Entacapone, a catechol- O -methyltransferase inhibitor, improves the motor activity and dopamine content of basal ganglia in a rat model of Parkinson's disease induced by Japanese encephalitis virus

• Published in: Brain research 2010-01, Vol.1309, p.110-115
• Main Authors: Hamaue, Naoya, Ogata, Akihiko, Terado, Mutsuko, Tsuchida, Shirou, Yabe, Ichiro, Sasaki, Hidenao, Hirafuji, Masahiko, Togashi, Hiroko, Aoki, Takashi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult and adolescent clinical studies; Animals; Antiparkinson Agents - pharmacology; Antiparkinson Agents - therapeutic use; Aromatic Amino Acid Decarboxylase Inhibitors; Basal Ganglia - drug effects; Basal Ganglia - enzymology; Basal Ganglia - virology; Biological and medical sciences; Catechol O-Methyltransferase - metabolism; Catechol O-Methyltransferase Inhibitors; Catechols - pharmacology; Catechols - therapeutic use; COMT; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Corpus Striatum - virology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopa Decarboxylase - metabolism; Dopamine - metabolism; Drug Combinations; Drug Synergism; Encephalitis Virus, Japanese - physiology; Encephalitis, Japanese - complications; Encephalitis, Japanese - physiopathology; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Levodopa - administration & dosage; Levodopa - adverse effects; Medical sciences; Motor activity; Neurology; Nitriles - pharmacology; Nitriles - therapeutic use; Organic mental disorders. Neuropsychology; Parkinson's disease; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - enzymology; Parkinsonian Disorders - virology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Inbred F344; Striatum; Treatment; Treatment Outcome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.10.055

Abstract Levodopa is the main medication used for the treatment of Parkinson's disease. However, dyskinesia and wearing-off appear after the administration of high-dose levodopa for a long period. To combat the dyskinesia and wearing-off, levodopa is used together with a dopamine (DA) receptor agonist, and the amount of levodopa is decreased. We have reported the monoamine oxidase (MAO)-B inhibitor selegiline to be effective for treating motor dysfunction in Parkinson's disease model rats. We analyzed the improvement in motor functions and catecholamine contents in various brain regions induced by a combination of the catechol- O -methyltransferase (COMT) inhibitor entacapone and a levodopa/dopadecarboxylase inhibitor (DDCI) in Japanese encephalitis virus (JEV) induced Parkinson's disease model rats. Entacapone (10 mg/kg) was administered via a single oral administration with levodopa/DDCI (10 mg/kg). The motor functions of the JEV model rats were significantly worsened, compared with those of the healthy control rats. The motor functions in the Parkinson's disease model rats were significantly recovered to the same levels as the healthy control rats by the combined administration of entacapone and levodopa/DDCI. A significant improvement in motor function was not demonstrated in the case of the administration of levodopa/DDCI alone. The striatal DA concentrations in the model rat brains were significantly increased by using levodopa/DDCI together with entacapone. Motor function was recovered by raising the striatum DA density in the model rats. Thus, COMT inhibitors are useful for decreasing the amount of levodopa administered to Parkinson's disease patients.