Levetiracetam improves choreic levodopa-induced dyskinesia in the MPTP-treated macaque
Introduction
Current treatments for Parkinson's disease are based largely on the dopamine precursor, l-3,4 dihydroxyphenylalanine (levodopa). Although initially successful, within 5 years of commencing levodopa treatment, up to 80% of patients will experience severe side effects (Rascol et al., 2000), such as loss of efficacy, marked unpredictable fluctuations in motor activity and dyskinesia (Bezard et al., 2001a). In levodopa-induced dyskinesia, there is a wide spectrum of phenomenology, including chorea, choreoathetosis, ballism, and dystonia (Bezard et al., 2001a).
Although the neural mechanisms underlying levodopa-induced dyskinesia in Parkinson's disease are far from clear, major advances have been made in recent years. On the one hand, there is evidence supporting the hypothesis that choreic and dystonic forms of dyskinesia are supported (or generated) by distinct pathophysiological mechanisms within the basal ganglia Bezard et al., 2001a, Vitek, 2002. On the other hand, as foreshadowed in Filion's ground-breaking studies (Filion, 1979), Levodopa-induced dyskinesia is associated with an abnormally decreased firing frequency of basal ganglia output neurons at the level of the internal segment of the globus pallidus Boraud et al., 2001, Hutchison et al., 1997. Moreover, both altered firing patterns (Boraud et al., 2001) and changes in the level of synchronization of globus pallidus pars internalis neurons have been suggested to contribute to dyskinesia genesis (Boraud et al., 2002). Interestingly, recordings performed in patients with generalized dystonia or hemiballism, a syndrome phenotypically related to levodopa-induced chorea in Parkinsonian patients, were suggestive of an increased degree of synchronization of globus pallidus pars internalis neurons in the patient with hemiballism that was not found in the dystonic patients (Vitek et al., 1999). Together these data suggest that choreiform levodopa-induced dyskinesia may be correlated to a persistent pathological synchronization that would not be fully normalized by the levodopa treatment (Boraud et al., 2002), i.e. a lack of desynchronization, while dystonic dyskinesia may not (Vitek, 2002).
We, thus, hypothesized that a drug able to reduce neuronal (hyper)synchronization may alleviate choreic Levodopa-induced dyskinesia whereas it would not affect the dystonic component of the levodopa induced side effects. Levetiracetam (Keppra®) is a novel anti-epileptic drug with proven efficacy as adjunctive therapy in patients with refractory partial epilepsy Cereghino et al., 2000, Marson et al., 2001. Interestingly, it has been shown that inhibition of epileptiform activity by levetiracetam appears to contrast with other anti-epileptic drugs by involving a significant ability to reduce neuronal (hyper)synchronization Klitgaard et al., 2003, Margineanu and Klitgaard, 2000. For this reason, levetiracetam appears to represent a powerful pharmacological tool for assessing the hypothesis that attenuation of synchronization may selectively decrease the severity of choreiform dyskinesia. This study, therefore, investigated the effect of levetiracetam on choreic and dystonic dyskinesia induced by chronic Levodopa treatment in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque model of Parkinson's disease.
Section snippets
Animals
Experiments were conducted on six female cynomolgus monkeys (Macaca fascicularis; Shared Animal Health, Beijing, China; age=3–4 years; weight=3–5 kg). Animals were housed in individual primate cages under controlled conditions of humidity (50±5%), temperature (24±1 °C), and light (12 h light/dark cycles, lights on 8:00 a.m.), food and water were available ad libitum, and animal care was supervised by veterinarians skilled in the healthcare and maintenance of nonhuman primates. Experiments were
Effect of levodopa monotherapy
Levodopa (76±7 mg/kg) alone fully reversed parkinsonian symptoms. Following chronic Levodopa treatment, the alleviation of parkinsonism was invariably accompanied by dyskinesia. Dyskinesia was characterized by an idiosyncratic mixture of chorea and dystonia in all six animals. In all animals, both forms of dyskinesia reached the “marked” to “severe” level at their peak of intensity, i.e. during a 10-min observation period. During the first hour post-drug administration, animals were fully
Discussion
The main finding of the present study is that levetiracetam, a novel anti-epileptic drug, which possesses unique desynchronizing properties in animal models of epilepsy, reduces choreic, but not dystonic, levodopa-induced dyskinesia in the MPTP-lesioned macaque model of Parkinson's disease.
The anti-choreic effect of levetiracetam was paralleled by a full preservation of the anti-parkinsonian efficacy of levodopa. A number of pharmacological approaches, dopaminergic or non-dopaminergic in
Acknowledgments
We are grateful to S. Fox for designing the rating system. We thank L. Qin, H. Sinclair and M. Zubair for their skilful technical assistance. This study was funded by UCB, Pharma Sector.
References (24)
- et al.
Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates
Trends Neurosci.
(1998) - et al.
From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control
Prog. Neurobiol.
(2002) - et al.
Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy
Seizure
(2003) - et al.
Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review
Epilepsy Res.
(2001) - et al.
Common neural mechanisms in experimental chorea and hemiballismus in the monkey. Evidence from 2-deoxyglucose autoradiography
Brain Res.
(1985) - et al.
Pathophysiology of levodopa-induced dyskinesia: potential for new therapies
Nat. Rev., Neurosci.
(2001) - et al.
Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson's disease
J. Neurosci.
(2001) - et al.
Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alteration of pallidal neurons in the MPTP-treated monkey
Brain
(2001) - et al.
Quantitative assessment of dyskinesias in subhuman primates
Mov. Disord.
(1999) - et al.
Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial
Neurology
(2000)
Effects of interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey
Brain Res.
Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease
Mov. Disord.
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