Neuroprotective effects of metformin on traumatic brain injury in rats is associated with the AMP-activated protein kinase signaling pathway.
AMP-Activated Protein Kinases
/ antagonists & inhibitors
Animals
Blood-Brain Barrier
/ drug effects
Brain
/ drug effects
Brain Injuries, Traumatic
/ drug therapy
Disease Models, Animal
Enzyme Inhibitors
/ pharmacology
Male
Metformin
/ pharmacology
Neuroprotective Agents
/ pharmacology
Phosphorylation
/ drug effects
Rats
Rats, Wistar
Signal Transduction
/ drug effects
AMPK
BBB disruption
Compound C
Metformin
Neuroprotective
TBI
Journal
Metabolic brain disease
ISSN: 1573-7365
Titre abrégé: Metab Brain Dis
Pays: United States
ID NLM: 8610370
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
23
12
2019
accepted:
29
06
2020
pubmed:
6
7
2020
medline:
21
8
2021
entrez:
5
7
2020
Statut:
ppublish
Résumé
Metformin is an activator of AMP-activated protein kinase (AMPK). Thus, it has the potential to restore energy in damaged neurons and attenuate secondary brain damage due to traumatic brain injury (TBI). This study aims to investigate the potential neuroprotective effects of metformin through the energy balance reestablishment in acute severe brain injury after TBI and explore the underlying mechanisms. Male Wistar rats were divided into eight groups. The veterinary coma scale (VCS) was used to assess short-term neurological deficits. Blood-Brain barrier (BBB) disruption was evaluated by Evans Blue method 6 h post-injury. Vestibulomotor function was evaluated by beam-walk and beam-balance methods. Brain water content and brain tissue phosphorylated and total AMPK were assessed by the wet/dry method and enzyme-linked immunosorbent assay (ELISA), respectively. In order to eliminate the effect of AMPK, compound C was used as an AMPK inhibitor. The presented study showed that TBI has led to significant brain edema, BBB disruption, neurological deficit, vestibulomotor dysfunction and decrease AMPK phosphorylation in the rat brain. Metformin (100 and 200 mg/kg doses) attenuated brain edema, improved BBB and vestibulomotor dysfunction compared to TBI or Vehicle groups (P < 0.001). Furthermore, the p-AMPK/AMPK ratio was increased by metformin administration compare to TBI or Vehicle groups (p < 0.0001). Inhibition of AMPK by compound C abolished Metformin neuroprotective effects (P < 0.05 compared to Met 200 group). This study suggests that metformin inhibits TBI-mediated secondary injury via phosphorylation of AMPK and improves neurobehavioral function following TBI, which provides a potential therapeutic opportunity in the treatment of TBI.
Identifiants
pubmed: 32621159
doi: 10.1007/s11011-020-00594-3
pii: 10.1007/s11011-020-00594-3
doi:
Substances chimiques
Enzyme Inhibitors
0
Neuroprotective Agents
0
Metformin
9100L32L2N
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1135-1144Références
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