METHYL-BETA-CARBOLINIUM ANALOGS OF MPP(-NIGRA INJECTIONS IN RATS() CAUSE NIGROSTRIATAL TOXICITY AFTER SUBSTANTIA)

Eleven beta-carbolinium compounds (beta C(+)s) and MPP(+) were stereot axically injected (40-200 nmol in 5 mu l of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum w as analyzed for dopamine and DOPAC levels with HPLC. The brainstem inj ection site was fixed and cut coronally. The largest lesion area in ea ch animal was measured using NIH IMAGE. Three beta C(+)s produced lesi ons whose mean areas were nearly as large as that produced by MPP(+) ( defined as 100%): 2,9-Me(2)-harman (94%), 2-Me-harmol (74%), and 2,9-M e(2)-norharman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Me-harman (29%), and 2-Me-harmi ne (25%). The remaining compounds were ineffective (less than or equal to 12%): norharman. 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6- MeO-harmalan. A 40 nmol dose of MPP(+) reduced ipsilateral striatal do pamine to 0.6% of control. None of the beta C(+)s approached this, alt hough several did significantly reduce striatal dopamine at doses of e ither 40 nmol (2,9-Me(2)-harman (37%), 2,9-Me(2)-norharman (42%), and 2-Me-harman (63%)) or 200 nmol (2-Me-harmaline (23%), norharman (63%), and 2-Me-norharman (64%)). There was a moderate negative correlation between lesion size and dopamine level (r = -0.65). There were also mo derately strong correlations (r = 0.39-0.78) between the beta C+ nigra l lesion area or striatal dopamine level potencies and their previousl y described IC50 values for inhibiting mitochondrial respiration or th eir toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between beta C+ K-i MAO-A values and their toxicity to PC12 LDH release (r = - 0.84) or PC 12 protein loss (r = 0.79). Although beta C+s appear to be less specif ic toxins than MPP(+), their levels in human substantia nigra are 8-20 -fold higher than in cortex, making their role as relatively selective nigral toxins in Parkinson's disease plausible.