Identification of novel targets of antidepressant on glia by using pharmacoproteomics

以单胺类神经元假说为基础的抗抑郁药物的发展正面临局限。神经胶质细胞，尤其是星形胶质细胞，是中枢神经系统中的主要细胞，起着储存多种神经营养因子的作用，如GDNF和BDNF，它们与抗抑郁作用有关。我们揭示了星形胶质细胞抗抑郁作用的药物分子机制。抗抑郁剂对星形胶质细胞GDNF和FGF-2表达的调节是单胺非依赖性机制。我们还发现了五个直接针对无胞体的抗肿瘤相关候选蛋白，神经营养因子的表达途径参与了基质金属蛋白酶-酪氨酸激酶-ERK-CREB级联反应。鉴定星形胶质细胞上特异的抗抑郁药物靶向蛋白和级联反应可能有助于从不同的角度开发抗抑郁药物。

Development of antidepresant besed on monoamine neuron hypothesis is facing limit. Glia, especially astrocytes, are major in the CNS and play a role of storage for several types of neurotrophic factors such as GDNF and BDNF, which are implicated in antidepressant effects. We revealed the pharmacomolecular mechanism of antidepressant effect on astrocytes. The expression of GDNF and FGF-2 by antidepressant in astrocytes was regulated by monoamine-independent mechanism. We also found five antideressant-related candidates directly targeting asytocyes by using pahrmacoproteomics, and that the pathway of neurotrophic factors expression was involved in the MMP-Tyrosine kinase-ERK-CREB cascade. Identification of specific antidepressant-targeting protein and cascade on astrocytes may contribute to development of antidepressant from a different view point.