# Valsartan Mitigates LPS-Induced Neuroinflammation and Cognitive Deficits via Modulation of RAS–ECS Crosstalk in Mice

## TL;DR

This study shows that valsartan reduces neuroinflammation and cognitive issues in mice by balancing the RAS and ECS systems.

## Contribution

The study reveals a novel mechanism of valsartan in modulating RAS–ECS crosstalk to combat LPS-induced neuroinflammation.

## Key findings

- Valsartan reduced Aβ 1–42 by 53% and AChE activity by 73% in LPS-treated mice.
- It inhibited TLR4 and TNF-α/NF-κB pathways, reducing neuroinflammation.
- Valsartan enhanced CB1R expression and restored antioxidant defenses via AKT and HO-1.

## Abstract

Neuroinflammation is a critical aspect implicated in cognitive dysfunctions and neurodegenerative ailments such as Alzheimer’s disease (AD). β-amyloid (Aβ) peptide deposits and alterations in behavior and memory are important contributors to neuro-inflammatory pathways. The renin-angiotensin system (RAS) and endocannabinoid system (ECS) play a vital role in the pathophysiology of AD. The aim of this study is to illuminate the ameliorative effect of the antihypertensive drug valsartan (VAL) against lipopolysaccharide (LPS)-induced AD and study the cross-talk between ECS and RAS. Thirty two male Swiss mice were randomly divided into 4 groups as follows: Normal control group; LPS group (250 µg/kg; ip); valsartan groups (20 and 40 mg/kg; po). All treatments continued daily with LPS for seven consecutive days. Neuroprotective effects exerted by VAL are emphasized by improving motor functions and enhancing animal performance via the activity cage and Y-maze behavioral tests respectively. VAL inhibited toll-like receptor 4 (TLR4), which in turn deactivated the tumor necrosis factor-α (TNF-α)/nuclear factor kappa-B (NF-κB) inflammatory pathway together with a reduction of angiotensin-1 receptor (AT1R1) levels as compared to LPS-injected animals. Additionally, VAL improved neuronal and cognitive dysfunction by reducing acetylcholine esterase activity (AChE) by 73% and amyloid beta (Aβ 1–42) by 53%, along with an elevation in the expression of cannabinoid 1 receptor (CB1R). Moreover, VAL enhanced the expression of protein kinase B (AKT) and heme oxygenase-1 (HO-1) gene levels and consequently restored the antioxidant cellular defense mechanism. VAL ultimately combats against microglial activation, mitigates cognitive dysfunction, and halts the neurodegenerative perturbations of LPS via inhibiting Aβ deposition, neuroinflammation, and RAS with stimulation of ECS.