PMID- 34354662
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240403
IS  - 1664-2295 (Print)
IS  - 1664-2295 (Electronic)
IS  - 1664-2295 (Linking)
VI  - 12
DP  - 2021
TI  - Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and 
      Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.
PG  - 689069
LID - 10.3389/fneur.2021.689069 [doi]
LID - 689069
AB  - Epilepsy is a complex neurological disorder, characterized by frequent electrical 
      activity in brain regions. Inflammation and apoptosis cascade activation are 
      serious neurological sequelae during seizures. Fisetin (3, 
      3',4',7-tetrahydroxyflavone), a flavonoid molecule, is considered for its 
      effective anti-inflammatory and anti-apoptotic properties. This study 
      investigated the neuroprotective effect of fisetin on experimental epilepsy. For 
      acute studies, increasing current electroshock (ICES) and pentylenetetrazole 
      (PTZ)-induced seizure tests were performed to evaluate the antiseizure activity 
      of fisetin. For the chronic study, the kindling model was established by the 
      administration of PTZ in subconvulsive dose (25 mg/kg, i.p.). Mice were treated 
      with fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable antiseizure 
      mechanism. The kindled mice were evaluated for seizure scores. Their hippocampus 
      and cortex were assessed for neuronal damage, inflammation, and apoptosis. 
      Histological alterations were observed in the hippocampus of the experimental 
      mice. Levels of high mobility group box 1 (HMGB1), Toll-like receptor-4 (TLR-4), 
      interleukin-1 receptor 1 (IL-1R1), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), 
      and tumor necrosis factor-alpha (TNF-alpha) were assessed in the hippocampus and cortex 
      by ELISA. The immunoreactivity and mRNA expressions of nuclear factor-kappaB (NF-kappaB), 
      cyclooxygenase-2 (COX-2), cytochrome C, and caspase-3 were quantified by 
      immunohistochemical analysis and real-time PCR. Phosphorylation ELISA was 
      performed to evaluate AkT/mTOR (mammalian target of rapamycin) activation in the 
      hippocampus and cortex of the kindled mice. The results showed that fisetin 
      administration increased the seizure threshold current (STC) in the ICES test. In 
      PTZ-induced seizures, fisetin administration increased the latency for myoclonic 
      jerks (MJs) and generalized seizures (GSs). In the PTZ-induced kindling model, 
      fisetin administration dose-dependently suppressed the development of kindling 
      and the associated neuronal damage in the experimental mice. Further, fisetin 
      administration ameliorated kindling-induced neuroinflammation as evident from 
      decreased levels of HMGB1, TLR-4, IL-1R1, IL-1beta, IL-6, and TNF-alpha in the 
      hippocampus and cortex of the kindled mice. Also, the immunoreactivity and mRNA 
      expressions of inflammatory molecules, NF-kappaB, and COX-2 were decreased with 
      fisetin administration in the kindled animals. Decreased phosphorylation of the 
      AkT/mTOR pathway was reported with fisetin administration in the hippocampus and 
      cortex of the kindled mice. The immunoreactivity and mRNA expressions of 
      apoptotic molecules, cytochrome C, and caspase-3 were attenuated upon fisetin 
      administration. The findings suggest that fisetin shows a neuroprotective effect 
      by suppressing the release of inflammatory and apoptosis molecules and 
      attenuating histological alterations during experimental epilepsy.
CI  - Copyright (c) 2021 Khatoon, Agarwal, Samim and Alam.
FAU - Khatoon, Saima
AU  - Khatoon S
AD  - Department of Medical Elementology and Toxicology, School of Chemical and Life 
      Sciences, Jamia Hamdard, New Delhi, India.
FAU - Agarwal, Nidhi Bharal
AU  - Agarwal NB
AD  - Centre for Translational and Clinical Research, School of Chemical and Life 
      Sciences, Jamia Hamdard, New Delhi, India.
FAU - Samim, Mohammed
AU  - Samim M
AD  - Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New 
      Delhi, India.
FAU - Alam, Ozair
AU  - Alam O
AD  - Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and 
      Research, Jamia Hamdard, New Delhi, India.
LA  - eng
PT  - Journal Article
DEP - 20210721
PL  - Switzerland
TA  - Front Neurol
JT  - Frontiers in neurology
JID - 101546899
PMC - PMC8333701
OTO - NOTNLM
OT  - caspase-3
OT  - epilepsy
OT  - fisetin
OT  - interleukin
OT  - pentylenetetrazole
OT  - toll like receptor-4
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/08/07 06:00
MHDA- 2021/08/07 06:01
PMCR- 2021/07/21
CRDT- 2021/08/06 06:49
PHST- 2021/03/31 00:00 [received]
PHST- 2021/06/14 00:00 [accepted]
PHST- 2021/08/06 06:49 [entrez]
PHST- 2021/08/07 06:00 [pubmed]
PHST- 2021/08/07 06:01 [medline]
PHST- 2021/07/21 00:00 [pmc-release]
AID - 10.3389/fneur.2021.689069 [doi]
PST - epublish
SO  - Front Neurol. 2021 Jul 21;12:689069. doi: 10.3389/fneur.2021.689069. eCollection 
      2021.