title: Iptakalim hydrochloride protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models.
abstract: 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.
authors.affiliation: Department of Pharmacology and Neurobiology, Nanjing Medical University, 140 HanZhong Road, Nanjing City, Jiangsu Province 210029, PR China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Yang
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Meng
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: He
authors.forename: Kevin
authors.initials: K
authors.lastname: Ellsworth
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D009498:Neurotoxins; D015221:Potassium Channels; D011437:Propylamines; D018698:Glutamic Acid