GLP-1R knockdown abrogates the protective effects of liraglutide on ischaemic stroke via inhibition of M2 polarisation and activation of NLRP3 inflammasome by reducing Nrf2 activation.
Male
Rats
Animals
Liraglutide
/ pharmacology
NF-E2-Related Factor 2
/ metabolism
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Brain Ischemia
/ drug therapy
Brain Edema
/ drug therapy
Lipopolysaccharides
/ pharmacology
Rats, Sprague-Dawley
Stroke
/ drug therapy
Ischemic Stroke
Infarction, Middle Cerebral Artery
/ drug therapy
GLP-1R
Ischemic stroke
Liraglutide
Neuroprotection
Nrf2
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
01 10 2023
01 10 2023
Historique:
received:
21
03
2023
revised:
18
05
2023
accepted:
23
05
2023
medline:
14
7
2023
pubmed:
27
5
2023
entrez:
26
5
2023
Statut:
ppublish
Résumé
Liraglutide has been recently discovered to penetrate the blood-brain barrier to exert neuroprotective effects. However, relevant mechanisms of the protective effects of liraglutide on ischaemic stroke remain to be elucidated. This study examined the mechanism of GLP-1R in regulating the protective effect of liraglutide against ischaemic stroke. Middle cerebral artery occlusion (MCAO) male Sprague-Dawley rat model with/without GLP-1R or Nrf2 knockdown was established and subjected to liraglutide treatment. Then neurological deficit and brain oedema of rats was evaluated and brain tissues were subjected to TTC, Nissl, TUNEL and immunofluorescence staining. Rat primary microglial cells firstly underwent lipopolysaccharide (LPS) treatment, then GLP-1R or Nrf2 knockdown treatment, and finally Liraglutide treatment to research the NLRP3 activation. As a result, Liraglutide protected rats' brain tissues after MCAO, which attenuated brain oedema, infarct volume, neurological deficit score, neuronal apoptosis and Iba1 expression but enhanced live neurons. However, GLP-1R knockdown abrogated these protective effects of liraglutide on MCAO rats. According to in vitro experiments, Liraglutide promoted M2 polarisation, activated Nrf2 and inhibited NLRP3 activation in LPS-induced microglial cells, but GLP-1R or Nrf2 knockdown reversed these effects of Liraglutide on LPS-induced microglial cells. Further, Nrf2 knockdown counteracted the protection of liraglutide on MCAO rats, whereas sulforaphane (agonist of Nrf2) counteracted the effect of Nrf2 knockdown on liraglutide-treated MCAO rats. Collectively, GLP-1R knockdown abrogated the protection of liraglutide on MCAO rats by activating NLRP3 via inactivating Nrf2.
Identifiants
pubmed: 37236529
pii: S0028-3908(23)00193-4
doi: 10.1016/j.neuropharm.2023.109603
pii:
doi:
Substances chimiques
Liraglutide
839I73S42A
NF-E2-Related Factor 2
0
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Lipopolysaccharides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109603Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose.