Iptakalim hydrochloride protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models.

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.

[Relationship between neurotoxicity of 6-hydroxydopamine and glutamate transport].

AIM: To study the relationship of neurotoxicity of 6-hydroxydopamine (6-OHDA) and the function of glutamate transporter. METHODS: Using in vivo microdialysis together with high performance liquid chromatography (HPLC) to detect the alteration of glutamate in the striatum and extracellular fluid of the PC12 cell. The rate of apoptosis and the activity of PC12 cells are read in a flow cytometer and a photometer for enzyme-labeled assays. The function of glutamate transporter is decided by detecting the ability of L-[3H]-glutamate uptake. RESULTS: 6-OHDA was shown to induce apoptosis and decrease the activity of PC12 cells. Increased release of glutamate was also found in PC12 cells and the injured striatum of the PD rats. But glutamate uptake in PC12 cells and rat striatum synaptosomes are inhibited obviously. CONCLUSION: The neurotoxicity of 6-hydroxydopamine is associated with declined function of glutamate transporters, which may be one important pathogenesis mechanisms of Parkinson's disease.