Intranasal irbesartan reverts cognitive decline and activates the PI3K/AKT pathway in an LPS-induced neuroinflammation mice model

Abstract

<p> <strong style="color:black">Background:</strong><span style="color:black"> New strategies are urgently needed to manage and delay the development of Alzheimer’s disease (AD). Neuroinflammation is a significant contributor to cognitive decline in neurodegenerative diseases, including AD. Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) protect hypertensive patients against AD, but the cellular and molecular mechanisms underlying these effects remain unknown.</span><span style="color:rgb( 34 , 34 , 34 )"> </span><span style="color:black">In light of this, the protective effects of three ARBs and three ACEIs against neuroinflammation and cognitive decline were investigated through comprehensive pharmacological </span><em style="color:black">in vitro</em><span style="color:black">/</span><em style="color:black">in vivo</em><span style="color:black"> screening.</span></p><p> <strong style="color:black">Methods:</strong><span style="color:black"> BV-2 microglia cells were exposed to lipopolysaccharide (LPS) and treated with ARBs and ACEIs to provide initial insights into the anti-inflammatory properties of the drugs. Subsequently, irbesartan was selected, and its efficacy was evaluated in C57/BL6 male mice intranasally administered irbesartan and injected with LPS. Long-term memory and depressive-like behavior were evaluated; dendritic spines were measured as well as neuroinflammation, neurodegeneration and cognitive decline biomarkers.</span></p><p> <strong style="color:black">Results: </strong><span style="color:black">Irbesartan mitigated memory loss and depressive-like behavior in mice treated with LPS, probably because it increased spine density, ameliorated synapsis dysfunction and activated the PI3K/AKT pathway. Irbesartan elevated the levels of hippocampal superoxide dismutase 2 and glutathione peroxidase and </span><span style="color:rgb( 34 , 34 , 34 )">suppressed LPS-induced astrogliosis.</span></p><p> <strong style="color:black">Conclusions:</strong><span style="color:black"> Overall, this study provides compelling evidence that multiple intranasal administrations of irbesartan can effectively prevent LPS-induced cognitive decline by activating pathways involved in neuroprotection and anti-inflammatory events. These findings underscore the potential of irbesartan as a preventive strategy against the development of AD and other neurodegenerative conditions associated with neuroinflammation.</span></p>