A New Approach to Assessing the Extent of Degradation of the Nigrostriatal Dopaminergic System in an Experimental Model of Parkinson’s Disease

Abstract

A characteristic feature of Parkinson’s disease (PD) is the fact that it is diagnosed only at the late, “clinical” stage due to onset of motor symptoms on the background of almost complete degradation of the dopaminergic nigrostriatal system. This explains the low efficacy of existing replacement therapy (dopamine agonists) and produces the need to develop early (preclinical) diagnosis and use of preventive neuroprotective therapy aimed at slowing neuron death. At the early phase of the preclinical stage of PD, neuroprotective therapy must clearly be provided with cognizance of the level of degradation of the dopaminergic system, and currently this can be achieved only using positron emission tomography, a method which has limited availability. The aim of the present work was therefore to pursue the experimental development of an alternative easily accessible low-invasive approach to assessment of the level of degradation of the dopaminergic system in a model of the preclinical stage of PD. This original approach is based on the search for the minimum dose of α-methyl-p-tyrosine– a reversible dopamine (DA) synthesis inhibitor – which at different phases of the preclinical stage of PD can decrease DA contents to the threshold at which motor function is degraded. Development used an original model of the early and late preclinical stages of PD reproduced in mice with one or two systemic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine – a protoxin which in the body is converted into a substance toxic to dopaminergic neurons. In the former case, the DA level in the striatum decreases to 80%, in the latter to 39% of control/normal, taken as 100%. Studies in these models found the minimum dose of α-methyl-p-tyrosine at which the DA level decreased to the threshold (30%) accompanied by impairment of motor and exploratory activity. The dose in the model of the early preclinical stage was 75 mg/kg, compared with 50 mg/kg for the model of the late preclinical stage. Thus, these studies showed that the extent of degradation of the nigrostriatal dopaminergic system at the preclinical stage of PD can be determined in terms of the minimum dose of the reversible DA synthesis inhibitor at which it elicits a decrease in the DA level in the striatum to the threshold (30%) accompanied by impairment of motor and exploratory activity.