Nrf2/HO-1 mediates the neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury in rats.
Adenosine Triphosphate
/ metabolism
Animals
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ metabolism
Behavior, Animal
/ drug effects
Brain
/ drug effects
Brain Injuries, Traumatic
/ drug therapy
Disease Models, Animal
Heme Oxygenase (Decyclizing)
/ metabolism
Lipid Peroxidation
/ drug effects
Male
Membrane Potential, Mitochondrial
/ drug effects
Mitochondria
/ drug effects
NF-E2-Related Factor 2
/ metabolism
Neuroprotective Agents
/ pharmacology
Oxidative Stress
/ drug effects
Pramipexole
/ pharmacology
Rats, Wistar
Reactive Oxygen Species
/ metabolism
Signal Transduction
Mitochondrial dysfunction
Neuroprotection
Nrf2
Oxidative damage
Pramipexole
Traumatic brain injury
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
19 08 2020
19 08 2020
Historique:
received:
21
03
2020
accepted:
26
05
2020
pubmed:
17
6
2020
medline:
24
8
2021
entrez:
17
6
2020
Statut:
epublish
Résumé
Pramipexole (PPX), a D2-like receptor agonist, is generally used in the treatment of Parkinson's disease and restless leg syndrome. Its neuroprotective effects have been shown against various neurological disorders. Recent research work has demonstrated that PPX exerts neuroprotection through mitochondria. However, the neuromodulator-related effects of PPX against traumatic brain injury (TBI) remain unexplored. The present study, therefore, investigated the mechanism of neuroprotection by PPX against oxidative stress, mitochondrial dysfunction and neuronal damage following TBI in rats. We hypothesized that the neuroprotection by PPX in TBI-subjected rats might involve activation of the Nrf2/HO-1 (also known as Nfe2l2/Hmox1) signaling pathway. PPX was injected intraperitoneally (0.25 mg/kg body weight and 1.0 mg/kg body weight) at different time intervals post-TBI. Several neurobehavioral parameters were assessed at 48 h post-TBI, and the brain was isolated for molecular and biochemical analysis. The results demonstrated that PPX treatment significantly improved the behavioral deficits, decreased the lipid peroxidation rate, increased glutathione levels and decreased 4-hydroxynonenal levels in TBI-subjected rats. PPX also increased the activities of glutathione peroxidase and superoxide dismutase enzymes. In addition, PPX treatment inhibited mitochondrial reactive oxygen species production, restored mitochondrial membrane potential and increased ATP levels after a TBI. Further, PPX treatment reduced the Bax/Bcl2 ratio and translocation of Bax to mitochondria and cytochrome-c to the cytosol. Finally, PPX treatment greatly accelerated the translocation of Nrf2 to the nucleus and upregulated HO-1 protein expression. We conclude that the neuroprotective effects of PPX are mediated by activation of the Nrf2/HO-1 signaling pathway following TBI.This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 32540990
pii: dmm.045021
doi: 10.1242/dmm.045021
pmc: PMC7449795
pii:
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
NF-E2-Related Factor 2
0
Neuroprotective Agents
0
Nfe2l2 protein, rat
0
Reactive Oxygen Species
0
Pramipexole
83619PEU5T
Adenosine Triphosphate
8L70Q75FXE
Heme Oxygenase (Decyclizing)
EC 1.14.14.18
Hmox1 protein, rat
EC 1.14.14.18
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing or financial interests.
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