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

在这项研究中，我们的目标是开发一种新药来治疗脊髓小脑性共济失调，这是最常见的神经疾病之一。据我们所知，很少有疗法能有效治疗这种疾病。在本研究中，我们研究了D-丝氨酸乙酯及其相关物质D-环丝氨酸作为小鼠共济失调的治疗药物的疗效。这两个化合物都能特异性地调节N-甲基-d-天冬氨酸(NMDA)型谷氨酸受体，谷氨酸介导的信号转导受损与脊髓小脑性共济失调有关。用微透析法首次发现，腹腔注射D-丝氨酸乙酯可使小鼠小脑细胞外D-丝氨酸含量增加至少3h，细胞外D-丝氨酸含量在注射后40min达到最大值。一项开放的研究被用来分析D-丝氨酸衍生物对运动和共济失调的影响。在出现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的方式减少下降指数。D-丝氨酸乙酯的作用是立体特异性的，L-丝氨酸乙酯在实验的最大剂量下对跌落指数没有影响，并能被甘氨酸结合部位的拮抗剂5，7-二氯尿酸抑制。D-丝氨酸乙酯处理不改变小鼠的运动活动。D-环丝氨酸还能显著降低小鼠的跌倒指数。与其他潜在的治疗共济失调的药物相比，D-丝氨酸乙酯和D-环丝氨酸乙酯具有更持久的效果。越来越多的证据表明内源性D-丝氨酸参与哺乳动物的脑功能，我们的结果表明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.