Coadministration of entacapone with levodopa attenuates the severity of dyskinesias in hemiparkinsonian rats.
Levodopa-induced dyskinesias (LIDs) have been associated with a sequence of events that includes pulsatile stimulation of dopamine receptors. The degree of nigrostriatal degeneration, the half-life of dopaminomimetic agents, and the dose of levodopa used to treat parkinsonian symptoms are factors directly correlated with the development of motor complications in Parkinson's disease patients. Long-acting agents producing continuous dopaminergic stimulation are less likely to prime for dyskinesia than short-acting drugs that produce pulsatile stimulation of dopamine receptors. Inhibition of the enzyme catechol-O-methyl transferase (COMT) by entacapone extends the half-life of levodopa and minimizes variability in plasma levodopa levels. The aim of the present study was to characterize the effect of the early administration of the COMT inhibitor entacapone in the recently described model of LIDs in rats with a nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. Animals were treated either with levodopa (6 mg/kg, twice at day, i.p.) plus entacapone (30 mg/kg per day, i.p.) or levodopa (6 mg/kg, twice at day, i.p.) plus vehicle for 22 consecutive days. Early administration of entacapone, in association with levodopa, induces a decrease in the severity of dyskinesia and delays their onset in hemiparkinsonian rats. All dyskinesia subtypes evaluated, such as axial, limb, and orofacial dyskinesias, have shown similar reductions. These results suggest that entacapone, by extending levodopa elimination half-life, might reduce its propensity to induce motor complications.
Marin
Concepció
C
Laboratori de Neurologia Experimental, Fundació Clínic-Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. cmarin@clinic.ub.es
Aguilar
Esther
E
Obeso
José A
JA
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002396:Catechols / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D009570:Nitriles; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013997:Time Factors
D000978:Antiparkinson Agents; D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D016627:Oxidopamine