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.
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.
Hamaue
Naoya
N
Department of Molecular Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan. hamaue@hoku-iryo-u.ac.jp
Ogata
Akihiko
A
Terado
Mutsuko
M
Tsuchida
Shirou
S
Yabe
Ichiro
I
Sasaki
Hidenao
H
Hirafuji
Masahiko
M
Togashi
Hiroko
H
Aoki
Takashi
T
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology / Q000821:virology; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D004296:Dopa Decarboxylase / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004338:Drug Combinations; D004357:Drug Synergism; D004664:Encephalitis Virus, Japanese / Q000502:physiology; D004672:Encephalitis, Japanese / Q000150:complications / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D002394:Catechol O-Methyltransferase; D004296:Dopa Decarboxylase; D004298:Dopamine