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Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system.

The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling