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

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 16; p. 5068
• Main Authors: Mohamed, Reem A, Abdallah, Dalaal M, El-Brairy, Amany I, Ahmed, Kawkab A, El-Abhar, Hanan S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.08.2021; MDPI
• Subjects: 5-HT3 receptor blocker; Acetylcholine receptors (nicotinic); Aconitine - analogs & derivatives; Aconitine - pharmacology; Adapter proteins; Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - genetics; Animals; Brain; CARD Signaling Adaptor Proteins - genetics; Caspase-1; caspase-1/IL-1β/IL-18; Caspase-11; Cognition; Cognition - drug effects; Cognitive ability; Cytokines; Dementia; Diabetes; Diet; Diet, Western - adverse effects; Disease Models, Animal; Glial fibrillary acidic protein; High fat diet; Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Humans; inflammasome; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - pathology; Insulin; Insulin resistance; Insulin Resistance - genetics; Interleukin 18; Interleukin-18 - genetics; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Memory; Memory tasks; Methyllycaconitine; Microglia; Microglia - drug effects; Microglia - pathology; Neurodegeneration; Neuroprotection; Palonosetron - pharmacology; Pathogenesis; Pattern recognition; Peptide Fragments - genetics; Peptides; Phenotypes; Pyroptosis; Pyroptosis - drug effects; Rats; Receptors, Serotonin, 5-HT3 - genetics; Recovery of function; Resistance factors; Risk analysis; Risk Factors; Serotonin S3 receptors; Spatial analysis; Spatial memory; Spatial Memory - drug effects; α7AChR; pyroptosis; caspase-1/IL-1β/IL-18; α7AChR; microglia; inflammasome; 5-HT3 receptor blocker
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26165068

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.