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Systematic administration of iptakalim, an ATP-sensitive potassium channel opener, prevents rotenone-induced motor and neurochemical alterations in rats.
- Source :
-
Journal of neuroscience research [J Neurosci Res] 2005 May 01; Vol. 80 (3), pp. 442-9. - Publication Year :
- 2005
-
Abstract
- Our previous studies revealed that iptakalim, a novel ATP-sensitive potassium channel opener, has a significant neuroprotective function against ischemia in vivo or rotenone-induced neurotoxicity in vitro. To investigate the potential pharmaceutical benefit of ATP-sensitive potassium channel openers on neurodegenerative diseases, we studied the effects of iptakalim and diazoxide, a selective mitochondrial ATP-sensitive potassium channel opener, on the rotenone-induced nigrostriatal degeneration in rats. Iptakalim (1.5 mg/kg/day, orally) or diazoxide (1.5 mg/kg/day, orally) alone was administered to rats for 3 days, and then for 4 weeks was used daily with an injection of rotenone (2.5 mg/kg/day, subcutaneously) 1 hr later each time. The results showed that rotenone-infused rats exhibited parkinsonian symptoms and had dopamine depletion in the striatum and substantia nigra. Pretreatment with iptakalim or diazoxide prevented rotenone-induced catalepsy and the reduction of striatum dopamine contents. Moreover, iptakalim and diazoxide reduced the enzymatic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. These neuroprotective effects of iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium channel blocker. In conclusion, our data suggested that mitochondrial ATP-sensitive potassium channels might play a key role in preventing both parkinsonian symptoms and neurochemistry alterations induced by rotenone in rats. The selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for prevention and treatment of neurodegenerative disorders such as Parkinson's disease.<br /> (2005 Wiley-Liss, Inc.)
- Subjects :
- ATP-Binding Cassette Transporters metabolism
Adenosine Triphosphate metabolism
Animals
Basal Ganglia drug effects
Basal Ganglia metabolism
Basal Ganglia physiopathology
Brain metabolism
Brain physiopathology
Brain Chemistry drug effects
Brain Chemistry physiology
Catalepsy chemically induced
Catalepsy drug therapy
Catalepsy prevention & control
Diazoxide pharmacology
Disease Models, Animal
Dopamine metabolism
Down-Regulation drug effects
Down-Regulation physiology
Drug Administration Schedule
Male
Nerve Tissue Proteins drug effects
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Nitric Oxide Synthase drug effects
Nitric Oxide Synthase genetics
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type I
Parkinsonian Disorders chemically induced
Parkinsonian Disorders metabolism
Potassium Channel Blockers pharmacology
Potassium Channels, Inwardly Rectifying metabolism
RNA, Messenger drug effects
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Rotenone pharmacology
Uncoupling Agents antagonists & inhibitors
Uncoupling Agents pharmacology
ATP-Binding Cassette Transporters agonists
Brain drug effects
Neuroprotective Agents pharmacology
Parkinsonian Disorders drug therapy
Potassium Channels, Inwardly Rectifying agonists
Propylamines pharmacology
Rotenone antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0360-4012
- Volume :
- 80
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of neuroscience research
- Publication Type :
- Academic Journal
- Accession number :
- 15795934
- Full Text :
- https://doi.org/10.1002/jnr.20467