EXPLORATORY STUDY FOR ESTABLISHING A NEW THERAPY WITH ENDOGENOUS D-AMINO ACIDS IN MOTOR ATAXIA

在这项研究中，我们的目的是开发一种新的药物来治疗脊髓小脑共济失调，这是最常见的神经系统疾病之一。据我们所知，很少有治疗方法能有效治疗这种疾病。在本研究中，我们研究了D-丝氨酸乙酯和相关物质D-环丝氨酸作为共济失调治疗剂在小鼠模型中的疗效。已知这两种化合物都能特异性调节N-甲基-d-天冬氨酸（NMDA）型谷氨酸受体，并且受损的谷氨酸介导的信号传导与脊髓小脑共济失调有关。利用微透析方法，我们首次发现腹腔注射D-丝氨酸乙酯可增加小鼠小脑细胞外内源性D-丝氨酸含量至少3小时。在注射后40分钟观察到细胞外D-丝氨酸的最大升高。采用旷场研究测定D-丝氨酸衍生物对运动和共济失调的影响。在表现出阿糖胞苷诱导的共济失调的小鼠中，D-丝氨酸乙酯以剂量依赖性方式降低下降指数。D-丝氨酸乙酯的作用是立体特异性的，因为L-丝氨酸乙酯在测试的最大剂量下对下落指数没有作用，并且被5，7-二氯犬尿酸盐（一种结合甘氨酸结合位点的拮抗剂）抑制。自发活动没有改变的D-丝氨酸乙酯治疗。D-环丝氨酸还显著降低小鼠的跌倒指数。D-丝氨酸乙酯和D-环丝氨酸都比其他潜在的共济失调治疗试剂具有更长的持续作用。越来越多的证据表明内源性D-丝氨酸参与了哺乳动物脑功能的调节，我们的研究结果表明，D-丝氨酸衍生物可能是治疗人类脊髓小脑性共济失调的一种有效的新疗法。

In this study, we aimed to develop a new medicine to treat spinocerebellar ataxia, which is one of the most common neurological disorders. To our knowledge, few therapeutics are effective for the treatment of this disorder. In the present study, we investigated the efficacy of D-serine ethylester and a related substance, D-cycloserine, as therapeutic agents for ataxia in a murine model. Both compounds are known to streospecific modulate N-methyl-d-aspartate (NMDA) type glutamate receptors, and impaired glutamate-mediated signaling has been implicated in spinocerebellar ataxia. Using a microdialysis method, we first found that intraperitoneal administration of D-serine ethylester increases the extracellular content of endogenous D-serine in the mouse cerebellum for at leas 3 h. Maximum elevation of the extracellular D-serine was observed at 40 min after injection. An open-field study was used to assay the effect of the D-serine derivatives on movement and ataxia. In mice exhibiting cytosine arabinoside-induced ataxia, D-serine ethylester reduced the falling index in a dose-dependent manner. The effect of D-serine ethylester was stereo-specific in that L-serine ethylester had no effect on the falling index at the maximum doses tested, and was inhibited by 5, 7-dichlorokynurenate, an antagonist that binds to the glycine-binding site. Locomotor activity was not changed by the D-serine ethylester treatment. D-cycloserine also significantly reduced the falling index of the mice. Both D-serine ethylester and D-cycloserine had longer lasting effects than other potential therapeutic reagents for ataxia. Growing evidence suggests the essential involvement of endogenous D-serine in mammalian brain function, and our results suggest that D-serine derivatives may represent an effective new therapeutic for the treatment of spinocerebellar ataxia in human.