Angiotensin Receptor Blockers as an Alternative Strategy for Addressing Neurodegeneration in a LPS Mice Model

Abstract

AbstractBackgroundTo identify new therapeutic strategies that impair the development of Alzheimer’s disease (AD), angiotensin receptor blockers (ARB) were investigated as promising candidates to reduce the risk of developing AD in hypertensive patients. However, the mechanism by which they are able to induce this effect remains unclear. On the other hand, it has been described that neuroinflammation plays an important role in neurodegenerative diseases, including AD, being key in the cognitive decline process. Therefore, the aim of this study is to evaluate the neuroprotective effect of ARB in in vivo and in vitro models of neuroinflammation induced by Lipopolysaccharide (LPS) and to disclose their mechanism of action.MethodBV‐2 microglia cell line was exposed to LPS and treated with the ARB. Meanwhile, 7–8‐week‐old C57/BL6 male exposed to LPS were used as a neuroinflammation model. Animals were treated with saline or intranasal ARB (40 mg/kg/day) for 10 days and LPS (1 mg/kg) was injected in last day, 24h before sacrifice. Before euthanizing, long‐term memory was evaluated by Novel Object Recognition test (NORT). Afterwards, analysis of the dendritic spines, neuroinflammation and molecules related to neurodegeneration and cognitive decline was performed.ResultOur results show a beneficial effect of ARB in neuroinflammation by reverting the memory loss observed in mice that received a LPS injection. This beneficial effect is also correlated to an amelioration of the synapsis dysfunction by the activation of pathways involved in neuroprotection, namely the PI3K/AKT pathway and by differences in spine density. Moreover, molecular studies show that previous treatment with ARB is able to stimulate the anti‐oxidant defense system by increasing SOD2 and Gpx‐1. Also, LPS increased neuroinflammatory markers that were significantly reduced in the ARB group as well as apoptotic factors that were decreased with the treatment. Therefore, contributing to the maintenance of cognitive function avoiding the development of neurodegenerative processes.ConclusionIn conclusion, results demonstrate that intranasal administration of ARB prevents LPS‐induced cognitive decline, through the reduction of neuroinflammation and the activation of neuroprotective pathways, highlighting the potential of ARB in the prevention of AD and other neurodegenerative diseases.