Idiopathic Parkinson's Disease

Introduction

Idiopathic Parkinson's disease (IPD) is a leading cause of neurologic disability in people over 60. Extensive human and animal research has been aimed at improving the management of this disorder, While contemporary animal models parallel many of IPD's clinical features, the value of these models to improve our understanding and treatment of IPD is questionable.

Background: Idiopathic Parkinson's Disease

IPD is the most common cause of "parkinsonism," a generic term for a group of movement disorders caused by degeneration, infection, injury, or intoxication of the dopaminergic neuronal system.(1) Normally, there is a balance in the striatum of the brain between dopaminergic inhibition and cholinergic excitation. In parkinsonism, this balance is disturbed by depletion of the dopaminergic system. However, Yahr has cautioned that dopamine loss may not be the sole defect and that it may not underly "all of the manifestations of parkinsonism."(1)

First described by Parkinson in 1817,(2) IPD has been identified only in humans. This progressive disease, which almost always occurs in elderly people, features varying degrees of tremor (including resting tremor), akinesia, rigidity, hunched over posture, muscular weakness, excessive sweating, and dementia. Pathologically, there is degeneration of melanin-containing neurons, particularly in the substantia nigra and the locus ceruleus of the brain.(3) Other brain areas are sometimes affected. When clinical symptoms become apparent, 80% of the neurons in the substantia nigra, which produces dopamine (DA), may already be dead.(1) Intraneuronal inclusions called Lewy bodies are characteristically seen in IPD.(4) The clinical significance of Lewy bodies is not known.

Background: Animal Models

The two main animal models of IPD use neurotoxic chemicals to damage the dopaminergic system. One involves unilateral injection of 6-hydroxy-dopamine (6-OHDA) into the substantia nigra of rodents. A more recent primate model uses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The parkinsonian effect of MPTP was discovered in a group of heroin addicts who mistakenly believed they were using a related synthetic drug, MPPP. Soon after their exposure to MPTP, the addicts developed severe parkinsonian symptoms.(5,6) As in IPD, there was destruction of the substantia nigra and disturbance of the dopaminergic system.

Part 1: Comparison of the Animal Models to Human IPD

1) 6-OHDA

Clinical Presentation

Administration of 6-OHDA causes an imbalance between the normal substantia nigra on one side and the lesioned substantia nigra on the other. After injection of 6-OHDA, rats are given amphetamine to induce rotational behavior. Amphetamine increases DA release from nerve terminals, which increases the imbalance between the 6-OHDA lesioned (denervated) side of the brain and the normal side. The resulting rotational behavior differs markedly from the tremors and rigidity that characterize IPD. In part, this may reflect the fact that this animal model involves selective destruction of the substantia nigra of one side of the brain, while IPD features bilateral degeneration of the substantia nigra and involvement of other brain structures. This model has been used primarily to assess the dopaminergic activity of different chemicals. As will be discussed below, in vitro models may be superior to this model in identifying and evaluating agents that influence the dopaminergic system.

Pathogenesis

The neurotoxicity of 6-OHDA seems to be due to the formation of free radicals, which are toxic to cells.(7) Human clinical evidence has suggested that IPD may be related to the accumulation of free radicals.(3) At present the mechanism of neurotoxicity in this animal model and in IPD remains unclear. As Langston et al. have noted, it remains uncertain whether "The production of free radicals" or "covalent bonding of quinone oxidation products underlies the potent neurodegerative action of 6-OHDA."(8) Oxygen radical scavengers protect against 6-OHDA toxicity in mice atria,(9) but their value in preventing IPD is not known.(10)

2) MPTP

Clinical Presentation

Clinically, human MPTP toxicosis and IPD share many features. These similarities include analogous clinical symptoms, destruction of nigrostriatal DA neurons, changes of amine metabolites in the cerebrospinal fluid, response. to DA precursors and DA agonists, an initial response to DA agonist therapy followed by periods of poor response to the treatment, and, at times, drug-induced dyskinesia (impaired voluntary movement) as a result of DA replacement therapy.(11) Langston and Tetrud have written that it is "difficult if not impossible" to distinguish between MPTP toxicosis and IPD.(11) Some cognitive deficits of human MPTP victims closely resemble IPD deficits.(12) MPTP victims, however, do not suffer severe dementia, which occurs in about 25% of IPD.(13)

Because human MPTP toxicosis is clinically similar to IPD, investigators have used MPTP to create a parkinsonian syndrome in animals. Monkeys poisoned with MPTP exhibit symptoms similar to those seen in IPD patients, including akinesia, bradykinesia, flexed posture, and frozen limb and eye positions.(15) However, rigidity and resting tremor -- both common manifestations of IPD -- are uncommon in the non-human primates.(16)

While several species of monkeys manifest similar symptoms after MPTP toxicosis,(15-19) the effects of MPTP on non-primates vary. Rats are almost insensitive to repeated doses of MPTP, as are guinea-pigs, rabbits, and several strains of mice.(20) DA uptake blockers prevent the DA depleting effect of MPTP in mice, but they fail to prevent MPTP-induced parkinsonism in primates.(21) Finally, two analogues to MPTP are more potent than MPT P in producing striatal DA depletion in the mouse, but less potent in the primate.(21) Because the specific activity and clinical effect of MPTP differ considerably between rodents and primates, the value of non-primate models of MPTP-induced parkinsonism seems to be even less than that of the nonhuman primate models.

Originally, the MPTP monkey model was criticized because, unlike IPD, it did not damage the locus ceruleus region of the brain and did not produce Lewy bodies.(15,18) Later studies revealed that frequent administration of low dose MFTP to older monkeys can damage the locus ceruleus.(17,22,23) In addition, eosinophilic inclusion bodies that appeared to be related to the IPD Lewy body were observed.(17,24) While Lewy bodies are a characteristic feature of IPD, "Lewy bodies have not," according to Forno et at, "previously been reported in any species other than the human."(24) Some investigators have suggested that the eosinophilic inclusions found in MPTP monkeys are related to Lewy bodies, but Fomo et al. have concluded, "The eosinophilic inclusions in nerve cells observed in our older monkeys probably represent a peculiar and perhaps unique type of nerve cell degeneration."(24) Forno et al. have found, "MPTP inclusions do not possess the classical ultrastructural features of the Lewy bodies."(24) MPTP does not produce classical Lewy bodies in either monkeys or humans; IPD neural degeneration appears to differ from that of MPTP toxicosis.

Forno et al.'s modified MPTP model using older primates has locus ceruleus involvement, but they have observed, "The severe, partially necrotizing lesions (found in the locus ceruleus) are not seen in IPD, but this is undoubtedly due to the manner in which the MPTP-induced lesion is produced and the amount of the neurotoxin administered over a short period."(17) Indeed, the natural history of MPTP toxicosis in animals differs markedly from that of IPD. While MPTP involves acute toxicity, IPD is a slowly progressive disorder that evolves over a course of years.

There appear to be differences between MPTP and IPD in the locations of the neurologic damage as well. Garvey et al. have found "no evidence for any change in choline acetyltransferase activity in the frontal cortex of MPTP treated animals. . . . Examination did not show any evidence of cell loss within the nucleus basalis of Meynert.. . . These findings contrast with what occurs in idiopathic PD where cell loss in this nucleus is associated with changes in frontal cortical cholinergic parameters."(25)

Dopamine depletion contributes heavily to IPD symptoms, but there are differences in DA levels in MPTP-treated monkeys and in IPD. Pifl et al. have reported that the experimental monkeys had over 99% reduction of DA levels in the caudate and putamen.(26) In IPD, in contrast, DA loss in the caudate is 84% and loss in the putamen is 98%.(27) Interestingly, the DA levels in the MPTP model more closely resemble postencephalitic parkinsonism, in which there are DA deficits of 98% and 99% in the caudate and putamen, respectively.(26) There are other neurotransmitter differences between this MPTP model and IPD. MPTP and IPD cause different changes in the concentrations of substance P and of leu- and met-enkephalin in certain basal ganglia regions.(28) The etiopathological and clinical significance of these findings are unknown. Kopin and Schoenberg, while advocating use of the MPTP model, have acknowledged:

In contrast to Parkinson's disease, dopaminergic neurons in the ventral tegmentum projecting to the mesocortical and mesolimbic dopaminergic systems are relatively unaffected by MPTP. Moreover, the low brain levels of norepinephrine and serotonin noted in ideopathic Parkinson's disease are absent. Although the classic parkinsonian tremor is slow in frequency, involves distal muscles of the extremities, and is present at rest, the MPTP-induced tremor involves the proximal muscles of the extremities and is present when the animals maintain or take on a new posture. In MPTP-treated animals, there is little if any progression after the toxin has taken effect. Often, as indicated above, there is improvement to a more stable level.(29)

Pathogenesis

MPTP itself is not toxic. After it crosses the blood brain barrier, it is converted by monoamine oxidase type B (MAO-B) to MPDP, which is very unstable and auto-oxidizes to the toxic form MPP+.(30) It appears that DA neurons take up MPP+, which kills these dopaminergic neurons.(31) In addition, MPTP may be converted to MPP+ by noradrenergic and serotoninergic neurons, This explains the partial toxicity to these neurons.(32) The reason that MPP+ has a greater effect on the nigrostriatal DA neurons than on other dopaminergic neurons is unknown.(20)

Obviously, IPD is not due to exposure to synthetic MPTP, but some investigators have suggested that a toxic effect from an analogue of MPTP may cause IPD. Nevertheless, differences in pathological presentation indicate that the mechanism of MPTP neurotoxicity differs from that of IPD. Garney et al. have concluded, "It is therefore likely that the mechanism by which MPTP exerts its neurotoxic actions does not mimic the underlying defects leading to neuronal cell death in idiopathic PD."(25)

Part 2: Clinical Review Articles

Three recent clinical review articles do not credit the animal model with important contributions. Kurlan's "Practical therapy of Parkinson's disease,"(33) and Pearce's Modern treatment of Parkinson's disease"(34) mention no animal models. Two other articles did discuss MPTP. Eadie's 1988 review discusses the MPTP monkey model: a "recent report of structures that resemble Lewy bodies in the brains of monkeys that [have] been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have incited speculation about a toxic origin for idiopathic Parkinson's disease; however, no more definitive evidence has emerged yet."(35) In conclusion, it does not appear that clinicians have been able to apply the animal model data to the management of IPD.

Part 3: Clinically Important Questions

Until we have a better understanding of IPD etiology, it will remain difficult to design effective prevention and treatment strategies. Consequently, a critical question is, "What is IPD's pathogenesis?" Historically, animals have been used to study the effects of central nervous system amine neurotransmitter depletion, but the value of animal research in elucidating IPD's pathogenesis is questionable. In 1957, Carlsson et al. treated mice with reserpine; they found that the mice were "markedly tranquilized."(36) Administration of 3,4-dihydroxyphenylalanine, an amine precursor, relieved the symptom. Because resperpine and 3,4-dihydroxyphenylalanine affect several amine neurotransmitters, the specific neurochemical(s) responsible for these findings remained unknown. Furthermore, there was dubious relevance to IPD, because these mice did not exhibit parkinsonism. In 1958, Carisson speculated that dopamine was involved in the control of motor activities,(37) but there was little evidence to support that theory. A close review of the literature indicates that clinical research was primarily responsible for the identification of dopamine depletion as the cause of parkinsonism. Long before Carisson's work, clinicians recognized the substantia nigra's role in parkinsonism. Clinicians found substantia nigra degeneration in patients who suffered from parkinsonism due to von Economo's encephalitis.(38) In the 1950s, clinicians noted that some psychiatric patients taking phenothiazides or reserpine developed a Parkinson-like syndrome, and subsequent studies showed that reserpine depletes monoamines, including dopamine.(38a) In 1959, Sano et al., using new biochemical techniques, found elevated dopamine levels in the human extrapyramidal system, particularly in the striatum. These findings indicated that dopamine was involved in motor function.(39) In 1960, Ehnnger and Hornykiewicz documented decreased dopamine in the substantia nigra of autopsied IPD brains.(40) Thus, it appears that identification of the substantia nigra as the locus of pathology and recognition that dopamine is depleted in the substantia nigra of IPD patients resulted from clinical investigation.

Are the contemporary animal models useful for understanding IPD? The 6-OHDA model has suggested that free radicals may be responsible for IPD, but this remains highly speculative. While there is some clinical evidence implicating free radicals in IPD, people deficient in vitamin E --which absorbs free radicals -- do not show basal ganglia pathology.(41)

The MPTP model resembles IPD clinically; consequently, several investigators have suggested that it may yield insights into IPD pathogenesis. However, Barker has commented:

The fact that MPTP is neurotoxic to DA neurons and so produces parkinsonism proves no more than that the nigrostriatal DA pathway is important in producing the clinical features of PD. It does not tell us anything about the aetiology of idiopathic PD because the pathology, age and speed of onset of symptoms and response to therapy are very different in MPTP parkinsonism patients from those with idiopathic PD.(42)

Langston et al. have noted, "A surprising number of toxins produce a Parkinsonian state in humans, and this has been known for some time."(8) Human clinical investigations have been of primary importance in implicating environmental agents among these toxins. However, as Tanner et al. have observed, "No study has demonstrated that a single environmental agent can account for a majority of PD cases."(47) Clinical studies have reported correlations between prevalence of IPD and manganese toxicity,(43,44) well water,(45) saw and paper mills,(46) and steel alloy plants.(46) In support of these findings, Calne and Peppard have noted, "The most difficult mechanism of pathogenesis to refute is chronic toxic damage, where the lesion may derive from long-term exposure to a relatively widespread noxious agent or agents."(47) The contribution of toxic agents remains unsettled, however, and Tanner et al. have observed, "No study has demonstrated that a single environmental agent can account for a majority of PD cases."(48) Although epidemiological research has so far failed to identify the cause(s) of IPD, it is probably the most promising approach.(49)

The search for a possible genetic predisposition to IPD has also relied on clinical research. In a study of identical twins, Ward et al.'s finding of a "low concordance rate in monozygotic twins suggests nongenetic factors are involved."(50) However, Calzetti et al. have cautioned, "failure to demonstrate a significant inherited component could be due to consideration of the disease as a single homogeneous entity."(51)

A second question is, "What therapeutic agents can relieve IPD symptoms?" The animal models have been used to assess the efficacy of different dopaminergic chemicals. However, the possible value of animal models for discovering new dopaminergic drugs has been diminished by the development of in vitro systems. An experimental drug, PHNO, was found in vitro to have dopaminergic activity that was selective for the D-2 receptor. This selectivity should reduce its systemic toxicity. While in vivo models have also demonstrated PHNO's dopaminergic effects, they were unnecessary. The in vitro test provided sensitive quantitative and qualitative analysis of PHNO.(52)

Can the animal models help discover other useful classes of drugs that are not dopamine agonists? Birkmayer et al. have demonstrated that addition of 1-deprenyl (an MAO inhibitor) to 1-dopa therapy increases life expectancy in IPD patients. This finding suggests that 1-deprenyl retards the IPD degenerative process.(53) There are several theories for 1-deprenyl's efficacy as adjunctive therapy to 1-dopa. L-deprenyl may inhibit MAO-mediated oxidation of DA. This may reduce DA fluctuation and lessen the on-off phenomenon.(54) Interestingly, 1-deprenyl protects monkeys from the effects of MPTP(55), and this had led some scientists to claim that that the animal model was necessary for this therapy.(55a) However, 1-deprenyl's efficacy for IPD was shown in human patients in the mid-1970s, long before the animal model was developed.(55b) Furthermore, the ability of MAO inhibitors to block MPTP toxicity to dopaminergic neurons was first shown in an in vitro system.(56) Some investigators have suggested that, if IPD is caused by a toxic compound with a structure similar to MPTP's, 1-deprenyl might prevent IPD. Given that 1-deprenyl's efficacy in IPD can be explained on the basis of MAO inhibition, it seems unlikely that its effect is actually mediated by blockage of an MPTP-like substance.

There has been considerable interest in transplantation of dopaminergic tissues to the substantia nigra in order to ameliorate IPD symptoms. In Mexico, Madrazo et al. reported encouraging results after transplanting adrenal medullary cells to the right caudate nucleus of two human IPD patients in 1987.(57) The surgical transplant technique was based on animal models of parkinsonism (58-62) and Backlund et al.'s experience with two adrenal medullary transplants in human patients in 1985.(63) Whereas Backlund et al. had obtained disappointing results, Madrazo claimed success. Preliminary results from more recent studies have indicated only modest to moderate benefits in some patients,(64,65) and overall results have been disappointing.(66) Several centers in the United States have stopped performing this procedure due to complications. Overall, investigators have failed to reproduce Madrazo's dramatic findings. Lewin has summarized, "The disparity between what we see in the American patients and what we have been told about the Mexican patients is substantial."(67) While success with both the MPTP(68) and the 6-OHDA models stimulated interest in this procedure, its value in IPD is still uncertain.

Sladek et al. improved the symptoms of MPTP-induced parkinsonism in primates by grafting fetal DA neurons into the primates' brains.(69) Subsequent human studies have been less encouraging. Lindvall et al. have reported two patients who experienced mild, temporary improvement in some symptoms, but "No major therapeutic effect from the operation was obsewed."(70) Human application may be impeded by immunological rejection(71) and by political opposition to the use of tissues from aborted fetuses.

Another clinical challenge is the early diagnosis of IPD. While no therapies have proven effective in preventing this disease, earlier diagnosis might permit studies that will yield insight into etiopathology and lead to novel therapeutic approaches. In PET scan studies of MPTP-poisoned drug addicts, Langston et al. found an intermediate dopamine-depletion state. They have suggested that PET scan screening of elderly people might permit IPD diagnosis before the onset of clinical symptoms.(11)

Conclusions

Animal models of IPD have been extensively used. The discovery that MPTP causes a parkinsonian syndrome in animals that clinically resembles IPD has caused considerable excitement in the scientific community. Nevertheless, this experimental condition differs considerably from IPD on pathological grounds, and its rapid natural history differs dramatically from IPD's insidious course. The search for IPD's etiology has relied on epidemiological and pathological studies of humans. The advent of noninvasive scanning techniques, such as MRI and PET scans, offers hope for further insights into this disease. In research to find effective therapeutics, animal models may have served some purpose in the past as a screen for dopaminergic compounds. This function, however, appears to be outdated by in vitro methodologies.

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