丁苯那嗪调节 TH 和突触囊泡转运改善 HD 的机制研究

As one of inherited autosomal-dominant neurodegenerative diseases, Huntington's disease (HD) is dominantly caused by an abnormally expanded CAG repeat near the N terminus of the huntingtin gene (HTT) which leads to the production of mutant huntingtin protein (mHTT). The predominant toxic gain-of-function mechanism of mHTT results in loss of striatal neurons, thereby reducing the level of dopamine (DA) in the striatum, and disrupting the balance of neurotransmitters between striatum and substantia nigra. 3-Nitropropionic acid （3-NP）is a mitochondrial toxic reagent which can damage the striatum and induce HD-like symptoms. In this study, a rat model of HD was established by intraperitoneal injection of 3-NP to investigate the effect and mechanism of tetrabenazine (TBZ) on HD-like symptoms. TBZ alleviated 3-NP-induced weight loss, dyskinesia, the expression of Htt and neuron loss. Meanwhile, it was found that TBZ regulated the content of DA and HVA in striatum by ELISA, which might be one of the reasons for the improvement of motor ability. Further mechanism study showed that TBZ inhibited the expression of tyrosine hydroxylase (TH), reducing the expression of vesicular monoamine transporter 2 (VMAT2) and enhancing synaptophysin. As a result, the synthesis and transportation of DA were reduced, protecting the synapses in the striatum. Our data suggested that TBZ reduced the release and synthesis of dopamine (DA) in the striatum by simultaneously regulating synaptic vesicular transportation and TH expression. These effects further protected neurons from damage, thereby alleviating HD-like symptoms. This study provides a new evidence for the mechanism of TBZ in the treatment of HD.