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Systematic administration of iptakalim, an ATP‐sensitive potassium channel opener, prevents rotenone‐induced motor and neurochemical alterations in rats
Author(s) -
Yang Yong,
Liu Xing,
Long Yan,
Wang Fang,
Ding JianHua,
Liu SuYi,
Sun YeHong,
Yao HongHong,
Wang Hai,
Wu Jie,
Hu Gang
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20467
Subject(s) - rotenone , diazoxide , pharmacology , neuroprotection , chemistry , potassium channel , potassium channel opener , atp sensitive potassium channel , striatum , dopamine , mitochondrion , endocrinology , biochemistry , medicine , glibenclamide , diabetes mellitus , insulin
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.