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

在这项研究中，我们旨在开发一种新的药物来治疗脊髓小脑性共济失调，这是最常见的神经系统疾病之一。据我们所知，很少有治疗方法对这种疾病有效。在本研究中，我们在小鼠模型中研究了d -丝氨酸乙酯及其相关物质d -环丝氨酸作为治疗共济失调的药物的疗效。已知这两种化合物对n -甲基-d-天冬氨酸（NMDA）型谷氨酸受体具有特异性调节作用，并且谷氨酸介导的信号通路受损与脊髓小脑性失调有关。通过微透析方法，我们首先发现，腹腔注射d -丝氨酸乙酯可增加小鼠小脑内内源性d -丝氨酸的细胞外含量至少3小时。注射后40分钟，细胞外d -丝氨酸的含量最高。采用野外实验的方法测定d -丝氨酸衍生物对运动和运动失调的影响。在表现阿糖胞嘧啶诱导的共济失调的小鼠中，d -丝氨酸乙酯以剂量依赖的方式降低了下降指数。d -丝氨酸乙基酯的作用是立体特异性的，在最大剂量下，l -丝氨酸乙基酯对下降指数没有影响，并被5,7 -二氯酸酯（一种与甘氨酸结合位点结合的拮抗剂）所抑制。运动活动未因d -丝氨酸乙基酯处理而改变。d -环丝氨酸还能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治疗共济失调的药物有更持久的效果。越来越多的证据表明，内源性d -丝氨酸在哺乳动物脑功能中的重要作用，我们的研究结果表明，d -丝氨酸衍生物可能为治疗人类脊髓小脑共济失调提供一种有效的新疗法。

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.