Dextrorphan attenuates the behavioral consequences of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate receptor antagonism and ATP replenishing action in its cerebroprotecting profile.
The acute anti-ischemic and anti-anoxic effects of dextrorphan (DX) were compared with those of dizocilpine (MK-801) in a variety of animal models, and in vivo and in vitro testings under anoxic conditions. DX reduced the incidence of death in ischemic mice and improved the rotarod performance of mice with brain ischemia. The ischemically-impaired memory of mice treated with DX markedly improved, as shown in the step-through type passive avoidance test, Morris water maze and in the habituation of exploratory behavior test. MK-801 likewise improved the water maze performance of the ischemically-impaired mice, but to a lesser extent. The step-through type passive avoidance performance of ischemic mice was not improved by MK-801. In the passive avoidance task with normal mice, DX, like MK-801, produced anterograde amnesia at doses higher than those needed to attenuate the behavioral effects of ischemia. DX, intravenously or centrally administered, markedly and dose-dependently reduced the incidence of death in mice receiving potassium cyanide (KCN). DX lessened the reduction in adenosine triphosphate (ATP) and increased lactate contents in mice dosed with KCN and also lessened the reduction in ATP in the TCA cycle and oxidative phosphorylation reactions caused by KCN (0.58 mmol/l), whereas MK-801 failed to show any effect on ATP formation pathways in vivo and in vitro, and failed to protect mice against KCN-induced lethal toxicity in vivo. In the in vitro studies, DX increased the adenylate kinase activity of the rat brain homogenate. DX was found to be a cerebroprotectant with anti-ischemic and anti-anoxic actions, the effects probably stemming from its N-methyl-d-aspartate receptor antagonistic property in cooperation with its ATP replenishing action.
Himori
N
N
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
Tanaka
Y
Y
Kurasawa
M
M
Mishima
K
K
Akaike
N
N
Imai
M
M
Ueno
K
K
Matsukura
T
T
Watanabe
H
H
D000255:Adenosine Triphosphate / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002545:Brain Ischemia / Q000523:psychology*; D003917:Dextrorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D002534:Hypoxia, Brain / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009410:Nerve Degeneration / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; D000262:Adenylyl Cyclases; D011190:Potassium Cyanide