Effects of lithium on cytokine neuro-inflammatory mediators, Wnt/β-catenin signaling and microglial activation in the hippocampus of chronic mild stress-exposed rats

Microglial in vivo production of pro-inflammatory cytokines is central to the pathogenesis of multiple neurological disorders including depression, with a rising role of Wnt/β-catenin signaling as potential regulator of microglia-mediated neuro-inflammation. This study aimed at investigating the hippocampal expression of the Wnt/ß-catenin pathway in chronic mild stress (CMS)-exposed rats and the effects of Lithium (Li) on the expression of this pathway as a method to identify a plausible link between exposure to chronic stress, microglial activation, and neuroinflammation. The effect of chronic administration of Li was investigated on behavioral changes, hippocampal expression of Wnt-DVL-GSK3β-β-catenin signaling pathway, and microglial activation in CMS-exposed male Wistar rats CMS induced a depressive-like behavior associated with increased pro-inflammatory microglial activation and reduced hippocampal expression of the Wnt/β-catenin signaling pathway. Chronic Li treatment ameliorated stress induced-behavioral changes, reduced microglial activation and enhanced the hippocampal expression of Wnt/β-catenin signaling pathway. This work highlights that Li-induced inhibition of GSK-3β with subsequent accumulation of β-catenin could impede pro-inflammatory microglia activation which is a key pathological hallmark associated with depression. Wnt/β-catenin signaling represents a promising therapeutic target, not only for alleviation of depression, but also for a wide array of neurological disorders.