1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine exposure fails to produce delayed degeneration of substantia nigra neurons in monkeys

We assessed the presence of degenerating neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) of parkinsonian monkeys. For this purpose, we used two histological markers of cellular death, Fluoro Jade B (FJB) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Eight monkeys were subacutelly treated with four to six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (1-1.5 mg/kg, cumulative dose) and sacrificed 1 week and 11 months after last MPTP injection. Eight additional monkeys were chronically exposed to MPTP (4.5-15.3 mg/kg, cumulative dose) and sacrificed 6-35 months after last MPTP dose. Three intact monkeys served as controls. The number of tyrosine hydroxylase (TH)- and TUNEL-positive cells was quantified in SNpc and VTA and colocalization of FJB-positive and TUNEL-positive cells with neuronal (TH, NeuN, MAP2) and glial markers (human ferritin, GFAP) assessed on doubly labelled tissue sections. Only MPTP monkeys with 1-week survival displayed few doubly FJB-TH-labelled cells. Both groups of subacute MPTP monkeys, but not chronic MPTP monkeys, showed a significant increased number of TUNEL-positive cells in SNpc. TUNEL-positive cells exhibited morphological features and histological markers indicative of glial cells, whereas TUNEL/NeuN or TUNEL/MAP-2 colocalization was not observed. Our results indicate that MPTP treatment produced a nonapoptotic cell death of dopaminergic cells and the activation of the apoptotic cascade in glial cells. More importantly, we failed to demonstrate the existence of a delayed neurodegenerative process in the dopaminergic neurons after concluding MPTP injection thus, casting doubt on the validity of the "progressive model" created by repeated MPTP administration to monkeys.