Studies on the Neurotoxicity of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine: Inhibition of NAD‐Linked Substrate Oxidation by Its Metabolite, 1‐Methyl‐4‐Phenylpyridinium

Abstract

The effects of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its 4-electron oxidation product 1-methyl-4-phenylpyridinium (MPP+) were studied in isolated mitochondria and in mouse brain striatal slices. ADP-stimulated oxidation of NAD-linked substrates was inhibited in a time-dependent manner by MPP+ (0.1-0.5 mM), but not MPTP, in mitochondria prepared from rat brain, mouse brain, or rat liver. Under identical conditions, succinate oxidation was relatively unaffected. In neostriatal slices prepared from the mouse, a species susceptible to the dopaminergic neurotoxicity of MPTP, incubation with either MPP+ or MPTP caused metabolic changes consistent with inhibition of mitochondrial oxidation, i.e., an increase in the formation of lactate and accumulation of the amino acids glutamate and alanine with concomitant decreases in glutamine and aspartate levels. The changes resulting from incubation with MPTP were prevented by the monoamine oxidase inhibitor pargyline, which blocks formation of MPP+ from MPTP. The results suggest that compromise of mitochondrial function and its metabolic sequelae within dopaminergic neurons could be an important factor in the neurotoxicity observed after MPTP administration.

D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

“…Mitochondria suspended in respiration buffer were incubated in the presence or absence of different substrates or inhibitors using the same incubation times as those of polarographical study. Phenazine methosulfate (0.1 mM) was used to oxidize NADH (21). Hydrogen peroxide, converted from superoxide by manganese-superoxide dismutase, was measured using 5 µM Amplex red (Molecular Probes, Eugene, Oregon, USA) and 5 U/ml HRP.…”

“…On the testing day, animals were first pretrained three times (1 hour apart) using an accelerating mode. After these training sessions, the time on the rod, with a maximum recording time of 240 seconds, was recorded for successive rotational speeds (15,18,21,24,27,30,32,36, and 40 rpm), and the overall rod performance (ORP) for each mouse was calculated by the trapezoidal method as the area under the curve in the plot of time on the rod versus rotation speed (27). To assess the responsiveness of the MPTP-related motor deficit to dopaminergic stimulation, mice were injected intraperitoneally with L-3,4-dihydroxyphenylalanine (L-DOPA) methyl ester/benserazide (100/25 mg/kg), and Rotarod performance was assessed 45 minutes later.…”

Inhibition by dizocilpine (MK‐801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter

“…Inside the terminal, MPP+ inhibits mitochondrial respiration (Vyas et al, 1986) with a consequent decline in ATP levels leading to a decline of energy-dependent processes (Scotcher et al, 1990;Chan et al, 1991).…”

Perioperative Neuroprotection Symposium

“…+ binding to Complex I, the flow of electrons along the respiratory chain is hampered in both dose-and time-dependent manners (Nicklas et al, 1985;Vyas et al, 1986;. The importance of the inhibition of Complex I in the MPTP-induced neurotoxicity in vivo is supported by the demonstration that strategies aimed at stimulating oxidative phosphorylation via by-passing the blockade of Complex I not only improve mitochondrial respiration but also mitigate dopaminergic neurodegeneration in mice (Tieu et al, 2003).…”