Possible role for chlorpheniramine in the treatment of l-DOPA induced dyskinesia in Parkinson’s disease

Abstract

Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective medication for the symptomatic relief of Parkinson’s disease (PD). However, chronic L-DOPA treatment is often complicated by a variety of involuntary movements, termed L-DOPA-induced dyskinesia (LID), which represents one of the major limitations in the treatment for PD. Depending on clinical presentation and chronology after a dose of L-DOPA, LID can be classified in peak-dose, diphasic, and off period dyskinesias. Peak-dose dyskinesia occurs at the time of the highest brain concentration of LDOPA and represents the most common type of LID. The current pharmacological treatment of this form of dyskinesia involves, as a first measure, the reduction of individual L-DOPA doses, which indeed can lead to improvement of dyskinesia, exacerbating however the symptoms of the disease. Slow-release L-DOPA preparations or spreading of the daily dose of L-DOPA into smaller but more frequent doses has been also used; however, only limited improvements have been reported so far. On the other hand, the only currently available drug with an evidence-based recommendation for dyskinesia is the glutamate antagonist amantadine, even though no large scale study of this drug has been conducted. Moreover, only a number of patients can tolerate effective doses of amantadine, and its effects decline over time. Finally, dyskinesias that become disabling must often be managed surgically, despite the high cost and risk for serious adverse events of such intervention. Thus, it is a common belief that the development of new safe and effective therapies that treat dyskinesias without aggravating parkinsonism are urgently needed. A rapid and excessive increase in extracellular DA, after L-DOPA administration, is considered one of the major causes for peak-dose LID. This is due to the fact that oral formulations of L-DOPA have short plasma half-lives, so each dose causes a rapid increase followed by a rapid decrease in striatal dopamine levels, leading to intermittent stimulation of striatal dopamine receptors. Interestingly, in experiments with rats, administration of 8-hydroxy-2-(d-npropylamino) tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, attenuated the increase in L-DOPA-induced extracellular DA [1] while alleviated L-DOPA induced motor complications, including LID [2]. In support of a role in receptor specificity, it was shown that these effects of 8-OH-DPAT were mediated mainly via stimulation of 5-HT1A receptors, since co-administration of a 5HT1A receptor antagonist (WAY100635) abolished the above mentioned effects of 8-OH-DPAT [1]. Moreover, in compliance with these animal studies, the use of the clinically available 5-HT1A agonist sarizotan, in the context of a multicenter trial, was proved to be effective in the treatment of LID in PD patients [3]. Taken together, all these data suggest that pharmaceutical agents capable of stimulating 5-HT1A receptors could avert the induction of L-DOPA induced motor complications in patients with PD. P. N. Karamanakos P. Pappas M. Marselos Department of Pharmacology, Medical School, University of Ioannina, Ioannina 451 10, Greece