Neuroprotective Effect of Clobenpropit against Lipopolysaccharide-Induced Cognitive Deficits via Attenuating Neuroinflammation and Enhancing Mitochondrial Functions in Mice.

Vasudevan Mani,Abdel-Moneim Hafez Abdel-Moneim,Minhajul Arfeen,Ahmad Alhowail,Maha Aldubayan,Hussein M Ali

doi:10.3390/brainsci11121617

Vasudevan Mani, Abdel-Moneim Hafez Abdel-Moneim + Show 4 more

Open Access

https://doi.org/10.3390/brainsci11121617

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Journal: Brain sciences	Publication Date: Dec 8, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Qassim University, Mansoura University

Abstract

Clobenpropit (CLO), an antagonist on histamine H3 receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice.

Highlights

IntroductionNeuroinflammation is defined as one of the key contributors involved in several
Neuroinflammation is defined as one of the key contributors involved in severalCNS-related disorders including neurodegenerative diseases
Memory functions of LPS-challenged mice pre-treated with CLO were examined in terms of selected three behavioral parameters such as taken to consume all five bites (TTB), working memory error (WME), and reference memory error (RME) in the radial arm maze (RAM)

Summary

Introduction

Neuroinflammation is defined as one of the key contributors involved in several. The inflammatory process in the neuron has been shown to cause cell death and neurodegeneration in Parkinson’s (PD), Alzheimer’s (AD), and other neurodegenerative diseases [1,2]. Neuroinflammation and mitochondrial dysfunction have a key role in AD and other neurodegenerative-related disorders [3,4]. Neuroinflammation is mediated by several factors, including cytokines, prostaglandin E2, oxidative stress, and reactive nitrogen species [5]. Inflammatory mediators, the cytokine TNF-α, can change cellular mitochondrial metabolism by inhibiting mitochondrial oxidative phosphorylation and related ATP synthesis while initiating mitochondrial reactive oxygen species formation. On the other hand, when damaged mitochondria are not appropriately eliminated by mitophagy, their contents can leak into the cytosol and extracellular environment, aggravating the inflammatory responses in brain tissue [6]

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