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LY503430: pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease.

机译：LY503430：帕金森氏病的啮齿动物模型的药理学，药代动力学和作用。

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Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-subtype of glutamate receptors have led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present studies we characterized a novel AMPA receptor potentiator, LY503430, on recombinant human GLU(A1-4) and native preparations in vitro, and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that at submicromolar concentrations LY503430 selectively enhanced glutamate-induced calcium influx into HEK293 cells transfected with human GLU(A1), GLU(A2), GLU(A3), or GLU(A4) AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal and substantia nigra neurones. LY503430 had good oral bioavailability in both rats and dogs. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity following unilateral infusion of 6-hyrdoxydopamine (6-OHDA) into either the substantia nigra or the striatum of rats and that following systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain derived neurotrophic factor (BDNF) in the substantia nigra and a dose-dependent increase in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators such as LY503430 offer the potential of a new disease modifying therapy for Parkinson's disease.
机译：谷氨酸是大脑中主要的兴奋性递质。谷氨酸受体的α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）亚型的分子生物学和药理学的最新进展导致发现了选择性，有效和全身活性的AMPA受体增强剂。这些分子增强突触传递，并在可塑性和认知过程中发挥重要作用。在本研究中，我们在重组人GLU（A1-4）和天然制剂上表征了新型AMPA受体增强剂LY503430，然后在帕金森氏病的啮齿动物模型中评估了该分子的潜在神经保护作用。结果表明，在亚微摩尔浓度下，LY503430选择性增强了谷氨酸诱导的钙向人GLU（A1），GLU（A2），GLU（A3）或GLU（A4）AMPA受体转染的HEK293细胞中的钙内流。该分子还增强了天然皮质，海马和黑质神经元中AMPA介导的反应。 LY503430在大鼠和狗中均具有良好的口服生物利用度。在这里我们还报道LY503430在帕金森氏病动物模型中提供了剂量依赖性的功能和组织学保护。在大鼠黑质或纹状体中单侧注入6-羟基多巴胺（6-OHDA）后以及在小鼠体内全身性1-​​甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）后产生神经毒性减少了。有趣的是，当治疗延迟至病变建立后（6或14天）很久，LY503430对功能和组织学结果也具有神经营养作用。 LY503430还使黑质中的脑源性神经营养因子（BDNF）有所增加，纹状体中与生长相关的蛋白43（GAP-43）表达也呈剂量依赖性。因此，我们建议AMPA受体增强剂（例如LY503430）为帕金森氏病提供一种新的疾病改良疗法。

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