Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation
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)-fe...
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MDPI AG
2021-08-01
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| Online Access: | https://www.mdpi.com/1420-3049/26/16/5068 |
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| author | Reem A. Mohamed Dalaal M. Abdallah Amany I. El-brairy Kawkab A. Ahmed Hanan S. El-Abhar |
| author_facet | Reem A. Mohamed Dalaal M. Abdallah Amany I. El-brairy Kawkab A. Ahmed Hanan S. El-Abhar |
| author_sort | Reem A. Mohamed |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:31:53Z |
| format | Article |
| id | doaj.art-1bc8919a0dbf45b695249958cb674a7c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T08:31:53Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1bc8919a0dbf45b695249958cb674a7c2023-11-22T08:56:09ZengMDPI AGMolecules1420-30492021-08-012616506810.3390/molecules26165068Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of NeuroinflammationReem A. Mohamed0Dalaal M. Abdallah1Amany I. El-brairy2Kawkab A. Ahmed3Hanan S. El-Abhar4Department 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, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str., Cairo 11562, EgyptDepartment 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, EgyptDepartment of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str., Cairo 11562, EgyptSince 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.https://www.mdpi.com/1420-3049/26/16/50685-HT3 receptor blockerinflammasomepyroptosiscaspase-1/IL-1β/IL-18microgliaα7AChR |
| spellingShingle | Reem A. Mohamed Dalaal M. Abdallah Amany I. El-brairy Kawkab A. Ahmed Hanan S. El-Abhar Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation Molecules 5-HT3 receptor blocker inflammasome pyroptosis caspase-1/IL-1β/IL-18 microglia α7AChR |
| title | Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation |
| title_full | Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation |
| title_fullStr | Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation |
| title_full_unstemmed | Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation |
| title_short | Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation |
| title_sort | palonosetron methyllycaconitine deactivate hippocampal microglia 1 inflammasome assembly and pyroptosis to enhance cognition in a novel model of neuroinflammation |
| topic | 5-HT3 receptor blocker inflammasome pyroptosis caspase-1/IL-1β/IL-18 microglia α7AChR |
| url | https://www.mdpi.com/1420-3049/26/16/5068 |
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