Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice.
Animals
Atrophy
Blood Glucose
Cicatrix
Diabetes Mellitus, Experimental
/ drug therapy
Diabetes Mellitus, Type 2
/ drug therapy
Exenatide
/ pharmacology
Glucagon-Like Peptide-1 Receptor
/ metabolism
Infarction, Middle Cerebral Artery
/ drug therapy
Insulin Resistance
Male
Mice
Parvalbumins
/ metabolism
Stroke
/ drug therapy
Vascular Remodeling
GLP-1R agonist
T2D
fibrotic scar
neurological recovery
stroke
vascular remodelling
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
revised:
30
03
2021
received:
08
02
2021
accepted:
27
04
2021
pubmed:
12
5
2021
medline:
14
4
2022
entrez:
11
5
2021
Statut:
ppublish
Résumé
Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor. Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D. This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice.
EXPERIMENTAL APPROACH
METHODS
We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry.
KEY RESULTS
RESULTS
Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor.
CONCLUSION AND IMPLICATIONS
CONCLUSIONS
Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.
LINKED ARTICLES
BACKGROUND
This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.
Identifiants
pubmed: 33973246
doi: 10.1111/bph.15524
pmc: PMC8820185
doi:
Substances chimiques
Blood Glucose
0
Glucagon-Like Peptide-1 Receptor
0
Parvalbumins
0
Exenatide
9P1872D4OL
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
677-694Informations de copyright
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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