Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation.

Reem A Mohamed,Dalaal M Abdallah,Kawkab A Ahmed,Hanan S El-Abhar,Amany I El-Brairy

doi:10.3390/molecules26165068

Reem A Mohamed, Dalaal M Abdallah + Show 3 more

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https://doi.org/10.3390/molecules26165068

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Abstract

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer’s disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia among neurodegenerative disorders, with around 90% of cases having a sporadic non-familial type [1].These patients usually present with more hippocampal volume loss, higher incidence of diabetes, obesity and circulatory disorders compared to the familial type [2]
In a previous work [21], we have proven that tropisetron, a 5-hydroxytryptamin (5-HT)3 receptor blocker, elevates the hippocampal levels of 5-HT in experimental animals; besides this, 5-HT3 receptor blockers were previously recorded to possess neuroprotective and anti-inflammatory effects [22]
high fat/high fructose diet (HFFD), LPS, and their combination caused comparable significantHFFD or (a)that hyperglycemia compared to normal fat diet a(NFD)

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia among neurodegenerative disorders, with around 90% of cases having a sporadic non-familial type [1]. These patients usually present with more hippocampal volume loss, higher incidence of diabetes, obesity and circulatory disorders compared to the familial type [2]. Though the deposition of senile plaques of beta amyloid peptide (Aβ) and neurofibrillary tangles (NFTs) is inevitably linked to AD pathogenesis [3], these biomarkers are not the causative factors for the disease progression, but rather are downstream cues of unrelated triggers [4]. LPS is known to trigger inflammation that partakes highly in the disease pathogenesis [6], a fact that supports the inflammatory neurodegenerative theory of non-familial

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