The acute histopathology of MPTP in the mouse CNS.

We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rapidly induced cytopathological changes in the brain, involving some neurons selectively, as well as astrocytes and blood vessels. Dopaminergic neurons in the midbrain, as identified by immunostaining for tyrosine hydroxylase, were damaged as early as 2.5 hr after MPTP administration. Ultrastructurally, there was disruption of the endoplasmic reticulum and cytoplasmic condensation and vacuolation of the tyrosine hydroxylase reactive neurons in the substantia nigra as well as their axon terminals in the striatum. Perivascular edema was associated with vacuolation and swelling of astrocytic cytoplasm and rupture of perivascular foot processes. There was also capillary and arteriolar endothelial damage. Surprisingly, there was no clear correlation of MPTP-induced pathology with mitochondrial damage in any cell type. Biochemically, dopamine was depleted in the substantia nigra and the striatum within a few hours following MPTP administration. However, in the substantia nigra, homovanillic acid (HVA), one of the metabolites of dopamine, showed relatively less depletion than did dopamine by MPTP. These results may indicate that the turnover of dopamine was stimulated in the brain as a homeostatic mechanism.