naloxone and Infarction--Middle-Cerebral-Artery

Although naloxone has been documented to exert neuroprotection in animal model of cerebral ischemia, the mechanism is not well understood. In this present study we investigated whether naloxone affected the mitochondrial apoptotic pathway in ischemic brain injury of rats. SD rats were subjected to a permanent middle cerebral artery occlusion surgery, and received naloxone (0.5, 1, 2 mg/kg, i.v.) immediately after ischemia. Neurological deficits were evaluated 24 h after ischemia using the McGraw Stroke Index, and then the rats were killed, and the brains were collected for further analyses. We show that naloxone treatment dose-dependently decreased the infarction volume and morphological injury, improved motor behavioral function, and markedly curtailed brain edema. Furthermore, naloxone administration significantly inhibited the nuclear translocation of NF-κB p65 and decreased the levels of nuclear NF-κB p65 in the ischemic penumbra. Naloxone administration also dose-dependently increased the NF-κB inhibitory protein (IκBα) levels and attenuated phosphorylated NIK and IKKα levels in the ischemic penumbra. In addition, naloxone administration dose-dependently increased Bcl-2 levels, decreased Bax levels, stabilized the mitochondrial transmembrane potential, and inhibited cytochrome c release and caspase 3 and caspase 9 activation. These results indicate that the neuroprotective effects of naloxone against ischemic brain injury involve the inhibition of NF-κB activation via the suppression of the NIK/IKKα/IκBα pathway and the obstruction of the mitochondrial apoptotic pathway in neurons.

Topics: Animals; Apoptosis; I-kappa B Kinase; Infarction, Middle Cerebral Artery; Male; Mitochondria; Naloxone; Neuroprotective Agents; NF-kappa B; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Signal Transduction

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