naloxone and Hypoxia-Ischemia--Brain

We investigated whether morphine plays a neuroprotective role in a neonatal rat pup model of bilateral carotid artery occlusion with hypoxia. At postnatal day 10, rats received either morphine (n = 7), naloxone (n = 7), or saline placebo (n = 15) after hypoxic-ischemic injury. Survival (days), weight gain and animal testing (negative geotaxis, surface righting, and rotarod) were compared between treatment groups. Lesion volume was delineated with magnetic resonance imaging at days 7 and 28-57 after injury. Survival in rats treated with morphine, naloxone, or saline was, respectively, 14, 29, and 73%. Median number of days of survival after bilateral carotid artery occlusion with hypoxia treated with morphine was 4 (95% confidence interval 4 to 22), with naloxone was 3 (95% confidence interval -1.4 to 21), and with placebo was 28 (95% confidence interval 18 to 28). There were no statistically significant differences in magnetic resonance imaging-derived ischemic lesion volumes, weight gain, or behavioral testing measures between the groups. Morphine was ineffective as a neuroprotectant in rat pups with severe hypoxic-ischemic injury and may have contributed to their decreased survival.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Hypoxia-Ischemia, Brain; Infusions, Subcutaneous; Male; Morphine; Naloxone; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Survival Rate

Cerebral ischemia/reperfusion involves inflammatory process and naloxone is able to reduce infarct volume and has been used as a therapeutic agent for brain injury. Hypoxia induces the immediate early genes (IEGs) rapidly and transiently that may initiate a cascade of cellular responses that are necessary for survival and normal function. However, the protective effect of naloxone on ischemic/hypoxic neuronal cells was only partly studied. Thus, the effects of naloxone on oxygen- and glucose-deprivation (OGD) and OGD followed by reoxygenation (OGD/R) on the expression of IEGs were examined in PC12 cells. The result showed that lactate dehydrogenase (LDH) released in the media was reduced by naloxone. The temporal response of IEG mRNA encoding c-fos, c-jun, nur77, and zif268 was induced with different degree of intensity following hypoxia, whereas the level of GAPDH mRNA was relatively constant. However, these signals of c-fos, c-jun, and nur77 by hypoxia were reduced significantly by naloxone. Treatment with OGD also activated mitogen-activated protein kinase (MAPK) pathway. The induction of c-fos, c-jun, nur77, and zif268 by hypoxia was inhibited by naloxone (0.1 microM) and MAPK inhibitors (10 microM of U0126, D98059, SB203580). However, naloxone increased the expression of ERK1/2 by OGD concomitantly diminished the LDH release. Thus, the present studies demonstrated that OGD induced IEGs including c-fos, c-jun, nur77, and zif268 and MAPK signaling pathways were regulated differently by naloxone.

Topics: Animals; Brain Infarction; Cytoprotection; DNA-Binding Proteins; Encephalitis; Enzyme Inhibitors; Gene Expression Regulation; Genes, Immediate-Early; Hypoxia-Ischemia, Brain; L-Lactate Dehydrogenase; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Naloxone; Narcotic Antagonists; Neurons; Neuroprotective Agents; Nuclear Receptor Subfamily 4, Group A, Member 1; Oxidative Stress; PC12 Cells; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Receptors, Steroid; Reperfusion Injury

Naloxone has been advanced as a potential neuroprotectant against ischemic injury. This study examined the involvement of classical opioid receptors in the reduction of middle cerebral arterial ligation-induced cortical infarction in rats. The infarct volume was significantly reduced after infusion of (-)-naloxone, but not its inert stereoisomer (+)-naloxone. Beta-funaltrexamine (beta-FNA), a mu opioid antagonist, also reduced ischemic infarct volume. Both (-)-naloxone and beta-FNA attenuated cerebral ischemia/reperfusion (I/R)-induced increases in neutrophil-associated myeloperoxidase activity and chemokine mRNA expression, including macrophage inflammatory protein-1 alpha and -2. However, (-)-naloxone and beta-FNA failed to decrease cerebral I/R-induced brain edema. The findings suggest that naloxone, acting through a blockade of mu opioid receptor activation, is beneficial to cerebral I/R insult in terms of reducing brain infarction, neutrophil accumulation, and chemokine expression.

Topics: Animals; Carotid Artery, Common; Cerebral Infarction; Coronary Disease; Functional Laterality; Hypoxia-Ischemia, Brain; Infarction, Middle Cerebral Artery; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors