近期研究发现，脑白质病变是精神分裂症的重要病理变化之一，并且与认知障碍密切相关。目前临床缺乏改善认知障碍的抗精神病药物。DHF是我们自行设计和合成的新化合物，前期研究发现DHF能够改善精神分裂症小鼠模型的高活动性和记忆障碍，减轻脑内髓鞘脱失，促进髓鞘再生。本申请项目拟应用Cuprizone复合MK-801致精神分裂症小鼠模型，以脑白质病变的髓鞘脱失为重点，研究：(1)DHF灌胃口服对模型小鼠认知障碍和其他症状的影响，评价其对精神分裂症的防治作用；(2)DHF对模型小鼠多个脑区髓鞘脱失和髓鞘再生的影响；(3)在作用机制方面研究DHF对Fyn--NMDA受体--少突胶质细胞--髓鞘形成--神经白质的调节作用。本项目研究将进一步明确DHF改善脑白质髓鞘脱失的作用机制及其对精神分裂症的防治作用，为开发新型抗精神分裂症药物打下基础；同时有助于阐释精神分裂症的发病机制，为药物研究提供新靶点。

Recent studies have discovered that white matter lesion is one of important pathological changes in schizophrenia, and is associated with cognitive impairment. Currently, there are almost no antipsychotic drugs which ameliorate cognitive impairment in the clinical use. DHF is a novel compound designed and synthesized by us. Our previous studies found that DHF improved the hyperactivity and memory impairment, alleviated the demyelination and promoted the remyelination in the brain of schizophrenia model mice. The present project will use a complex mouse model of schizophrenia induced by Cuprizone and MK-801, focus on the demyelination of white matter lesion, and investigate: (1) the effects of DHF on the cognitive impairment and other symptoms in the model mice for the evaluation of its therapeutic effect on schizophrenia; (2) the effects of DHF on demyelination and remyelination in the brain of model mice; and (3) the mechanisms of DHF through its regulating tyrosine kinase Fyn -- NMDA receptor -- oligodendrocytes -- myelination -- white matter. The present project may further clarify the mechanisms of DHF’s alleviating demyelination and its potential to treat schizophrenia, laying the foundation for the development of new antipsychotic drugs.