MPTP-INDUCED DEGENERATION - INTERFERENCE WITH GLUTAMATERGIC TOXICITY

Parkinson's disease (PD) is characterised by the progressive degenerat ion of nigrostriatal dopamine (DA) neurons resulting in the major symp toms of akinesia and rigidity. Although the primary cause of PD is sti ll not known some features make this disorder a model for neurodegener ative diseases in general. It has been known for some time that sympto matic PD can be attributed to insults with symptoms occurring many yea rs later such as post-encephalitic PD or PD following manganese poison ing. More recently, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ) has been identified as a neurotoxin selective for melanin-containing dopaminergic neurons in humans and non-human primates. The specificit y of this neurotoxin and the striking clinical similarities to idiopat hic PD, seen in primates, make MPTP-induced parkinsonism the most usef ul animal model of a neurological disease. There are numerous theoreti cal possibilities to interfere with both MPTP-induced neurotoxicity an d the symptomatology of PD. In recent years excitatory amino acids hav e gained considerable interest since they can cause excitotoxic lesion of neurons under a number of pathological conditions (Olney et al., 1 989; Choi, 1988). Here we summarise the present data and provide new e xperimental evidence indicating that MPTP-induced degeneration of dopa minergic neurons does involve glutamate-mediated toxicity. It is concl uded that glutamate-mediated excitotoxicity results in the destruction of DAergic somata in the substantia nigra. Non-competitive or competi tive NMDA antagonists protect nigral neurons from MPTP-induced degener ation whereas their striatal terminals still seem to degenerate.