Methyl-β-carbolinium analogs of MPP + cause nigrostriatal toxicity after substantia nigra injections in rats

Abstract

Eleven β-carbolinium compounds (βC +s) and MPP + were stereotaxically injected (40–200 nmol in 5 μl of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum was analyzed for dopamine and DOPAC levels with HPLC. The brainstem injection site was fixed and cut coronally. The largest lesion area in each animal was measured using NIH IMAGE. Three βC +s produced lesions 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-Me 2-norhaman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Meharman (29%), and 2-Me-harmine (25%). The remaining compounds were ineffective (⩽ 12%): norharman, 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6-MeO-harmalan. A 40 nmol dose of MPP + reduced ipsilateral striatal dopamine to 0.6% of control. None of the βC +s approached this, although several did significantly reduced striatal dopamine at doses of either 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 moderately strong correlations ( r = 0.39−0.78) between the βC + nigral lesion area or striatal dopamine level potencies and their previously described IC50 values for inhibiting mitochondrial respiration or their toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between βC + K i MAO-A values and their toxicity to PC12 LDH release ( r = −0.84) or PC12 protein loss ( r = 0.79). Although βC +s appear to be less specific 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.