Background Previous studies indicate a close association between the altered immune system and major depressive disorders. and inhibition of neuroinflammation may represent an alternative mechanism to treat depression. Recently, the anti-inflammatory activity of ibrutinib has been reported, however, the effect of ibrutinib on neuroinflammation allied depression and its underlying mechanism has not been comprehensively studied. Therefore, we aimed to elucidate the potential anti-depressive role and mechanism of ibrutinib against neuroinflammation induced depression as well as synaptic defects. Methods Adult C57BL/6J male mice weighing 25–30 g (age 7–8 weeks) were treated with LPS (2 mg/kg BW i.p) and 50 mg/kg BW ibrutinib, orally. Depressive-like behaviors were assessed by FST and SPT, cytokine levels were determined by ELISA, ROS, TBARs, and Nitric oxides were measured via biochemical assays, Iba-1 and GFAP expression were determined by immunofluorescence. Further, spine density was measured by Golgi staining, while NF-kB, Nrf2, SOD2, HO-1, NLRP3, P38, Caspase-1, BDNF, PSD95, and synaptophysin were measured by immunoblotting. Results Our results showed that ibrutinib treatment significantly reduced LPS induced depressive-like behaviors and neuroinflammation via inhibiting NF-kB activation, decreasing pro-inflammatory cytokines level, normalizing redox signaling and it’s a downstream component including Nrf2, HO-1, and SOD2 as well as glial cells activation markers such as Iba-1 and GFAP expression. Further, ibrutinib treatment inhibited LPS activated inflammasome activation by targeting NLRP3/P38/Caspase-1 signaling. Interestingly, LPS reduced dendritic spines numbers, expression of BDNF and synaptic related markers including PSD95, snap25, and synaptophysin were improved by ibrutinib treatment in the hippocampal area of the mice brain. Conclusion In conclusion, our finding suggested that ibrutinib could alleviate neuroinflammation and synaptic defects, rendering its antidepressant potential against LPS induced neuroinflammation and depression.

A wide spectrum of changes occur in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunctions is one of the significant processes and factors associated with age. Adiponectin (APN), an adipokine important in glucose and lipid metabolism, is involved in the aging; however, their roles in brain aging have not been explored adequately. Here, we aimed to mechanistically illuminate the causal relation of brain aging with APN deficiency via multiple biochemical and pharmacology approaches while using APN KO mice, primary microglia, and BV2 cells. Initially, we found that declined APN levels in aged subjects correlated with dysregulated cytokine levels in human individuals. Interestingly, APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. Accordingly, adiponectin receptor agonist AdipoRon could alleviate the mitochondrial deficits and aging markers induced by rotenone or antimycin A in BV2 cells. Further results indicated that HDAC1 antagonism by Cpd 60 reduced the mitochondrial dysfunction and improved aging-related inflammation, as validated in D-galactose treated APN KO mice. Altogether, these findings indicate that APN is a critical regulator of aging by preventing neuroinflammation associated with mitochondrial impairment of the brain via HDAC1 signaling.