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.
2005 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / agonists*
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ATP-Binding Cassette Transporters / metabolism
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Adenosine Triphosphate / metabolism
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Animals
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Basal Ganglia / drug effects
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Basal Ganglia / metabolism
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Basal Ganglia / physiopathology
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Brain / drug effects*
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Brain / metabolism
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Brain / physiopathology
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Brain Chemistry / drug effects
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Brain Chemistry / physiology
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Catalepsy / prevention & control
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Diazoxide / pharmacology
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Disease Models, Animal
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Dopamine / metabolism
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Drug Administration Schedule
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Male
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuroprotective Agents / pharmacology*
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Nitric Oxide Synthase / drug effects
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type I
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / drug therapy*
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Parkinsonian Disorders / metabolism
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Potassium Channel Blockers / pharmacology
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Potassium Channels, Inwardly Rectifying / agonists*
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Potassium Channels, Inwardly Rectifying / metabolism
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Propylamines / pharmacology*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Rotenone / antagonists & inhibitors*
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Rotenone / pharmacology
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Uncoupling Agents / antagonists & inhibitors
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Uncoupling Agents / pharmacology
Substances
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ATP-Binding Cassette Transporters
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N-(1-methylethyl)-1,1,2-trimethylpropylamine
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Nerve Tissue Proteins
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Neuroprotective Agents
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Potassium Channel Blockers
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Potassium Channels, Inwardly Rectifying
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Propylamines
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RNA, Messenger
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Uncoupling Agents
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Rotenone
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Adenosine Triphosphate
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type I
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Nos1 protein, rat
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Diazoxide
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Dopamine