Activation of mitochondrial ATP-sensitive potassium channels improves rotenone-related motor and neurochemical alterations in rats.
Our previous studies revealed that activation of mitochondrial ATP-sensitive potassium channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive potassium-channel opener, and diazoxide, a selective mitochondrial ATP-sensitive potassium-channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium-channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive potassium channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.
Yang
Yong
Y
Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
Liu
Xing
X
Long
Yan
Y
Wang
Fang
F
Ding
Jian-Hua
JH
Liu
Su-Yi
SY
Sun
Ye-Hong
YH
Yao
Hong-Hong
HH
Wang
Hai
H
Wu
Jie
J
Hu
Gang
G
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001479:Basal Ganglia / Q000201:enzymology; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D003652:Decanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D003981:Diazoxide / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006880:Hydroxy Acids / Q000008:administration & dosage / Q000494:pharmacology; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone; D013378:Substantia Nigra / Q000201:enzymology
D000978:Antiparkinson Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011437:Propylamines; D012333:RNA, Messenger; C117780:mitochondrial K(ATP) channel; D012402:Rotenone; D007980:Levodopa; C052853:5-hydroxydecanoic acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; D003981:Diazoxide; D004298:Dopamine