n-(1-methylethyl)-1-1-2-trimethylpropylamine and Parkinsonian-Disorders

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.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Catalepsy; Decanoic Acids; Diazoxide; Disease Models, Animal; Dopamine; Hydroxy Acids; Levodopa; Male; Motor Activity; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Parkinsonian Disorders; Potassium Channel Blockers; Potassium Channels; Propylamines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotenone; Substantia Nigra

The function of ATP-sensitive potassium (KATP) channels in nigrostriatal pathway in Parkinson's disease (PD) was studied by employing a novel KATP channel opener iptakalim (Ipt). Apomorphine-induced rotation behavior test and microdialysis experiment were carried out in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Behavior test showed that systemic administration of Ipt failed to significantly alleviate apomorphine-induced rotation in unilateral 6-OHDA-lesioned PD model rats. However, using in vivo microdialysis in this PD model rats, it was found that Ipt could increase extracellular dopamine levels in the lesioned side of the striatum and decrease dopamine levels in the intact side of the striatum. Meanwhile, Ipt had no influence on glutamate levels in the intact side, but it did decrease glutamate levels in the lesioned side of the striatum of PD rats. Additionally, in primary cultured rat astrocytes, 6-OHDA decreased overall glutamate uptake activity, but this decrease was recovered and glutamate uptake activity was restored by the opening of KATP channels induced by Ipt and pinacidil. The classical KATP channel blocker glibenclamide completely abolished the effects of Ipt and pinacidil. The present study suggests that (i) the function of KATP channels in the lesioned and intact nigrostriatal pathway is different in unilateral 6-OHDA-lesioned PD model rats. (ii) KATP channels regulate extracellular neurotransmitter levels in the striatum of unilateral 6-OHDA-lesioned rats and may play neuroprotective roles due to their effects on glutamate transporters.

Topics: Adenosine Triphosphate; Animals; Antihypertensive Agents; Apomorphine; Astrocytes; Cells, Cultured; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Agonists; Extracellular Fluid; Glutamic Acid; Male; Microdialysis; Neurotransmitter Agents; Parkinsonian Disorders; Pinacidil; Potassium Channels, Inwardly Rectifying; Presynaptic Terminals; Propylamines; Rats; Rats, Sprague-Dawley; Synaptic Transmission

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.

Topics: Adenosine Triphosphate; Animals; ATP-Binding Cassette Transporters; Basal Ganglia; Brain; Brain Chemistry; Catalepsy; Diazoxide; Disease Models, Animal; Dopamine; Down-Regulation; Drug Administration Schedule; Male; Nerve Tissue Proteins; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Parkinsonian Disorders; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotenone; Uncoupling Agents

Iptakalim hydrochloride (Ipt), a novel antihypertensive drug, exhibits K(ATP) channel activation. Here, we report that Ipt remarkably protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models. Chronic exposure of cultured PC12 cells to neurotoxins, such as 6-OHDA, MPP+, or rotenone, decreased overall [3H]-glutamate uptake in a concentration-dependent manner. Pre-treatment using 10 microM Ipt significantly protected cells against neurotoxin-induced glutamate uptake diminishment, and this protection was abolished by the K(ATP) channel blocker glibenclamide (20 microM), suggesting that the protective mechanisms may involve the opening of K(ATP) channels. In 6-OHDA-treated rats (as an in vivo Parkinson's disease model), [3H]-glutamate uptake was significantly lower in synaptosomes isolated from the striatum and cerebral cortex, but not the hippocampus. Pre-conditioning using 10, 50, and 100 microM Ipt significantly restored glutamate uptake impairment and these protections were abolished by blockade of K(ATP) channels. It is concluded that Ipt exhibits substantial protection of cells against neurotoxicity in in vitro and in vivo models. The cellular mechanisms of this protective effect may involve the opening of K(ATP) channels. Collectively, Ipt may serve as a novel and effective drug for PD therapy.

Topics: Amino Acid Transport System X-AG; Animals; Cerebral Cortex; Disease Models, Animal; Glutamic Acid; Male; Neostriatum; Neuroprotective Agents; Neurotoxins; Parkinsonian Disorders; PC12 Cells; Potassium Channels; Propylamines; Rats; Rats, Sprague-Dawley; Synaptosomes