Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats

•Agmatine inhibited depression, anxiety in HFD fed rats.•HFD fed rats showed reduced agmatine levels and enhanced agmatinase expression in hippocampus.•Agmatine reversed the increased IL-6 and TNF-α level in hippocampus in HFD fed rats.•Agmatine increased the BDNF expression in HFD fed rats. Epidemiological studies indicated that mood disorders like depression and anxiety are highly prevalent in type-II diabetes mellitus (T2DM). However, the neurobiological mechanisms underlying the relationship between T2DM and depression have yet to be identified. Thus, understanding the neural mechanisms that mediate the co-morbidity of depression and type-II diabetes mellitus may unlock new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in T2DM induced depression using forced swim test (FST) and anxiety in the elevated plus-maze (EPM)in rats. T2DM was induced by the combination of high-fat diet (HFD) and streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 12 weeks, HFD fed and STZ injected rats exhibited depression-like behaviors and anxiety. It was associated with increased expression of pro-inflammatory cytokines like IL-6 and TNF-α, and reduced BDNF immunocontent in the hippocampal tissues. The T2DM-induced depression, anxiety, and neuroinflammatory markers were significantly inhibited by agmatine (10–20 mg/kg, i.p.), by once-daily administration during 9th to 12th week of the protocol. Agmatine levels were significantly reduced in the hippocampus of T2DM rats as compared to the normal fed (NF) control animals. In conclusion, the present study suggests the importance of endogenous agmatine in T2DM induced anxiety and depressive-like behavior in rats. The data projects agmatine as a potential therapeutic target for T2DM-associated depression, anxiety, and comorbidities.