| Parkinson's disease (PD) is a common neurodegenerative disorder characterized mainly by resting tremor, slowness of movement, rigidity, and postural instability and associated with a dramatic loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc) and the appearance of Lewy bodies. The pathophysiological hallmark of PD is the selective loss of dopaminergic neurons. There is an impressive body of evidence now available suggesting that two major mechanisms responsible for the selective loss of dopaminergic neurons in substantia nigra: excitatory glutamate neurotoxicity and dopamine-dependent oxidative stress. Therefore, regulation of the balance of dopamine and glutamate appears to be the new therapeutic intervention for PD. Previous studies suggest that K channels may participate in the pathological process of PD and play an important role in neuroprotection. Here we investigated the experimental therapy of a new ATP-sensitive potassium channels opener IPT on haloperidol-treated rats; according to the conclusions of the first part, further experiment was exerted on PD cellular model induced by rotenone and the relevant mechanisms of IPT were explored.Part I. The protective effect of IPT on haloperidol-treated ratsAIM: To investigate the effects of IPT on parkinsonian synptoms induced by haloperidol.METHODS: By counting the latency time of forepaws, walkingtime and the number of rearing and grooming, the effects of IPT on catalepsy and hypolocomotion induced by haloperidol in rats were observed.RESULTS: IPT can decrease the latency time of forepaws, increase walking time and the number of rearing and grooming.CONCLUSION: IPT can assuage catalepsy and hypolocomotion induced by haloperidol, indicating that IPT might be protective to PD.Part n. The protective effect of IPT on cytotoxicity induced by rotenoneAIM: To explore the protective effect and the possible mechanism of IPT on cytotoxitity induced by rotenone.METHODS: PC12 cells were cultured and preconditioned with IPT and/or glibenclamide for 15 minutes. Then the media were added with rotenone. 48 hours later, cells viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and morphological changes were observed under phase contrast microscopy. High performance liquid chromatography (HPLC) was used to measure extracellular levels of dopamine and glutamate after the treatment of different concentrations of rotenone with or without IPT. Extracellular level of dopamine was determined by HPLC after the treatment of GBR-12909 with or without IPT.RESULTS: Pretreament with IPT alleviated cytotoxicity induced by rotenone; reversed the effects of rotenone on dopamine and glutamate release; GBR-12909 elevated the extracellular level of dopamine; IPT prevented the effect of GBR-12909 and decreased the extracellular level of dopamine, an effect not completely blocked by glibenclamide.CONCLUSION: The mechanisms of rotenone-induced cytotoxicity may be due to the increase of extracellular level of dopamine and glutamate, which contributes to the excitatory neurotoxicity and auto-oxidative stress. IPT exerted protective effects against thecytotoxicity induced by rotenone, and this protective role may be via opening sarcolemma and mitochondrial K, maintaining normal ion grads and volumn of mitochondria, promoting the synthesization of ATP, and consequently regulating the conduction of dopamine and glutamate.Innovations in tbe present study1. In our investigation, iptakalim, a novel KCO, which is exerted on the praxiological animal model of PD, can significantly assuage parkinsonian symptoms induced by haloperidol; it may be a potential drug for treating PD.2. Here, the cytotoxicity of rotenone may be due to the increase of extracellular levels of dopamine and glutamate; the protective mechanisms of iptakalim are concerned with the reverse effect on extracellular levels of the two neurotransmissions.
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