Kainic acid lesion-induced nigral neuronal death

Parkinson's disease (PD) is characterized by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta. We report a rat model that exhibits progressive death of nigral neurons following unilateral injection of kainic acid in the striatum. In situ end-labeling revealed significant numbers of dying nigral neurons ipsilateral to the lesion during the first 3 weeks following injection. An indication of the gradual nature of death was that similar small numbers of cells were detected at each time point. These early morphological markers of neuronal death led to a significant reduction (20%) at 5 months of tyrosine hydroxylase-positive neurons and total number of neurons in the ipsilateral substantia nigra compared with the contralateral control. To examine the role of nigrostriatal DA metabolism in the observed nigral neuronal death, we manipulated DA metabolism during the initial 2 weeks following kainic acid lesion. Neurons in the ventral tier of the substantia nigra pars compacta were protected from death by treatment with 2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydrolase, the initial enzyme in the synthesis of the tyrosine hydroxylase co-substrate, tetrahydrobiopterin (BH(4)). Neurons in both the dorsal and ventral tier of substantia nigra pars compacta were protected from death by treatment with DAHP and L-DOPA. These experiments suggest that intrastriatal kainic acid lesion is an in vivo model of trophic support withdrawal. This experimental procedure is useful for studying mechanisms underlying protracted death of nigral DA neurons and may provide valuable mechanistic information relevant to understanding the etiology of PD.