Effects of 1‐Methyl‐4‐Phenyl‐ 1,2,3,6‐Tetrahydropyridine and 1 ‐Methyl‐4‐Phenylpyridinium Ion on ATP Levels of Mouse Brain Synaptosomes

Abstract

Mouse brain synaptosomes, essentially devoid of mitochondrial contamination, were used as a model to study the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) on the levels of ATP of neuronal terminals. Similar to known inhibitors of ATP synthesis, both MPTP and MPP+ caused a dramatic depletion of synaptosomal ATP. This depletion was dose dependent and occurred as a relatively early biochemical event in the absence of any apparent damage to synaptosomal membranes. MPP+ was more effective than its parent compound in decreasing ATP; it induced a significant loss at concentrations (10-100 microM) similar to those it reaches in the brain in vivo. MPTP-induced ATP depletion was completely prevented by the monoamine oxidase B inhibitor deprenyl, which, on the contrary, was ineffective against MPP+. As expected in view of the heterogeneous population of nerve terminals present in our synaptosomal preparations, the catecholamine uptake blocker mazindol did not significantly affect the ATP loss caused by both compounds. Data indicate that (1) administration of MPTP may cause a depletion of ATP within neuronal terminals resulting from the generation of MPP+, and (2) exposure to the levels of MPP+ reached in vivo may cause biochemical changes that are nonselective for dopaminergic terminals.

Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein

“…A single exposure to MPTP will predominantly result in transient dysfunction within the dopaminergic axon terminal including reduction in vesicular DA, ATP loss and free radical formation (Di Monte et al, 1986; Hasegawa et al, 1990; Jackson-Lewis et al, 1995; Lotharius and O'Malley, 2000; Chan et al, 2006; Scotcher et al, 2006). Chronic MPTP exposure has been shown to result in relatively sustained DA axon terminal loss, motor abnormalities, as well as necrotic and apoptotic like cell death (Jackson-Lewis et al, 1995; Tatton and Kish, 1997; Lotharius and O'Malley, 2000; Petroske et al, 2001).…”

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

“…Frequent sampling was employed, revealing a dopamine-releasing action that was very rapid, with a latency comparable to the dopamine-releasing actions of nicotine, high K+, and amphetamine. Such a rapid action is unlikely to be due to the inhibition of mitochondrial respiration and depletion of intracellular ATP levels, a process which tends to occur more gradually after MPP+ administration (Scotcher et al, 1990;Chan et al, 1991). In all of the present experiments, the monoamine oxidase inhibitor, pargyline, was included in the superfusion buffer, and thus the acute effect of MPTP did not depend on conversion to MPP+.…”

“…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).…”

Mitochondrial Biology and Parkinson's Disease

“…Supporting this view, MPP þ (MPTP's active metabolite) causes a rapid and profound depletion of cellular ATP levels in isolated hepatocytes (Di Monte et al 1986), in brain synaptosomal preparations (Scotcher et al 1990) and in whole mouse brain tissues (Chan et al 1991). In mice, however, MPTP causes only a mild ( 20%) and transient reduction in striatal and midbrain ATP levels (Chan et al 1991).…”