PMID- 34443654
OWN - NLM
STAT- MEDLINE
DCOM- 20210930
LR  - 20240403
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 26
IP  - 16
DP  - 2021 Aug 21
TI  - Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome 
      Assembly and Pyroptosis to Enhance Cognition in a Novel Model of 
      Neuroinflammation.
LID - 10.3390/molecules26165068 [doi]
LID - 5068
AB  - Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's 
      disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid beta 
      (Abeta)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 alpha7 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)-1beta, 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.
FAU - Mohamed, Reem A
AU  - Mohamed RA
AUID- ORCID: 0000-0001-7419-0124
AD  - 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.
FAU - Abdallah, Dalaal M
AU  - Abdallah DM
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kappaasr El-Aini Str., Cairo 11562, Egypt.
FAU - El-Brairy, Amany I
AU  - El-Brairy AI
AD  - 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.
FAU - Ahmed, Kawkab A
AU  - Ahmed KA
AUID- ORCID: 0000-0001-7376-7411
AD  - Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 
      12211, Egypt.
FAU - El-Abhar, Hanan S
AU  - El-Abhar HS
AUID- ORCID: 0000-0001-8819-9891
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kappaasr El-Aini Str., Cairo 11562, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20210821
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (CARD Signaling Adaptor Proteins)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-18)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (PYCARD protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Pycard protein, rat)
RN  - 0 (Receptors, Serotonin, 5-HT3)
RN  - 0 (amyloid beta-protein (1-40))
RN  - 21019-30-7 (methyllycaconitine)
RN  - 5D06587D6R (Palonosetron)
RN  - X8YN71D5WC (Aconitine)
SB  - IM
MH  - Aconitine/*analogs & derivatives/pharmacology
MH  - Alzheimer Disease/*drug therapy/etiology/genetics/pathology
MH  - Amyloid beta-Peptides/genetics
MH  - Animals
MH  - CARD Signaling Adaptor Proteins/genetics
MH  - Cognition/drug effects
MH  - Diet, Western/adverse effects
MH  - Disease Models, Animal
MH  - Hippocampus/drug effects/pathology
MH  - Humans
MH  - Inflammasomes/drug effects/metabolism
MH  - Inflammation/*drug therapy/genetics/pathology
MH  - Insulin Resistance/genetics
MH  - Interleukin-18/genetics
MH  - Lipopolysaccharides/pharmacology
MH  - Microglia/drug effects/pathology
MH  - Palonosetron/*pharmacology
MH  - Peptide Fragments/genetics
MH  - Pyroptosis/drug effects
MH  - Rats
MH  - Receptors, Serotonin, 5-HT3/genetics
MH  - Risk Factors
MH  - Spatial Memory/drug effects
PMC - PMC8401912
OTO - NOTNLM
OT  - 5-HT3 receptor blocker
OT  - caspase-1/IL-1beta/IL-18
OT  - inflammasome
OT  - microglia
OT  - pyroptosis
OT  - alpha7AChR
COIS- The authors declare no competing interests.
EDAT- 2021/08/28 06:00
MHDA- 2021/10/01 06:00
PMCR- 2021/08/21
CRDT- 2021/08/27 01:17
PHST- 2021/06/21 00:00 [received]
PHST- 2021/08/10 00:00 [revised]
PHST- 2021/08/17 00:00 [accepted]
PHST- 2021/08/27 01:17 [entrez]
PHST- 2021/08/28 06:00 [pubmed]
PHST- 2021/10/01 06:00 [medline]
PHST- 2021/08/21 00:00 [pmc-release]
AID - molecules26165068 [pii]
AID - molecules-26-05068 [pii]
AID - 10.3390/molecules26165068 [doi]
PST - epublish
SO  - Molecules. 2021 Aug 21;26(16):5068. doi: 10.3390/molecules26165068.