MPTP公司
胶质细胞源性神经生长因子
利拉鲁肽
神经保护
内分泌学
内科学
兴奋剂
黑质
酪氨酸羟化酶
神经营养因子
化学
医学
多巴胺
药理学
受体
2型糖尿病
糖尿病
多巴胺能
作者
Ziyue Yuan,Dongfang Li,Feng Peng,Guofang Xue,Chenhui Ji,Yanqing Han,Christian Hölscher
标识
DOI:10.1016/j.ejphar.2017.06.029
摘要
Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25 nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25 mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.
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