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Article

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

1
Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts, 26 July Mehwar Road Intersection with Wahat Road, 6th of October City, Giza 12451, Egypt
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Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str., Cairo 11562, Egypt
3
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
*
Author to whom correspondence should be addressed.
Academic Editors: Alejandro Samhan-Arias and Clementina Manera
Molecules 2021, 26(16), 5068; https://doi.org/10.3390/molecules26165068
Received: 21 June 2021 / Revised: 10 August 2021 / Accepted: 17 August 2021 / Published: 21 August 2021
(This article belongs to the Special Issue Chemical Processes in Degenerative Diseases)
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. View Full-Text
Keywords: 5-HT3 receptor blocker; inflammasome; pyroptosis; caspase-1/IL-1β/IL-18; microglia; α7AChR 5-HT3 receptor blocker; inflammasome; pyroptosis; caspase-1/IL-1β/IL-18; microglia; α7AChR
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MDPI and ACS Style

Mohamed, R.A.; Abdallah, D.M.; El-brairy, A.I.; Ahmed, K.A.; El-Abhar, H.S. Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation. Molecules 2021, 26, 5068. https://doi.org/10.3390/molecules26165068

AMA Style

Mohamed RA, Abdallah DM, El-brairy AI, Ahmed KA, El-Abhar HS. Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation. Molecules. 2021; 26(16):5068. https://doi.org/10.3390/molecules26165068

Chicago/Turabian Style

Mohamed, Reem A., Dalaal M. Abdallah, Amany I. El-brairy, Kawkab A. Ahmed, and Hanan S. El-Abhar 2021. "Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation" Molecules 26, no. 16: 5068. https://doi.org/10.3390/molecules26165068

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