多巴胺代谢受损与小鼠的易疲劳性和帕金森病患者的疲劳有关

Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson's disease patients.

Keywords：fatigue; Parkinson’s disease; reserpine; dopamine; physical activity

关键词：疲劳;帕金森病；利血平；多巴胺；体力活动

哺乳动物：小鼠
作者：Scheffer Debora da Luz, Freitas Fernando Cini, Silva Aguiar Jr Aderbal, Ward Catherine, Guglielmo Luiz Guilherme Antonacci, Prediger Rui Daniel, Cronin Shane J F, Walz Roger, Andrews Nick A, Latini Alexandra 
出版期刊：《Brain Communications》 2021/6/8

Abstract：

Fatigue is a common symptom of Parkinson’s disease that compromises significantly the patients’ quality of life. Despite that, fatigue has been under-recognized as symptom, its pathophysiology remains poorly understood, and there is no adequate treatment so far. Parkinson’s disease is characterized by the progressive loss of midbrain dopaminergic neurons, eliciting the classical motor symptoms including slowing of movements, muscular rigidity and resting tremor. The dopamine synthesis is mediated by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin as a mandatory cofactor. Here, we showed that reserpine administration (1 mg/kg, two intraperitoneal injections with an interval of 48 h) in adult Swiss male mice (8–10 weeks; 35–45 g) provoked striatal depletion of dopamine and tetrahydrobiopterin, and intolerance to exercise. The poor exercise performance of reserpinized mice was not influenced by emotional or anhedonic factors, mechanical nociceptive thresholds, electrocardiogram pattern alterations or muscle-impaired bioenergetics. The administration of levodopa (100 mg/kg; i.p.) plus benserazide (50 mg/kg; i.p.) rescued reserpine-induced fatigability-like symptoms and restored striatal dopamine and tetrahydrobiopterin levels. Remarkably, it was observed, for the first time, that impaired blood dopamine metabolism inversely and idependently correlated with fatigue scores in eighteen idiopathic Parkinson’s disease patients (male n = 13; female n = 5; age 61.3 ± 9.59 years). Altogether, this study provides new experimental and clinical evidence that fatigue symptoms might be caused by the impaired striatal dopaminergic neurotransmission, pointing to a central origin of fatigue in Parkinson’s disease.

文章摘要：

疲劳是帕金森病的常见症状，严重影响患者的生活质量。尽管如此，疲劳作为症状一直未被充分认识，其病理生理学仍然知之甚少，迄今为止还没有足够的治疗方法。帕金森病的特征是中脑多巴胺能神经元的进行性丧失，引发经典的运动症状，包括运动减慢、肌肉僵硬和静止性震颤。多巴胺合成由限速酶酪氨酸羟化酶介导，该酶需要四氢生物蝶呤作为强制性辅因子。在这里，我们发现在成年瑞士雄性小鼠（8-10 周；35-45 g）中给予利血平（1 mg/kg，两次腹腔内注射，间隔 48 h）会引起纹状体多巴胺和四氢生物蝶呤的消耗，以及对锻炼。 reserpinized 小鼠的不良运动表现不受情绪或快感因素、机械伤害性阈值、心电图模式改变或肌肉受损的生物能量学的影响。给予左旋多巴（100 mg/kg；腹腔注射）加苄丝肼（50 mg/kg；腹腔注射）可挽救利血平诱导的疲劳样症状，并恢复纹状体多巴胺和四氢生物蝶呤水平。值得注意的是，首次观察到血液多巴胺代谢受损与 18 名特发性帕金森病患者（男性 n = 13；女性 n = 5；年龄 61.3 ± 9.59 岁）的疲劳评分呈负相关且独立相关。总而言之，这项研究提供了新的实验和临床证据，表明疲劳症状可能是由纹状体多巴胺能神经传递受损引起的，指出了帕金森病疲劳的主要根源。

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