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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Parkinson's Disease

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Correspondence to J. Sian, Division of Clinical Neurochemistry, Department of Psychiatry, University of Würzburg, 97080 Würzburg, Germany.

Parkinson's disease was first described in a classic monograph, “The Shaking Palsy,” published in 1817 by the London physician James Parkinson. The cardinal features of Parkinson's disease are (i) tremor, mainly at rest; (ii) muscular rigidity, which leads to difficulties in walking, writing, speaking and masking of facial expression; (iii) bradykinesia, a slowness in initiating and executing movements; and (iv) stooped posture and instability. Many of these clinical features are also manifested by other basal ganglia disorders and, thus, often referred to as parkinsonian syndromes (Table 45-3). Parkinsonian symptoms may occur with any disorder that causes damage to the nigrostriatal DA neurons or that results in an imbalance diminishing the disinhibition in the indirect circuit. SNc DA fibers would normally increase the total disinhibition of the thalamus through both the excitatory D1 receptors in the direct circuit and the inhibitory D2 receptors in the indirect circuit (Fig. 45-1). Thus, lesions of the pallidum, as well as those of the SNc, result in the appearance of parkinson-like movement disorders [4].

Table 45-3. Classification of the Various Forms of Parkinsonism, Based on Differential Etiology.

Table 45-3

Classification of the Various Forms of Parkinsonism, Based on Differential Etiology.

Neurological disorders such as progressive supranuclear palsy, multiple system atrophy and the Parkinson—amyotrophic lateral sclerosis (ALS)—dementia complex that include parkinsonian movement abnormalities in addition to other neurological deficits are termed “parkinsonism-plus” syndromes (Table 45-3) [5]. Infectious disease, tumors, metabolic disturbances and toxins may also produce forms of parkinsonism. Parkinson's disease progresses slowly but may ultimately produce akinesia and complete helplessness. Although the clinical features were well described, the pathological basis of the disease remained unknown for over 100 years. The frequent occurrence of parkinsonism as a sequel to von Economo's encephalitis lethargica, which reached epidemic proportions in 1918 to 1921, led to the discovery that depigmentation of the substantia nigra is a constant feature of parkinsonism, whether as a result of a virus, exposure to toxins or unknown causes. In view of widespread changes elsewhere, there was, however, hesitancy in attributing to so small a brain lesion so extensive a movement disorder.

The chemical pathology of Parkinson's disease includes degeneration of the dopaminergic nigrostriatal tract and reduction in striatal dopamine

Nearly two generations elapsed before the next major advances in understanding Parkinson's disease. In 1958, Carlsson and coworkers [6] reported on the distribution of DA in the brain, its highest concentrations in the striatum, its depletion by reserpine and the dramatic effect of l-DOPA in reversing reserpine-induced tranquilization, impoverished motor activity and ptosis in mice and rabbits. They showed also that pretreatment with an MAO inhibitor potentiated the effects of l-DOPA in reversing the effects of reserpine. The uneven distribution of DA in the brain suggested that this substance may function as a neurotransmitter. Two years later, Ehringer and Hornykiewicz [7] noted the greatly reduced DA concentrations, to about one-tenth of normal, in the caudate, putamen and substantia nigra in brains from parkinsonian patients (Fig. 45-2B). Shortly thereafter, newly developed histofluorescence techniques demonstrated the previously unknown nigrostriatal DA-containing tract with cell bodies in the SNc and axonal projections to the striatum. These techniques also showed that the striatal DA deficit was not due to a reduction in the activity of TH, the dopaminergic rate-limiting enzyme, but rather to loss of the nigrostriatal dopaminergic neurons. Similarly, DA depletions were also found in all of the parkinsonian syndromes. The DA deficit appeared to be confined to disorders exhibiting striatal pathology (Table 45-2).

Diminished formation and metabolism of DA in Parkinson's disease are reflected in low postmortem concentrations of DA, DOPAC and HVA in the caudate nucleus and putamen (Table 45-4). Very small amounts of DA are detectable in the CSF. In contrast, some HVA normally diffuses, in particular from the caudate nucleus into the CSF, where it is readily detectable [8]. In Parkinson's disease, particularly in more severely affected patients, the CSF concentrations of HVA are far below those found in patients with neurological disorders not involving the basal ganglia. Because HVA is a substrate for the active transport mechanism that removes acidic compounds into the circulation, there is a steep gradient in CSF concentrations of HVA, with the highest concentrations in the lateral ventricles and the lowest in the lumbar CSF. This acid-transport system is inhibited in a dose-dependent manner by probenecid (p-dipropylsulfamylbenzoic acid). Probenecid has been used to differentiate low concentrations of HVA in CSF in other disorders of the CNS from those found in Parkinson's disease. Parkinsonian patients given probenecid show a lower increase in HVA than do patients with other neurological disorders. Also, it is now possible, using positron-emitting analogs of l-DOPA such as [18F]6-fluorodopa, to demonstrate the deficiency in forming and storing DA in living parkinsonian patients (see Chap. 54). Parkinsonian syndromes that primarily involve the DA system may benefit from therapies aimed at DA replacement, whereas those involving other pathways are generally unresponsive to such treatments.

Table 45-4. Neurobiochemical Changes in the Dopaminergic System in the Nigrostriatal Pathway in Parkinson's Disease.

Table 45-4

Neurobiochemical Changes in the Dopaminergic System in the Nigrostriatal Pathway in Parkinson's Disease.

l-DOPA is used to treat Parkinson's disease

l-DOPA treatment was first advocated by Birkmayer and Hornykiewicz (intravenously) [9] and Barbeau and colleagues (orally) [10] in 1961. Both of these groups found highly favorable responses of most of the motor deficits associated with Parkinson's disease, and the findings from these studies established the contention that most of the clinical signs and symptoms of Parkinson's disease are a result of DA deficiency.

There is also marked loss of norepinephrinergic neurons in the locus ceruleus. In addition, there appears to be a dysfunction in the serotonergic system in Parkinson's disease. This contention is reflected by reduced concentrations of serotonin metabolites in the CSF of parkinsonian patients, particularly in depressed patients. There has been a strong suggestion of dysfunction of both the norepinephrinergic and serotonergic systems in Parkinson's disease-related depressive psychosis.

Although there are other biochemical abnormalities in the parkinsonian brain, such as diminished concentrations of serotonin, NE, GABA and GAD, these are not as striking as the loss of DA, which appears to be crucial. Strategies were then focused on enhancing the efficacy of l-DOPA treatment to improve its access to the brain and to reduce its peripheral side effects.

l-DOPA treatment is potentiated by inhibition of peripheral decarboxylation

Passage of ingested l-DOPA into the brain parenchyma entails its absorption from the intestine, passage through the hepatic circulation and transfer to the brain from blood through the endothelial cells lining the capillaries. Considerable AADC activity is present in the intestinal wall, the liver, the kidneys and the brain capillary endothelium; DA formed by decarboxylation of l-DOPA at these sites is excluded from the brain. Selective inhibition of extracerebral AADC was therefore explored as a means of enhancing l-DOPA efficacy. The first compound found to inhibit AADC was α-methyldopa (Fig. 45-3). This drug inhibits the decarboxylation of l-DOPA but is itself a substrate for the enzyme and is converted to α-methyldopamine and α-methylnorepinephrine, which can replace the physiological neurotransmitters. Since they are not as effective at activating receptors, these “false transmitters” reduce catecholaminergic activity. Although α-methyldopa proved useful in treating hypertension, it occasionally results in the appearance of parkinsonian symptoms by diminishing brain DA.

It has long been known that DA does not penetrate the blood—brain barrier, while its amino acid precursor, l-DOPA, readily enters the brain, where it is decarboxylated to form DA. This has been shown through behavioral and biochemical studies. However, brain DA replacement with l-DOPA was greatly limited because of severe side effects, particularly nausea and vomiting. Thus, the discovery and introduction by Birkmayer and Mentasti [11] of the decarboxylase inhibitor benserazide proved to be highly useful in the potentiation of centrally mediated l-DOPA effects. Consequently, this allowed the gradual decrease in oral doses of l-DOPA to achieve symptomatic improvement without loss of efficacy. More importantly, reduction of the l-DOPA dose resulted in curtailing the notorious adverse peripheral side effects of the drug [12]. Carbidopa and benserazide (Fig. 45-3) can be administered in doses that affect only extracerebral AADC, including that of the brain capillaries, and both have been found to be useful adjuncts to l-DOPA treatment [13].

When l-DOPA has crossed the blood—brain barrier, aided by an active transport mechanism, it must be converted to DA. Some question arises as to the source of the decarboxylase for this since many of the dopaminergic neurons, including the AADC found in them, are absent in the disease. Studies of postmortem striatum, however, have not yet revealed any cases with a total deficiency of AADC in the striatum; there has always been at least a residue of enzyme activity (Table 45-4). Moreover, cells of the striatum receive connections from many sources, including serotonin-producing raphe nuclei. Hence, l-DOPA could also be converted to DA by the decarboxylase within those neurons. The DA formed would then be available in brain tissue, although its path of diffusion to sensitive receptors might be longer than usual. Untreated parkinsonian patients have elevated densities of D2 receptors in the striatum, presumably reflecting a “supersensitive” state in which responses could be elicited by lower DA concentrations. Treatment with l-DOPA lowers the density of D2 receptors to that in control tissue.

Chronic l-DOPA treatment induces other complications, such as dyskinesia, or involuntary movement, and dystonia. These complications associated with long-term l-DOPA treatment led to the quest for alternative pharmacological approaches to ameliorate the undesirable actions of l-DOPA. Consequently, the actions of MAO and COMT inhibitors were explored.

l-DOPA treatment is potentiated by monoamine oxidase or catechol-O-methyltransferase inhibition

The revelation that the striatal DA deficit elicits the motor symptoms in Parkinson's disease gave rise to another strategy to potentiate the effects of endogenous DA. This strategy was based on blocking two key enzymes involved in the catabolism of DA, namely, MAO and COMT. The inhibition of DA catabolism was suggested to be an adjunct to l-DOPA to enhance its availability at postsynaptic receptor sites [14]. DA is a substrate for both forms of MAO; however, in the human brain, it exhibits a preference for MAO-B. Since it was observed that inhibitors of this enzyme potentiate the effects of l-DOPA in reversing reserpine-induced tranquilization, it was apparent that this might also be true for l-DOPA used in treating Parkinson's disease. However, the use of nonselective MAO inhibitors produced a distinct untoward reaction, referred to as the “cheese effect.” This revelation was precipitated in depressed patients treated with MAO inhibitors who ingested foods rich in tyramine, such as cheese and wine, and consequently developed acute severe hypertensive reactions. Since similar reactions could occur with concurrent use of l-DOPA and MAO inhibitors then in use, these drugs were contraindicated in parkinsonian patients being treated with l-DOPA.

However, after the discovery that the hypertensive reactions were due to inhibition of MAO-A, it was found that deprenyl, or selegiline, an irreversible inhibitor of MAO-B, is devoid of the “cheese effect” (Fig. 45-3). Birkmayer and colleagues [14] found that the use of deprenyl as an adjunct to l-DOPA therapy, including a peripheral decarboxylase inhibitor, not only enhanced the efficacy of l-DOPA but appeared to stabilize fluctuations in response and to prolong the effects of l-DOPA [14]. Deprenyl has a twofold beneficial role as an adjunct in l-DOPA therapy. First, it inhibits the metabolism of DA, thereby allowing the preservation of DA in the basal ganglia and, thus, allowing lower l-DOPA doses without loss of efficacy. Additionally, it delays starting l-DOPA treatment by at least 1 year, thereby reducing the occurrence of l-DOPA-related adverse effects, including “on—off” plasma fluctuations, dyskinesia and dystonia. Deprenyl monotherapy is usually administered in the early, mild stages of the disease since it appears to have only a modest beneficial effect on the clinical deficits.

The clinical benefits of another, but reversible, MAO-B inhibitor, labazemide, appear similar to those of deprenyl. Rasagiline, an irreversible MAO-B inhibitor similar to deprenyl, may be marginally superior in comparison with the other inhibitors in so far as it is not metabolized to amphetamine. Indeed, there is evidence suggesting that the l-amphetamine produced from deprenyl may be detrimental to the beneficial actions of the drug itself. Moclobamide, a MAO-A inhibitor, has been shown to produce both alleviation of parkinsonian clinical symptoms and depression. l-DOPA is a substrate for COMT, and when decarboxylation is blocked, plasma levels of 3-O-methyldopa (3-OMD) are elevated. Because both l-DOPA and 3-OMD are absorbed from the intestine and transported into the brain by the same saturable carrier system for which many large neutral amino acids (LNAAs) are substrates, 3-OMD and dietary amino acids influence the efficacy of l-DOPA treatment. Furthermore, 3-O-methylation contributes to the rapid metabolism of l-DOPA. Clinical assessment of the COMT inhibitors (Fig. 45-3) tolcapone and entacapone has shown that these drugs enhance the efficacy of l-DOPA; in addition, they appear to reduce the fluctuations related to “wearing-off,” a period when the plasma levels of l-DOPA decline. Thus, these drugs are beneficial as adjunct therapy. In preclinical studies, tolcapone has been shown to enhance the effects of l-DOPA by virtue of its dual action, including inhibition of l-DOPA metabolism in the periphery and DA break-down in the brain. Entacapone primarily acts peripherally.

There are other alternatives and adjuncts to l-DOPA treatment of Parkinson's disease

Unfortunately, chronic l-DOPA treatment manifests some clinical and pharmacological complications, including dyskinesia, “on—off” and “wearing-off” syndromes and psychosis. Regardless of the l-DOPA regimen, it has been reported that more than 50% of patients develop “on—off”-induced dyskinesias after a period of 5 years of treatment. The “on” and “off” periods have been ascribed to adaptations in receptor or neuronal responses to variations in brain or plasma concentrations of l-DOPA or DA. Therefore careful titration of l-DOPA doses may be warranted, to maintain more steady plasma l-DOPA concentrations.

The actions of l-DOPA in Parkinson's disease or of DA at receptor sites in the CNS are mimicked by a number of compounds. Apomorphine, a semisynthetic ergot alkaloid, has a brief dopaminergic action (Fig. 45-5) and affects both D1 and D2 receptors. It is chiefly administered, usually by subcutaneous infusion, in the event of abrupt “off” attacks. It acts both pre- and postsynaptically, and the presynaptic autoreceptors are particularly sensitive to this drug. Its best recognized action is at the DA receptor sites making up the area postrema. Like l-DOPA, apomorphine affects certain neuroendocrine systems. In humans, subemetic doses provoke striking increases in concentration of growth hormone in the plasma, presumably by acting on cells producing the appropriate releasing factor. In many species, it depresses the concentration of serum prolactin by a direct action on D2 receptors. More importantly, it has potent iron-chelating properties, which may explain its antioxidant abilities.

Figure 45-5. Dopamine receptor agonists.

Figure 45-5

Dopamine receptor agonists.

Three other DA agonists (Fig. 45-5), bromocriptine (D2), lisuride (D1 and D2) and pergolide (D1 and D2), all of which are ergoline derivatives and act predominantly as D2-receptor agonists, have found some practical use in the treatment of early symptoms of Parkinson's disease or as adjuncts to l-DOPA/carbidopa or l-DOPA/benserazide in later stages [15]. Long-term studies have revealed that the efficacy of l-DOPA is enhanced when it is administered in combination with DA agonists, including bromocriptine, lisuride or pergolide. It has been reported that a combination of bromocriptine and l-DOPA in early Parkinson's disease appears to be more effective at reducing the onset of development of l-DOPA-related dyskinesias. In addition, it can be employed as monotherapy in early Parkinson's disease. Lisuride is significantly more potent than bromocriptine; unfortunately, it is relatively short-acting, which may severely limit its clinical use. Similar to deprenyl, it may delay starting l-DOPA treatment by at least 1 year. The newly launched DA agonists ropinirole (D2) and pramipexole (mainly D3 but also D1, D2L and D4), both of which are devoid of the ergot structure, and long-acting cabergoline (Fig. 45-5), may also reduce the incidence of dyskinesia, probably by decreasing the required dose of l-DOPA. Therefore, effective pharmacological management of Parkinson's disease appears to involve direct and constant stimulation of the dopaminergic system.

Before the advent of l-DOPA, anticholinergic agents were among the most commonly used drugs and were the therapeutic mainstay in the treatment of Parkinson's disease. Anticholinergics such as trihexyphenidyl and benztropine may offer marginal clinical benefit to the parkinsonian tremor. They appear to restore the balance that is disturbed when striatal cholinergic neurons are released from the inhibitory action of DA fibers that synapse with them. Nevertheless, they are contraindicated in parkinsonian patients with dementia since administration of anticholinergics in these patients would aggravate the cognitive dysfunction.

The noncompetitive NMDA receptor antagonist memantine has shown modest advantage in curtailing Parkinson's disease motor deficits, particularly akinesia. In contrast, budipine, which is also an NMDA antagonist, is particularly effective at alleviating tremor, akinesia and rigidity.

There may be an involvement of the serotonergic inhibitory pathway from the raphe nucleus to the nigrostriatal pathway in the etiology of parkinsonian tremor (see above). Indeed, this notion is supported by the marked improvement of tremor demonstrated in parkinsonian patients treated with the 5-HT2 receptor antagonist ritanserin.

Parkinson's disease can also be treated surgically

The surgical technique of pallidotomy was first employed in Parkinson's disease in the early 1950s [16]. It was later superseded by thalamotomy, which appeared to be more effective at relieving tremor. However, in the wake of the highly successful l-DOPA treatment, the utilization of surgical treatment in Parkinson's disease gradually waned. Currently, the focus on surgical intervention in Parkinson's disease has awakened once again. This is chiefly due to the beneficial effects of ventrolateral medial pallidotomy demonstrated by Laiten and colleagues [17] in advanced Parkinson's disease, which rekindled worldwide interest in this procedure and reinforced its potential in the management of the disease.

Pallidotomy is primarily engineered to reduce the hyperactivity in the internal segment of the GPm caused by an excessive input from the STN. Indeed, the overactivity of the globus pallidus has been implicated in the motor disabilities associated with Parkinson's disease. This is in accordance with the suggestion that striatal DA deficit results in the overactivity of the GPm as a result of disinhibition of glutamatergic innervations from the STN to the globus pallidus (Fig. 45-1). This technique has proven particularly effective in advanced Parkinson's disease.

Some other dramatic effects of pallidotomy include the almost complete abolition of l-DOPA-induced dyskinesia contralateral to the side of the lesion and enhancement of the efficacy of dopaminergic drugs. It also reduces motor fluctuations associated with the “on” states, as well as both the severity and occurrence of the “off” periods. In addition, pallidotomy appears to be more beneficial than thalamotomy, which is highly effective at eliminating tremor and rigidity only. The progression of the disease is largely governed by the course of bradykinesia, which does not appear to be grossly altered by thalamotomy. However, the mechanism(s) underlying the effect of surgery on the rate of degenerative process is not clearly understood.

A pertinent observation is reflected by the impressive reduction in tremor achieved in parkinsonian patients by high-frequency stimulation of the STN. This is achieved by implanting a microstimulating device in this region [18]. This procedure allows the functional inhibition of specific brain regions without the application of a lesion. Therefore, it is considered to be safer than and superior to pallidotomy or thalamotomy. Another advantage of subthalamic stimulation is that, by virtue of its attenuation of tremor, it consequently reduces both the required dose of l-DOPA and l-DOPA-related dyskinesias.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28062