Scheffer 2021 Brain Commun

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Scheffer DDL, Freitas FC, Aguiar AS Jr, Ward C, Guglielmo LGA, Prediger RD, Cronin SJF, Walz R, Andrews NA, Latini A (2021) Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson's disease patients. Brain Commun 3:fcab116.

» PMID: 34423297 Open Access

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 (2021) Brain Commun

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. Keywords: Parkinson’s disease, Dopamine, Fatigue, Physical activity, Reserpine Bioblast editor: Plangger M O2k-Network Lab: BR Florianapolis Latini A, BR Criciuma Dal-Pizzol F

Labels: MiParea: Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology  Pathology: Parkinson's 

Organism: Rat  Tissue;cell: Skeletal muscle  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k