naltrindole and Asphyxia

The aim of this study was to investigate whether the DOR agonist BW373U86 conferred neuroprotection following ACA when given after resuscitation and to determine the long-term effects of chronic BW373U86 treatment on ACA-elicited brain injury.. Animals were divided into acute and chronic treatment groups. Each group consisted of four sub-groups, including Sham, ACA, BW373U86 (BW373U86+ACA), and Naltrindole groups (Naltrindole and BW373U86+ACA). The DOR antagonist Naltrindole was used to confirm the possible receptor-dependent effects of BW373U86. ACA was induced by 8min of asphyxiation followed by resuscitation. All drugs were administered either immediately after the restoration of spontaneous circulation (ROSC) in acute-treatment groups or over 6 consecutive days in chronic-treatment groups. Alterations of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) were analyzed by western blot and immunohistochemistry. Neurological functions were assessed by neurological deficit score (NDS) and Morris Water Maze performance. Neurodegeneration was monitored by immunofluorescence and Nissl staining.. ACA induced massive neuron loss and serious neurological function deficits. BW373U86 significantly reduced both of these negative effects and increased CREB and pCREB expression in the hippocampus; these effects were reversed with acute Naltrindole treatment. The protective effects of BW373U86 persisted until 28d post-ROSC with chronic treatment, but these effects were not reversed by Naltrindole.. BW373U86 attenuates global cerebral ischemic injury induced by ACA through both DOR-dependent and DOR-independent mechanisms. CREB might be an important molecule in mediating these neuroprotective effects.

Topics: Animals; Asphyxia; Benzamides; Blotting, Western; Brain Damage, Chronic; Cardiopulmonary Resuscitation; CREB-Binding Protein; Disease Models, Animal; Heart Arrest; Immunoenzyme Techniques; Male; Naltrexone; Neuroprotective Agents; Piperazines; Rats, Sprague-Dawley

This study was designed to investigate whether delta opioid receptor (DOR) is involved in the neuroprotective effect induced by hypoxic preconditioning (HPC) in the asphyxial cardiac arrest (CA) rat model. Twenty-four hours after the end of 7-day HPC, the rats were subjected to 8-min asphyxiation and resuscitated with a standardized method. In the asphyxial CA rat model, HPC improved the neurological deficit score (NDS), inhibited neuronal apoptosis, and increased the number of viable hippocampal CA1 neurons at 24 h, 72 h, or 7 days after restoration of spontaneous circulation (ROSC); however, the above-mentioned neuroprotection of HPC was attenuated by naltrindole (a selective DOR antagonist). The expression of hypoxia-inducible factor-1α (HIF-1α) and DOR, and the content of leucine enkephalin (L-ENK) in the brain were also investigated after the end of 7-day HPC. HPC upregulated the neuronal expression of HIF-1α and DOR, and synchronously elevated the content of L-ENK in the rat brain. HIF-1α siRNA was used to further elucidate the relationship between HIF-1α and DOR in the HPC-treated brain. Knockdown of HIF-1α by siRNA markedly abrogated the HPC induced upregulation of HIF-1α and DOR. The present study demonstrates that the expression of DOR in the rat brain is upregulated by HIF-1α following exposure to 7-day HPC, at the same time, HPC also increases the production of endogenous DOR ligand L-ENK in the brain. DOR activation after HPC results in prolonged neuroprotection against subsequent global cerebral ischemic injury, suggesting a new mechanism of HPC-induced neuroprotection on global cerebral ischemia following CA and resuscitation.

Topics: Animals; Apoptosis; Arousal; Asphyxia; Behavior, Animal; Blotting, Western; Brain Ischemia; Brain Stem; Enkephalin, Leucine; Fluorescent Antibody Technique; Heart Arrest; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia, Brain; In Situ Nick-End Labeling; Ischemic Preconditioning; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Postural Balance; Rats; Real-Time Polymerase Chain Reaction; Receptors, Opioid, delta; RNA, Small Interfering; Seizures; Survival Analysis

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