Identification of novel targets of antidepressant on glia by using pharmacoproteomics

基于单胺神经元假说的抗抑郁药发展面临瓶颈。神经胶质细胞，尤其是星形胶质细胞，在中枢神经系统中占有重要地位，并储存多种神经营养因子，如GDNF和BDNF，这些神经营养因子与抗抑郁作用有关。我们揭示了抗抑郁作用对星形胶质细胞的药物分子机制。抗抑郁药对星形胶质细胞中GDNF和FGF-2的表达具有单胺不依赖性。我们还通过药物蛋白质组学发现了5种直接靶向无近视的抗抑郁药候选药物，并且神经营养因子的表达途径参与了mmp -酪氨酸激酶- erk - creb级联反应。星形胶质细胞特异性抗抑郁靶向蛋白和级联的鉴定可能从不同的角度促进抗抑郁药物的发展。

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.