Reversible Pharmacological Induction of Motor Symptoms in MPTP-Treated Mice at the Presymptomatic Stage of Parkinsonism: Potential Use for Early Diagnosis of Parkinson's Disease

摘要

A crucial event in the pathogenesis of Parkinson's disease is the death of dopaminergic neurons of the nigrostriatal system, which are responsible for the regulation of motor function. Motor symptoms first appear in patients 20-30 years after the onset of the neurodegeneration, when there has been a loss of an essential number of neurons and depletion of compensatory reserves of the brain, which explains the low efficiency of treatment. Therefore, the development of a technology for the diagnosing of Parkinson's disease at the preclinical stage is of a high priority in neurology. In this study, we have developed at an experimental model a fundamentally novel for neurology approach for diagnosis of Parkinson's disease at the preclinical stage. This methodology, widely used for the diagnosis of chronic diseases in the internal medicine, is based on the application of a challenge test that temporarily increases the latent failure of a specific functional system, thereby inducing the short-term appearance of clinical symptoms. The provocation test was developed by a systemic administration of alpha-methyl-p-tyrosine (alpha MpT), a reversible inhibitor of tyrosine hydroxylase to MPTP-treated mice at the presymptomatic stage of parkinsonism. For this, we first selected a minimum dose of alpha MpT, which caused a decrease of the dopamine level in the striatum of normal mice below the threshold at which motor dysfunctions appear. Then, we found the maximum dose of alpha MpT at which a loss of dopamine in the striatum of normal mice did not reach the threshold level, and motor behavior was not impaired. We showed that alpha MpT at this dose induced a decrease of the dopamine concentration in the striatum of MPTP-treated mice at the presymptomatic stage of parkinsonism below a threshold level that results in the impairment of motor behavior. Finally, we proved that alpha MpT exerts a temporal and reversible influence on the nigrostriatal dopaminergic system of MPTP-treated mice with no long-term side effects on other catecholaminergic systems. Thus, the above experimental data strongly suggest that alpha MpT-based challenge test might be considered as the provocation test for Parkinson's disease diagnosis at the preclinical stage in the future clinical trials.