enkephalin--leucine-2-alanine and Heart-Arrest

The introduction of therapeutic mild hypothermia after cardiac arrest allows the neuronal damage caused by global cerebral ischemia to be advantageously influenced for the first time. Currently, hypothermia is induced by external or internal cooling of the patient (forced hypothermia). However, this results in activation of counter-regulation mechanisms which could be possible risk factors for the patient. The aim of this article is to give a review of possible, but at present only experimental, methods which could allow the body temperature set point to be decreased pharmacologically (regulated hypothermia). Various classes of substances will be discussed based on their effect on thermoregulation and their performance in animal experiments on cerebral ischemia.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Body Temperature; Body Temperature Regulation; Brain Ischemia; Enkephalin, Leucine-2-Alanine; Heart Arrest; Humans; Hypothermia, Induced; Neurotensin; Risk Factors; Serotonin Receptor Agonists

To compare the effect of δ-opioid receptor agonist, d-Ala2-d-Leu5 enkephalin (DADLE) with normothermic control and therapeutic hypothermia on post resuscitation myocardial function in a model of extracorporeal life support (ECLS).. Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32 °C) and DADLE intravenous infusion (1 mg/kg/h). Cooling to 32 °C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS.. DADLE administration resulted in a significantly enhanced recovery of LV systolic function expressed by slope of the LV end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than hypothermia and normothermia. LV stiffness indicated by end-diastolic pressure volume relationship (EDPVR) was significantly lower after DADLE administration (P<0.01). LV relaxation described by Tau was preserved after DADLE treatment but not after normothermia or mild hypothermia (P<0.01). Plasma lactate concentrations were lower in DADLE group (P<0.05). DADLE and not conventional hypothermia significantly increased phosphorylation of the kinases ERK1 and 2 (3.9±0.3 and 3.1±0.5 vs. 0.4±0.1 and 0.3±0.1-fold of baseline levels) (P<0.001). Both DADLE and hypothermia but not normothermia increase phosphorylation of Akt.. DADLE was more effective than mild therapeutic hypothermia in recovering myocardial function and activation of the pro-survival kinases Akt and ERK after ECLS.

Topics: Advanced Cardiac Life Support; Animals; Enkephalin, Leucine-2-Alanine; Heart Arrest; Hypothermia, Induced; Male; Rats; Rats, Wistar; Receptors, Opioid, delta

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