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

Abstract

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.

Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress

“…This is of significance in view of the role that these AK-catalysis dependent events play in protecting the myocardium under hypoxic insult (37). In fact, AK gene expression is induced by hypoxia (47), and agents that increase AK activity are beneficial in preserving tissue functions under hypoxic conditions (48). Therefore, the absence of hypoxiainduced adenosine production observed here in AK1-knockout hearts may reduce the ability of AK1-deficient heart muscle to withstand hypoxic injury.…”

Studies on Cerebral Protection of Digoxin against Ischemia/Reperfusion Injury in Mice

“…Theseˆnd-ings are in line with our earlier reports 9 12) and reports from other laboratories. 23,25) Recently it was reported that a signiˆcant impairment of memory and motor coordination can be induced by increasing the extent of ischemic insult to 17 min. 36) Therefore, we adopted the procedure described by Wong et al, who reported that global ischemic insult of 17 minutes duration produce ischemic damage along with excellent behavioral impairments in mice.…”

“…Global cerebral ischemia was induced by occluding the carotid arteries. After 17 min of global cerebral ischemia, the incision was sutured back in layers and reperfusion was allowed for 24 h. 23) The sutured area was cleaned with 70％ ethanol and was sprayed with antiseptic dusting powder. The animals were shifted individually to their home cage and were allowed to recover.…”

Possible Role of Opioids and KATP Channels in Neuroprotective Effect of Postconditioning in Mice

“…Thereafter, blood was allowed to reflow through carotid arteries. 29,30) Incision was sutured back in layers. The sutured area was cleaned with 70% ethanol and was sprayed with antibiotic (Neosporin) dusting powder.…”