MPTP-induced Parkinson-like disease in sheep: clinical and pathologic findings

Eight ewes, divided into two groups based on age, with group 1 7-8 and group 2 1-3 years old, respectively, were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously (IV) at cumulative doses of 2.0 to 34.6 mg/kg body weight. Two group 1 sheep, given cumulative doses of 2 and 8.5 mg/kg, developed persistent severe neurologic signs of body stiffness and rigidity, paucity of movement, intention body tremors, and abnormal body posture and stance similar to those signs in MPTP-induced disease in people and primates. After their acute onset, these persistent signs were nonprogressive up to the observation period of 32 days post infusion. None of the younger ewes had persistent neurologic symptoms at equivalent cumulative doses (9.0 mg/kg). The only pathologic changes were microscopic lesions in the central nervous system, consisting of bilaterally symmetrical neuronal chromatolysis and necrosis limited to the substantia nigra and locus ceruleus. These lesions were found in two persistently affected and two younger sheep, suggesting age-based differences in dose response and the threshold of clinical expression of disease. Serum MPTP half-life was 11 days. Thus sheep exposed to MPTP could be an alternative model to the primate for the comparative study of clinical, pathologic, and biochemical mechanisms in MPTP neurotoxicity and Parkinson's disease in people.