Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats.
The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of "wearing-off" phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines "wearing-off" motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.
Marin
C
C
Laboratori de Neurologia Experimental, Servei de Neurologia, Fundació Clínic-Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. cmarin@clinic.ub.es
Aguilar
E
E
Bonastre
M
M
Tolosa
E
E
Obeso
J A
JA
D000818:Animals; D001545:Benserazide / Q000008:administration & dosage; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007980:Levodopa / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D008297:Male; D009570:Nitriles; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D001545:Benserazide; D016627:Oxidopamine; D002394:Catechol O-Methyltransferase