Parkinson's disease is a progressive neurodegenerative disease characterized primarily by degeneration of dopamine-containing neurons in the pars compacta of the substantia nigra The early symptoms of Parkinson's disease are bradykinesia, rigidity, tremor but with disease progression, postural instability, immobility and confinement to a wheel-chair are commonly observed The effectiveness of the most widely used treatment L-Dopa, which is converted to dopamine, wanes with disease progression Alternatives to L-Dopa therapy include direct agonists that activate the targets of dopamine, D1 and D2 dopamine receptors Several dopamine agonists have been tried as monotherapies at the onset of therapy (Hoehn and Yahr stage I-III), as substitutes for L-Dopa in patients with advanced Parkinson's disease (Hoehn and Yahr stage III-V) and as adjuncts to L-Dopa The antiparkinsonian activity of D2-like agonists (bromocriptine, lisuride, pergolide) are effective in early Parki nson 's disease and newer D2-like agonists (pramipexole, ropinirole and cabergoline) are efficacious when used as monotherapy for symptomatic treatment of early as well as advanced stages of Parkinson's disease The therapeutic efficacy of D1 agonists at different stages of the disease are not known To investigate whether D1 agonists will produce different therapeutic relief at different stages of Parkinson's disease, we developed a model of mild and advanced parkinsonism in monkeys with two dosing regimens of the neurotoxin1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) To create a model of mild Parkinsonism, 2 doses of 0 6 mg/kg MPTP were administered i v 1 month apart Advanced Parkinsonism was developed by administering 3 doses of 0 6 mg/kg MPTP within 10 days, i v Motor function was evaluated using a rating scale of general activity, locomotor activity, bradykinesia, rigidity, posture, imbalance, tremor frequency, body freeze, and feeding ability The majority of behaviors w ere measured on a normal (0), slight (1) and absent (2) scale The effects of the two dosing regimens led to a mild and an advanced form of Parkinsonism that were distinguishable statistically from each other and from normal animals Prominent differences were the higher incidence of body freeze, feeding ability, rigidity, and general activity in advanced parkinsonism Tremor frequency was more pronounced in the mild than in the advanced Parkinsonism The scale also permitted rating of dyskinesia and imbalance The two models were used to effectively evaluate the therapeutic and undesirable side effects of the two full D1 agonists and two very selective D2 agonists These data demonstrate that 1 mild and severe parkinsonism can be produced by two different dosing regimens of MPTP 2 The motor dysfunction engendered by the two dosing regimens can be distinguished from one another by a rating scale and these differences are statistically significant 3 The two models of Parkinsoni sm are distinguishable from normal animals 3 The therapeutic effectiveness of D1 and D2 agonists depends on the degree of parkinsonism This model is useful for the evaluation of anti-parkinsonian medications at different degrees of motor impairment
NIH ExPorter
NIH ExPorter