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

Abstract

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 α-methyl-p-tyrosine (αMpT), 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 αMpT, 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 αMpT 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 αMpT 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 αMpT 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 αMpT-based challenge test might be considered as the provocation test for Parkinson's disease diagnosis at the preclinical stage in the future clinical trials.

A Monoiodotyrosine Challenge Test in a Parkinson’s Disease Model

“…Interestingly, the same dose (100 mg/kg) of α-methyl- p -tyrosine was previously shown to reduce the striatal dopamine level more efficiently, by 40.2%, 4 h after its administration [ 5 ]. In this case, according to in vitro estimates, MIT is a more effective TH inhibitor in comparison with α-methyl-p-tyrosine [ 10 ].…”

“…The use of such an inhibitor at a dose that lowers the striatal dopamine level by 30–40% relative to its control values will not cause motor disorders in healthy people. In turn, the striatal dopamine level at the preclinical PD stage is initially reduced and its further decrease by an inhibitor will lead to hitting the threshold of motor symptoms manifestation, which enables the diagnosis to be made [ 5 ].…”

Development of early diagnosis of Parkinson's disease: Illusion or reality?

“…137,138 An initial study showed that αMpT at the dose of 170 mg/kg decreased the dopamine level in the striatum in intact mice to a threshold (73%), followed by impaired motor behavior, while at the dose of 125 mg/kg dopamine level reduced by 45%, and this did not lead to motor disorders ( Figure 2B). 136 Then, it was shown that the administration of αMpT at the dose of 125 mg/kg to mice at modeling the preclinical stage of PD caused a decrease in striatal dopamine to a superthreshold level, which caused motor disorders ( Figure 2C,D). Twenty-four hours or, probably, even earlier after the αMpT administration, the dopamine content in the striatum returned to a normal level, followed by normalization of motor behavior (Figure 2C,D Thus, it was shown for the first time that a provocative test can be potentially used for ED of PD.…”

“…The most suitable neurological disease for this development is apparently PD, since it was determined that motor symptoms appear at the threshold of degradation of the nigrostriatal dopaminergic system, with a loss of 70% dopamine in the striatum and 50-60% dopaminergic neurons in the substantia nigra ( Figure 1A). 31,136 We used α-methyl-p-tyrosine (αMpT) as a provocative agent, which has a dose-dependent reversible short-term inhibitory effect on tyrosine hydroxylase and, hence, on dopamine synthesis (Figure 2A). 137,138 An initial study showed that αMpT at the dose of 170 mg/kg decreased the dopamine level in the striatum in intact mice to a threshold (73%), followed by impaired motor behavior, while at the dose of 125 mg/kg dopamine level reduced by 45%, and this did not lead to motor disorders ( Figure 2B).…”

“…First, it was proved in animal models that αMpT has no side effects. [136][137][138] Then, αMpT, as a commercial medicine Demser/Metyrosine (Aton Pharma, Inc., USA; Demser®/…”