Selective and Nonselective Effects of 1‐Methyl‐4‐ Phenylpyridinium on Oxygen Consumption in Rat Striatal and Hippocampal Slices

Abstract

Insights into the etiology and pathophysiology of Parkinson's disease may derive from elucidation of the neurotoxic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+). In previous studies, MPP+ provoked oxidation of cytochrome b and K+ leakage into the extracellular space of rat striatal slices. Magnitudes of these time-dependent responses were far greater than expected had the MPP+ effects been limited to dopaminergic terminals. To determine whether cytochromes become oxidized from K(+)-induced increases in ion transport activity or from electron transport inhibition at complex I, oxygen consumption was measured because this should be increased by the former and decreased by the latter mechanism. Low MPP+ concentrations (1 microM) decreased O2 consumption (approximately 40% in 3 h) in striatal slices. This decrease was diminished by mazindol and did not occur in hippocampal slices. High toxin concentrations (100 microM) inhibited oxygen consumption to a greater extent (approximately 60%) in striatal slices; this inhibition was still greater in hippocampal slices. These results support the hypothesis that acute effects of low ("selective") MPP+ concentrations require the presence of dopaminergic terminals to trigger a sequence of destructive metabolic events but that the metabolic consequences of MPP+ spread to neighboring cells. In contrast, high MPP+ concentrations nonselectively inhibit metabolic and ion transport activity without requiring the presence of dopaminergic terminals. These results also suggest that physiological effects of "selective" MPP+ concentrations extend to nondopaminergic cells.

Inhibitors of Mitochondrial Respiration, Iron (II), and Hydroxyl Radical Evoke Release and Extracellular Hydrolysis of Glutathione in Rat Striatum and Substantia Nigra

“…The mechanism proposed in Scheme 1 is consistent with many factors associated with the neurotoxicity of MPTP/MPP + . These include the loss of nigrostriatal GSH without corresponding increases of GSSG levels, elevation of extracellular Glu levels as the neuron energy impairment subsides, roles for NMDA receptor activation, intraneuronal O 2 ‐• , mobilization of low‐molecularweight iron, extracellular OH • , DA release/reuptake (Martin et al, 1991 ; Santiago et al, 1995), and delayed inhibition of complex I (Sriram et al, 1997). However, there is presently no evidence for the participation of 5‐ S ‐CyS‐DA and its dihydrobenzothiazine/benzothiazine metabolites in the neurotoxic mechanism evoked by MPTP/MPP + .…”

Lack of involvement of glutamate‐induced excitotoxicity in MPP+ toxicity in striatal dopaminergic terminals: possible involvement of ascorbate

“…As has been shown for MK‐801 (Clarke & Reuben, 1995; Venero et al , 1996) another possible mechanism by which PDC could prevent the striatal depletion produced by MPP + is through inhibition of the dopamine transporter. Inhibition of dopamine uptake protects against MPTP/MPP + (Martin et al , 1991) and methamphetamine toxicity (Marek et al , 1990). In contrast with MK‐801, PDC did not show an inhibitory effect on the uptake of dopamine.…”