Liu Xiaoguang, Hebron Michaeline L, Stevenson Max, Moussa Charbel
Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA.
Int J Mol Sci. 2025 Apr 30;26(9):4251. doi: 10.3390/ijms26094251.
Levodopa is the gold standard symptomatic treatment for Parkinson's disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson's patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson's disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels.
左旋多巴是帕金森病症状性治疗的金标准。由于α-突触核蛋白积累、脑部炎症和多巴胺能神经元丧失导致的疾病进展，以及左旋多巴血浆水平变化引起的运动波动，仍然是帕金森病患者面临的重大问题。开发一种能够同时减少与α-突触核蛋白聚集相关的神经病理学、减轻氧化应激和炎症，并克服左旋多巴血浆水平变化的治疗选择，是治疗帕金森病尚未满足的需求。我们确定了一种名为珀加索斯（Pegasus）的小分子的药代动力学和药效学，该小分子通过分子连接体将多巴胺与一种非抗生素强力霉素衍生物结合。携带人类α-突触核蛋白A53T突变或用MPTP处理的小鼠，每天注射一次50mg/kg的珀加索斯，持续2周，并评估其运动、行为和认知影响，随后进行生化和组织化学分析。珀加索斯的脑渗透性较差，但它被代谢为稳定的多巴胺和四环素衍生物，并在血浆和脑中检测到这些代谢物的丰富水平。珀加索斯降低了可溶性和不可溶性α-突触核蛋白水平，保护了产生多巴胺的神经元，并减少了A53T小鼠中的星形胶质细胞活化。用珀加索斯处理的小鼠表现出运动改善（6.5小时）和焦虑样行为减少。当用珀加索斯或左旋多巴处理MPTP处理的小鼠时，转棒试验和握力得到改善。珀加索斯可能是一种多模式治疗选择，能够将稳定的多巴胺输送到中枢神经系统，减少错误折叠的α-突触核蛋白，激活多巴胺受体，并减轻多巴胺水平的变化。
