Weber Matthew A, Sivakumar Kartik, Tabakovic Ervina E, Oya Mayu, Aldridge Georgina M, Zhang Qiang, Simmering Jacob E, Narayanan Nandakumar S
Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
NPJ Parkinsons Dis. 2023 Mar 2;9(1):32. doi: 10.1038/s41531-023-00477-1.
Terazosin is an α-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
特拉唑嗪是一种α-肾上腺素能受体拮抗剂，它通过与磷酸甘油酸激酶1（PGK1）结合来增强糖酵解并增加细胞内三磷酸腺苷（ATP）。最近的研究表明，特拉唑嗪对帕金森病（PD）啮齿动物模型中的运动功能障碍具有保护作用，并且与PD患者运动症状进展减缓有关。然而，PD的特征还包括严重的认知症状。我们检验了特拉唑嗪可预防与PD相关的认知症状这一假设。我们报告了两个主要结果。第一，在腹侧被盖区（VTA）多巴胺耗竭以模拟PD相关认知功能障碍的啮齿动物中，我们发现特拉唑嗪可保留认知功能。第二，我们发现，在匹配人口统计学、合并症和疾病持续时间后，与不增强糖酵解的α-肾上腺素能受体拮抗剂坦索罗辛相比，新开始使用特拉唑嗪、阿夫唑嗪或多沙唑嗪的PD患者被诊断为痴呆的风险更低。总之，这些发现表明，除了减缓运动症状进展外，增强糖酵解的药物还可预防PD的认知症状。
