Microglial Mitigation: A Novel Avenue for Antidepressant Research

Depression is a serious mental health condition with an average incidence rate of 4.4 percent worldwide. The pathophysiology of depression is generally linked to the monoamine neurotransmitter reduction, disturbed hypothalamus–pituitary–adrenal (HPA) axis, heightened oxidative load and altered neuroplasticity. Antidepressants have historically targeted monoamine neurotransmitters and HPA-axis hyperactivity restoration. However, there is mounting evidence that neuroinflammation and immunological dysregulation, specifically involving microglia, are key factors in depression. Thus, we aimed to explore the insights of antidepressant drugs in terms of their ability to mitigate the microglial activity and modulations of their phenotype functioning. In the present review, we have highlighted the biological basis of some common clinically used antidepressants (like SSRIs, TCAs, MAOIs, NMDA receptor antagonists) and relevant therapeutic targets (like immunomodulators, anti-inflammatory molecules, PPAR γ agonists), and attempted to provide insights about the role of microglial activity and phenotype shifting in normalizing depressive-like behaviours. We observed that most of the antidepressants are working through modulating redox state, maintaining inflammatory response, restoring synaptic plasticity, enhancing neurogenesis factors, and regulating monoamine levels. Interestingly all these mechanisms are directly associated with microglial activation specially in brain structures which are involved in the pathophysiology of depression such as frontal cortex and hippocampus. This review provided a new perspective of evaluating antidepressant potential of various already used and upcoming novel drugs based on microglial perturbations in the CNS. Keywords: Antidepressants, Microglial cells, Monoamines, Neuroinflammation, ROS. Ausaf Ahmad Amity Institute of Biotechnology, Amity University, Lucknow, UP, India-226028

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