enkephalin--leucine-2-alanine and Asphyxia

The delta opioid receptor (DOR) agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been implicated as a novel neuroprotective agent in the CNS. The current study was designed to evaluate the effects of intracerebroventricular (ICV) application of DADLE on neurological outcomes following asphyxial cardiac arrest (CA) in rats. Male Sprague-Dawley rats were randomly assigned to four groups: Sham group, CA group, DADLE group (DADLE+CA), and Naltrindole group (Naltrindole and DADLE+CA). All drugs were administered into the left cerebroventricle 30 min before CA. CA was induced by 8-min asphyxiation and the animals were resuscitated with a standardized method. DOR protein expression in the hippocampus was significantly increased in the CA group at 1 h after restoration of spontaneous circulation (ROSC) compared with the Sham group. As time progressed, expression of DOR proteins decreased gradually in the CA group. Treatment with DADLE alone or co-administration with Naltrindole reversed the down-regulation of DOR proteins in the hippocampus induced by CA at 24 h after ROSC. Compared with the CA group, the DADLE group had persistently better neurological functional recovery, as assessed by neurological deficit score (NDS) and Morris water maze trials. The number of surviving hippocampal CA1 neurons in the DADLE group was significantly higher than those in the CA group. However, administration of Naltrindole abolished most of the neuroprotective effects of DADLE. We conclude that ICV administration of DADLE 30 min before asphyxial CA has significant protective effects in attenuating hippocampal CA1 neuronal damage and neurological impairments, and that DADLE executes its effects mainly through DOR.

Topics: Animals; Asphyxia; CA1 Region, Hippocampal; Cell Survival; Enkephalin, Leucine-2-Alanine; Heart Arrest; Injections, Intraventricular; Male; Maze Learning; Naltrexone; Neurons; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta

Development of posthypoxic and reoxygenation depression of cardiac activity following a time-portioned disconnection of the apparatus for artificial ventilation of the lungs in rats was restricted by a preventive intravenous infusion of a synthetic opioid peptide--dalargin. Resistance to a stressor effect of hypoxia (ischemia-reperfusion) which was assessed by the degree of restoration of the integral index of the blood circulation--cardiac output could be mediated by correction of Ca-homeostasis of cardiomyocytes by means of dalargin. Elimination of all side effects with a blocker of opioid receptors--naloxon points to a possibility of realization of a protective antihypoxic action.

Topics: Acute Disease; Animals; Asphyxia; Disease Models, Animal; Drug Evaluation, Preclinical; Enkephalin, Leucine-2-Alanine; Hemodynamics; Hypoxia; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Respiration, Artificial; Time Factors