Effects Of Iptakalim On The Extracellular Glutamate And Dopamine Levels In The Striatum Of Unilateral 6-Hydroxydopamine-Lesioned Rats: A Microdialysis Study

摘要

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Our previous study, demonstrated that iptakalim (Ipt) could significantly ameliorate hypolocomotion and catalepsy induced by haloperidol in rats and significantly decrease the rotation turns of unilateral 6-hydroxydopamine-lesioned rats induced by apomorphine. To further understand its mechanism, using rat model of PD induced by unilateral substantia nigral 6-OHDA and reverse microdialysis technique, we investigated the effects of Ipt on the extracellular glutamate, dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) levels in the striatum of the conscious and freely moving unilateral 6-hydroxydopamine-lesioned rats. Levels of the extracellular glutamate and DA as well as DOPAC in microdialysate samples were assayed with HPLC. The results indicated that Ipt can reduce the extracellular glutamate levels in both sides of striatum of the unilateral 6-OHDA-lesioned rats and in the control rats in a concentration-dependence manner. Ipt can elicit a significant enhancement in the extracellular DA levels in the lesion-side striatum of the unilateral 6-OHDA-lesioned rats at lower concentrations of Ipt (0.01, 0.1, 1μM), while, caused no significant changes in the intact-side striatum of unilateral 6-OHDA-lesioned rats and even a significant decline in striatum of control rats at higher concentrations of Ipt (10, 100μM). These data suggest that altering the levels of extracellular neurotransmitters such as glutamate, DA in the striatum of unilateral 6-OHDA-lesioned rats may be the major mechanism of Ipt ameliorating rotational behavior of unilateral 6-OHDA-lesioned rats. Abbreviations PD, Parkinson’s disease; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; SNpc, substantia nigra pars compacta; KATP, ATP-sensitive potassium channel; ACSF, artificial cerebrospinal fluid; Ipt, iptakalim; 6-OHDA, 6-hydroxydopamine; GABA, ?-aminobutyric acid; HPLC, high performance liquid chromatography Introduction Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The primary pathological change of PD is the loss of the dopaminergic neurons in substantia nigra pars compacta (SNpc). Its etiology remains unclear to date. It has been demonstrated that neurotoxity of excitatory glutamate is responsible for the onset of PD [1]. The glutamate acts as a principal excitatory neurotransmitter in the mammalian central nervous system as well as a potent neurtoxin [2]. According to current theories of functional anatomy of basal ganglia [3], the neurotransmitters dopamine (DA) and glutamate interactions underlie brain functions, including regulation of normal movements [4]. The information from cortex to neostriatium, the input nuclei of basal ganglia, is processed within neostriatium and transmitted to the output nuclei of basal ganglia by direct and indirect pathways. Under-activity of ?-aminobutyric acid (GABA)ergic neurons which activated by D1 receptors within the direct pathway and over-activity of glutamatergic neurons which inhibited by D2 receptors within the indirect pathway [5] are thought to be a common mechanism for the dopaminergic neuron degeneration in PD [6]. Therefore, enhancing the activity of DA in direct pathway and reducing the activity of glutamate in indirect pathway have been proposed as two therapeutic strategies for PD.ATP-sensitive potassium (KATP) channels are distributed widely in the brain and directly couple the metabolic state of a cell to its electrical activity. KATP channels comprise heteromultimers of two pore-forming subunits of the inward rectifer (Kir6.1, Kir6.2) family and two regulatory sulfonylurea receptor subunits (SUR1, SUR2). These channels are not only relevant to acute metabolic challenges, but also to chronic genesis of neurodegenerative disorders like PD [7]. Moreover, studies of mid-brain dopaminergic neurons in the weaver mouse, a genetic mouse model used to study dopaminergic degeneration si