The discovery that 1 -methyl4-phenyl1,2,3,6-tetrahydropyndine (MPTP), a contaminant of a synthetic pethidine analogue sold as a street drug, produced a condition resembling Parkinson’s disease has been described in detail (for reviews, see Langston, 1985; Snyder and DAmato, 1986). MPTP was shown to cause a selective destruction of nigrostriatal dopaminergic neurons in primates and some other animal species, and this stimulated a great deal ofwork on the mechanisms involved in its neurotoxic effects and their possible relationship to idiopathic Parkinson’s disease. Earlier work on the mechanism by which MPTP exerts its selective neurotoxic effects has been reviewed before, and the present account will concentrate on more recent discoveries concerning its biochemical actions and the unresolved problems that remain.

Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds

The development of monoamine oxidase (MAO) inhibitors has followed a winding path. At the origin was the finding of E. A. Zeller that iproniazid, a hydrazine derivative designed to improve the tuberculostatic action of isoniazid, caused potent inhibition of MAO in vitro and in vivo. The inhibitor also exerted in vivo activity in the brain, subsequent pharmacological research indicating that this inhibition led to changes of cerebral functions [1]. Although the drug had no overt behavioral effects in animals when given alone, it modified the action of reserpine, one of the first modern psychotropic drugs. Thus, administration of iproniazid prior to reserpine unexpectedly antagonized the decreases in locomotor activity and in 5-hydroxy-tryptamine (5 HT) levels induced by reserpine in the brain, the animals sometimes even showing locomotor stimulation [1]. Since one serious side effect of reserpine in man was known to be mental depression, the antagonism of reserpine by iproniazid hinted at the possibility that this drug might be of use in the treatment of mood disorders. However, the actual breakthrough for the development of iproniazid as an antidepressant came from clinical observations. Various investigators had reported psychostimulant side effects of the MAO inhibitor in patients with tuberculosis and other chronic diseases.

The new generation of monoamine oxidase inhibitors.

During the last decade there has been a tremendous resurgence of interest in the etiology of Parkinson's disease (PD), despite the fact that there is, as yet, no direct evidence as to its cause. Nonetheless, most of those working in the field remain undaunted, proceeding full steam ahead to take advantage of the clues and leads that now seem so plentiful. While much of the original stimulus for this "etiological renaissance" stems from the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a simple pyridine moiety that is selectively toxic to the dopaminergic neurons of the substantia nigra, the research on the cause of PD has taken on a life of its own. Avenues of investigation range from the newly evolving field of molecular epidemiology to neurochemical studies of nitric oxide, gas that is also a neurotransmitter, and perhaps a killer of nerve cells.

In this article, some of the history that has gotten us to this point will be reviewed, with a particular emphasis on the MPTP story. Where appropriate, future research directions will be sketched out. At the same time however, one of the broader purposes of this article is to perform what might be called a "reality check" on current research, by providing a gentle reminder of the many phenomena that must be explained by any etiologic hypothesis which is to be seriously considered.

Interest in the cause of PD has waxed and waned throughout this century. One of the peaks almost certainly occurred with the advent of postencephalitic parkinsonism, which enhanced interest in the syndrome not only because of its widespread appearance after the great pandemic of 1918 to 1920, but also because it appeared to hold clues to the cause of the disease, since the syndrome so clearly followed an encephalitic illness. While it is now clear that postencephalitic …

The etiology of Parkinson's disease with emphasis on the MPTP story

Previous studies from this laboratory demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent neurotoxicity to dopaminergic neurons in mice produced by systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, Turski et al. [Nature 349, 414-418 (1991)] reported that extended treatment of rats with NMDA receptor antagonists (six injections at 4-h intervals) did prevent the loss of nigral dopaminergic neurons resulting from an intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of MPTP. The present studies examined if a similar extended treatment with MK-801 would protect mice from the neurotoxicity of systemically administered MPTP. Six intraperitoneal injections of MK-801 given at 4-h intervals did not protect mice against the MPTP-induced neostriatal dopamine loss measured 1 week after treatment. In other experiments, designed to replicate and expand on the results of Turski et al. (1991), the extended treatment of rats with MK-801 did not prevent MPP(+)-induced cell loss in the infused substantia nigra pars compacta or the dopamine depletion in the ipsilateral neostriatum at 7-11 days after MPP+ infusion. These results do not support the hypothesis that NMDA receptors are involved with MPTP/MPP(+)-induced neurodegeneration.

MK-801 fails to protect against the dopaminergic neuropathology produced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice or intranigral 1-methyl-4-phenylpyridinium in rats.

The in vivo generation of OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA Levels of 2,5-DHBA detected in the brain dialysate may reflect the OH adduct plus some enzymatic hydroxylation of salicylate in the brain After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of OH formation in the brain Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful OH trapping procedure for monitoring the time course of OH generation in the extracellular fluid of the brain These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of OH free radicals in the iron-rich basal ganglia Moreover, a site-specific generation of cytotoxic OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons This free-radical-induced nigral injury can be suppressed by antioxidants (ie, U-78517F, DMSO, and deprenyl) and possibly hypothermia as well In the future, this in vivo detection of OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al, this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO in cell cultures was discussed and debated at the symposium (Wink et al, this issue; Dawson et al, this issue; Lipton et al, this issue)(ABSTRACT TRUNCATED AT 400 WORDS)

In Vivo Generation of Hydroxyl Radicals and MPTP-Induced Dopaminergic Toxicity in the Basal Ganglia

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients. All 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 of the MAO inhibitors to decrease the brain content of the pyridinium species after administration 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.

K. A. McKeown

Papers

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

Postmortem stability of the GABAA receptor complex: a study using rat brain cerebrocortical membranes