Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion

The neurotoxin 6-hydroxydopamine (6-OHDA) has been used extensively in anim al models of Parkinson's disease. Typically, rodents develop severe unilate ral movement deficiencies coupled with apomorphine-induced rotation behavio r at least 1 week after an ipsilateral 6-OHDA lesion of the nigrostriatal d opamine (DA) system. The short-term morphological effects of 6-OHDA have no t been determined in detail, however, and the exact process by which neuron s die has not been elucidated. Thus, novel degenerative markers were used t o determine the temporal pattern of acute phenotypic and degenerative alter ations following a unilateral 6-OHDA injection into the medial forebrain bu ndle of adult rats. 6-Hydroxydopamine administration resulted in an increas e in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining as early as 6 hours postlesion. Staining for FluoroJade, a marker of neuronal degeneration, was evident at all time points examined b ut was maximal at 48 hours. Loss of tyrosine hydroxylase (TH) immunoreactiv ity began in axons at 6 hours, and progressed to cell bodies at later time points postlesion. Morphological examination of these neurons supported the conclusion of their death via apoptosis. Thus, whereas behavioral manifest ations typically become evident 1 week or more following a 6-OHDA lesion, i t is evident that nigral cell degeneration begins much earlier. This sugges ts multiple therapeutic possibilities, including the prevention of apoptosi s, in affected neurons. Published 2000 Wiley-Liss, Inc.