In Brown Norway Rats, MPP⁺ Is Accumulated in the Nigrostriatal Dopaminergic Terminals but It Is Not Neurotoxic: A Model of Natural Resistance to MPTP Toxicity

Abstract

Rats have been described as being insensitive to relatively high doses of systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that in primates induces a neurological syndrome identical to idiopathic Parkinson's disease. The current explanation for the rat resistance is that most of the MPTP is converted into the toxic metabolite 1-methyl-4-phenylpyridium (MPP¹) by the MAO-B present in the brain vessel endothelium. Since MPP⁺ is a polar compound, a very low amount could cross the blood-brain barrier and be present inside the brain. We administered C57 BL mice and Brown Norway rats with either MPTP (30 mg/kg, ip) or the combined treatment MPTP + diethyldithiocarbamate (DDC). In mice, DDC prolonged the striatal exposure to MPP⁺, potentiated the MPTP-induced acute syndrome, and enhanced the MPTP-induced striatal dopamine depletion. In rats, DDC potentiated the MPTP-induced acute syndrome, but no changes in the striatal dopamine were observed after either MPTP or DDC + MPTP administration. Also in rats, however, high doses of MPP⁺ were measured in the striatum of MPTP-alone treated rats and DDC delayed the MPP⁺ elimination from the striatum. When MPTP alone or DDC + MPTP was administered to rats unilaterally lesioned with 6-hydroxy dopamine (6-OH-DA), the levels of MPP⁺ measured in the intact striatum were significantly higher than those found in the 6-OH-DA-lesioned striatum. Taken together these data indicate that in Brown Norway rats MPP⁺ could be formed inside the brain and selectively accumulated in the striatal dopaminergic terminals without exerting its neurotoxicity; they also suggest that not only the MPP¹ formation or elimination but also the intraneuronal distribution of MPP⁺ could be crucial for species differences in the sensitivity to the toxin.