Nonhuman Primate Models Of Motor Response Complications

The Parkinson's-Reversing Breakthrough

Parkinson Disease Causes

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A. MPTP and Parkinson Disease

In 1982, several young drug addicts in California developed a severe Parkinson-like syndrome after injecting a potent synthetic drug containing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al. 1983; Jenner 2003). Exposure to MPTP produced bradykinesia and rigidity, almost identical to signs exhibited by patients with idio-pathic Parkinson disease (PD) (Ballard et al. 1985; Jenner 2003). Moreover, these symptoms showed optimal therapeutic response to dopamine and dopamine agonist.

B. MPTP and Nonhuman Primate Model of Parkinson Disease

The possibility of recreating a syndrome resembling the major characteristics of PD triggered researchers to develop an experimental animal model using systemic administration of MPTP. Previously, the commonly used animal model of PD was the 6-hydroxydopamine (6-OHDA) rat, which is an excellent model for testing and determining modes of action of new pharmacological compounds. However, the model lacks the behavioral features of idiopathic PD and the ability to develop motor complications closely resembling those commonly observed in Parkinsonian patients. With the exception of a few strains of mice, most rodents were highly resistant to MPTP administration. On the other hand, primates were sensitive to MPTP and developed a syndrome that resembled that observed in intoxicated humans (Burns et al. 1983). Nonhuman primates treated with MPTP show clear Parkinsonian features such as bradykinesia, rigidity, stooped posture and tremor, which, unlike idiopathic PD, are mostly postural. Once induced, the Parkinsonian syndrome remains stable over time and its symptoms show an excellent response to levodopa and other direct dopamine agonists.

Among nonhuman primates, several species develop Parkinsonism following exposure to MPTP, including marmosets, macaques, squirrel monkeys, and vervet monkeys. In addition to the bilateral model, a unilateral lesion can be produced by intracarotid administration of the neurotoxin resulting in an ipsilateral brain lesion and a contralateral hemiparkinsonian syndrome (Bankiewicz et al. 1986). This procedure yields faster lesioning of the brain and, since it is unilateral, might alleviate the invalidity that sometimes accompanies the bilateral model. Acute MPTP administration, however, does not consistently reproduce all clinical features of the disease and does not mimic the gradual evolution seen in the human pathology. The progressive degeneration of dopamine neurons observed in idiopathic Parkinson disease was first produced by injecting low doses of MPTP in baboons on a chronic basis (Hantraye et al. 1993) and successfully replicated in cynomolgus monkeys (Bezard et al. 1997; Blanchet et al. 1998).

Biochemical and histological investigations have shown that MPTP-induced Parkinsonism reflects the human disease as demonstrated by the selective degeneration of the nigro-

striatal dopaminergic pathway (Stern 1990). The nerve cells in the ventrolateral portion of the substantia nigra pars compacta were particularly vulnerable (as observed in idiopathic PD) but the typical formation of Lewy bodies, another peculiar characteristic of idiopathic PD, was not observed in the monkey model. Inclusion bodies, found quite consistently in aged MPTP-lesioned monkeys, appear to be the pathological consequence of lesions in the experimental model and show some similarities to Lewy bodies (Forno et al. 1993).

C. MPTP and Nonhuman Primate Model of Motor Response Complications

After dopaminomimetic treatment is initiated, Parkin-sonian primates develop motor response complications (MRCs) that include motor fluctuations and dyskinesias (Blanchet et al. 1996). After the MPTP lesioning cycle, which takes approximately five to six weeks adopting the chronic administration regimen of a weekly dose of 0.5 to 1 mg/kg subcutaneously, all animals are left drug-free for six to eight weeks. They are scored on a regular basis using the Laval University Disability Scale for MPTP Monkeys (Gomez-Mancilla et al. 1993), where the normal state extends from 0 to 2 points and maximal disability is 10 points. When a mild to moderate Parkinsonian syndrome stabilizes (baseline disability scores between 4 to 6 points), monkeys begin receiving chronic treatment with 0.5 to 2 tablets of carbidopa/levodopa (25/100 mg) every other day, orally administered by means of a pet piller. All monkeys develop dyskinesias within one month, which can be reproduced consistently and predictably following the same oral dose of carbidopa/levodopa (Bibbiani et al. 2001). The dyskinesias predominantly observed are of the choreiform type and, less frequently, of the dystonic variety. These movements are usually observed beginning twenty to forty minutes after administering a dopaminergic agent and are most severe midway through to the end of each therapeutic dose (peak-dose dyskinesias).

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