Importance of monoamine oxidase A in the bioactivation of neurotoxic analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Abstract

ABSTRACT1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MITP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients.AUl of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity ofthe MAO inhibitors to decrease the brain content ofthe pyridinium species after adm ration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process.The inadvertent self-administration of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by several young drug abusers resulted in a severe parkinsonian syndrome (1-3). Moreover, the administration of MPTP to nonhuman primates causes behavioral, biochemical, and pathological deficits very similar to those observed in patients with idiopathic Parkinson disease (4, 5). There are at least two necessary steps involved in the MPTP-induced destruction of nigrostriatal dopaminergic neurons. First, MPTP is oxidized by monoamine oxidase B (MAO-B) to the 1-methyl4phenyl-2,3-dihydropyridinium species (MPDP+), which is then transformed either spontaneously or enzymatically to the 1-methyl-4-phenylpyridinium species (MPP+), the primary metabolite of MPTP found in the brains of experimental animals (6-9). Second, MPP+ is actively transported into the dopaminergic neurons by the dopamine-uptake system (10, 11). The importance of these two steps is indicated by the observations that pretreatment of experimental animals with inhibitors of either or dopamine uptake (10,16,17) prevents MPTP-induced neurotoxicity.We recently found that a 2'-substituted analog of MPTP, 1-methyl4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-MeMPTP) (18,19) was a more potent nigrostriatal dopaminergic neurotoxin than MPTP in mice. As with MPTP, pretreatment with inhibitors of dopamine uptake prevented 2'-MeMPTP-induced neurotoxicity (19). However, unlike the case with MPTP, pretreatment with low and selective doses of MAO-B inhibitors did not prevent 2'-MeMPTPinduced neurotoxic...

In vivo trapping of hydroxyl free radicals in the striatum utilizing intracranial microdialysis perfusion of salicylate: effects of MPTP, MPDP+, and MPP+

“…Prior in vitro studies indicate that MPP+-induced neurotoxicity in dopamine producing neurons in cultures can be blocked either by a daily feeding of cells with fresh medium "to remove oxidants" (Reinhard et al, 1990) or by co-cultures in the medium containing lazaroid antioxidants (U-78518F, Sanchez-Ramos et al, 1992) and monoamine oxidase inhibitor (deprenyl, Mytilineou and Cohen, 1985). Despite the fact that deprenyl and clorgyline suppress the "OH formation (Chiueh etal., 1992) and the dopamine toxicity (Heikkila et al, 1988) elicited by 2'-methyl-MPTP, the exact free radical formation pathway induced by MPTP analogues ist not presently known. It has been proposed that MPTP analogues can potentiate the autoxidation of dopamine catalyzed by transition metals and the non-enzymatic formation of the free radicals in vitro (Poirier et al, 1985;Rossetti et al, 1988).…”

Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

“…Nevertheless, results obtained here also suggest that MAO-A might somehow accomplish the oxidation of MPTP under certain circumstances, and particularly, at low concentration of the toxin. Indeed, previous studies have shown that MPTP and MPTP analogs which are also neurotoxic substances might be oxidized with the participation of MAO-A 37,38 . A good correlation usually exists between the oxidation of MPTP (or MPTP analogs) with the pyridinium cations generated and the neurotoxic effects observed in vivo 37 , and also, between the ability to protect against the neurotoxic action of tetrahydropyridines (i.e.…”

“…Indeed, previous studies have shown that MPTP and MPTP analogs which are also neurotoxic substances might be oxidized with the participation of MAO-A 37,38 . A good correlation usually exists between the oxidation of MPTP (or MPTP analogs) with the pyridinium cations generated and the neurotoxic effects observed in vivo 37 , and also, between the ability to protect against the neurotoxic action of tetrahydropyridines (i.e. MPTP and its analogs) and the reduction of pyridinium cations exerted by MAO inhibitors (Figure 1).…”

“…In this regard, the oxidation of MPTP by MAO could be successfully used for preliminary screening of MAO inhibitors and potential protective agents. As shown, MAO-B is the main isozyme involved in the bioactivation of MPTP, although MAO-A might play a role in the metabolism of MPTP and analogs 1,37,38 . In this research, MAO inhibitors and potential neuroprotectants such as deprenyl, highly reduced the oxidation of MPTP to pyridinium cations.…”

“…The oxidation of biogenic amines and neurotransmitters by MAO produces reactive oxygen species (ROS) 2,16 , and the elevation of MAO-B is associated with an increased susceptibility to neurodegeneration 6 . In addition, MAO may oxidize neurotoxins like MPTP and analogs to directly-acting toxic pyridinium metabolites (MPDP + and MPP + ) 10,11,15,17,37,46 ( Figure 1). Therefore, a convenient use of MAO-inhibiting substances may result in protection against oxidative stress and toxicants 1,2,16,17 .…”