Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy.
Comparable studies
Other narrative reviews on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression | 2021 | Review | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review | 2020 | Review | |
| From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders | 2021 | Review |
Citations in the library
Cited by 6
- Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments Proceedings of the National Academy of Sciences November 27, 2023
- Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells Current Issues in Molecular Biology August 15, 2023
- Psilocybin and Eugenol Reduce Inflammation in Human 3D EpiIntestinal Tissue Life December 15, 2023
- Deciphering psilocybin: Cytotoxicity, anti-inflammatory effects, and mechanistic insights International Immunopharmacology February 23, 2024
- Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling. International Immunopharmacology June 26, 2025
and 1 more in the library
Cites 16
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up Journal of Psychopharmacology February 1, 2022
and 11 more in the library