morphinans and Brain-Ischemia

Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro. SINO administration intraperitoneally alleviated the cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency after MCAO induction. SINO also attenuated astrocytic and microglial activation in the ischemic hemisphere. NLRP3 inflammasome activation after MCAO and OGD induction, with the up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and pro-inflammatory cytokines, was significantly inhibited by SINO treatment both in vivo and in vitro. In addition, SINO reversed the OGD-induced inhibition of AMPK phosphorylation in vitro. Further, the suppressive effect of SINO on NLRP3 inflammasomes was blocked by an AMPK inhibitor, Compound C. Our findings demonstrate that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Astrocytes; Brain Ischemia; Cells, Cultured; Glucose; Humans; Inflammasomes; Male; Mice; Mice, Inbred C57BL; Morphinans; Neuroprotection; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Stroke

Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen-glucose deprivation-reperfusion (OGD-R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism.. Middle cerebral artery occlusion in rats was used as an animal model of ischaemic stroke in vivo. The mechanisms of the effects of SN were investigated in vitro using whole-cell patch-clamp recording, calcium imaging in PC12 cells and rat cortical neurons subjected to OGD-R.. Pretreatment with SN (10 and 30 mg·kg(-1) , i.p.) significantly decreased brain infarction and the overactivation of calcium-mediated events in rats subjected to 2 h ischaemia followed by 24 h reperfusion. Extracellular application of SN inhibited the currents mediated by acid-sensing ion channel 1a and L-type voltage-gated calcium channels, in the rat cultured neurons, in a concentration-dependent manner. These inhibitory effects contribute to the neuroprotection of SN against OGD-R and extracellular acidosis-induced cytotoxicity. More importantly, administration of SN (30 mg·kg(-1) , i.p.) at 1 and 2 h after cerebral ischaemia also decreased brain infarction and improved functional recovery.. SN exerts potent protective effects against ischaemic brain injury when administered before ischaemia or even after the injury. The inhibitory effects of SN on acid-sensing ion channel 1a and L-type calcium channels are involved in this neuroprotection.

Topics: Acid Sensing Ion Channels; Animals; Animals, Newborn; Blotting, Western; Brain Ischemia; Calcium Channels, L-Type; Cell Culture Techniques; CHO Cells; Cricetinae; Cricetulus; Cytoprotection; Disease Models, Animal; Glucose; Male; Morphinans; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Oxygen; Patch-Clamp Techniques; PC12 Cells; Rats; Rats, Sprague-Dawley; Sodium Channels

Dimemorfan, an antitussive and a sigma-1 (sigma(1)) receptor agonist, has been reported to display neuroprotective properties. We set up an animal model of ischemic stroke injury by inducing cerebral ischemia (for 1 h) followed by reperfusion (for 24 h) (CI/R) in rats to examine the protective effects and action mechanisms of dimemorfan against stroke-induced damage. Treatment with dimemorfan (1.0 microg/kg and 10 microg/kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative sigma(1) receptor agonist, PRE084 (10 microg/kg, i.v.), ameliorated the size of the infarct zone by 67-72% or 51-52%, respectively, which was reversed by pre-treatment with the selective sigma(1) receptor antagonist, BD1047 (20 microg/kg, i.v.). Major pathological mechanisms leading to CI/R injury including excitotoxicity, oxidative/nitrosative stress, inflammation, and apoptosis are all downstream events initiated by excessive accumulation of extracellular glutamate. Dimemorfan treatment (10 microg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1beta, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammation-related signals (p38 mitogen-activated protein kinase, nuclear factor-kappaB, and signal transducer and activator of transcription-1), expression of neuronal and inducible nitric oxide synthase, oxidative/nitrosative tissue damage (lipid peroxidation, protein nitrosylation, and 8-hydroxy-guanine formation), and apoptosis in the ipsilateral cortex after CI/R injury. Dimemorfan treatment at the time of reperfusion, although did not prevent an early rise of glutamate level, significantly prevented subsequent glutamate accumulation after reperfusion. This inhibitory effect was lasted for more than 4 h and was reversed by pre-treatment with BD1047. These results suggest that dimemorfan activates the sigma(1) receptor to reduce glutamate accumulation and then suppresses initiation of inflammation-related events and signals as well as induction of oxidative and nitrosative stresses, leading to reductions in tissue damage and cell death. In conclusion, our results demonstrate for the first time that dimemorfan exhibits protective effects against ischemic stroke in CI/R rats probably through modulation of sigma(1) receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events.

Topics: Analysis of Variance; Animals; Brain Infarction; Brain Ischemia; Chemokine CCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Glutamic Acid; Lipid Peroxidation; Male; Morphinans; Morpholines; NF-kappaB-Inducing Kinase; Nitric Oxide Synthase; Peroxidase; Protein Serine-Threonine Kinases; Rats; Rats, Long-Evans; Receptors, sigma; Reperfusion Injury; Sigma-1 Receptor; Signal Transduction; STAT1 Transcription Factor

The N-methyl-D-aspartate (NMDA) antagonists dextromethorphan (DM) and dextrorphan (DX) were found to reduce significantly neocortical severe ischemic neuronal damage (SIND) when administered in a delayed fashion after the ischemic insult. Rabbits underwent occlusion of the left internal carotid artery and anterior cerebral artery for 1 h, followed by 4 h of reperfusion. Immediately after the completion of the 1 h arterial occlusion, animals were blindly treated intravenously with 20 mg/kg loading dose followed by 10 mg/kg/h of DM, 15 mg/kg loading dose followed by 15 mg/kg/h of DX, or an equivalent volume of normal saline (NS) alone. The area of neocortical SIND was 3.7% in the DM group, 4.4% in the DX group, and 41.3% in the normal saline controls. These drugs may have considerable therapeutic potential in clinical stroke.

Topics: Animals; Aspartic Acid; Brain Ischemia; Dextromethorphan; Dextrorphan; Levorphanol; Male; Morphinans; N-Methylaspartate; Rabbits

The dextrorotatory opioid derivatives, dextrorphan and dextromethorphan, can attenuate hypoxic injury in cortical cell cultures. This effect is concentration-dependent in the micromolar range, and not strongly stereospecific, as it can also be demonstrated with the levorotatory enantiomer of dextrorphan, levorphanol. The possibility that these clinically available compounds may have therapeutic utility in hypoxic or ischemic encephalopathy warrants further investigation.

Topics: Animals; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Dextromethorphan; Dextrorphan; Hypoxia; Levorphanol; Mice; Morphinans; Neurons

The effects are reported of acute and long-term continuous administration of three opiate antagonists--naloxone, naltrexone, and diprenorphine--on neurological function, survival, and infarct size in a feline model of acute focal cerebral ischemia. All three drugs produced statistically significant improvement in motor function following acute administration without concomitant changes in level of consciousness; saline had no effect. Naloxone and naltrexone significantly prolonged survival (p less than 0.01); diprenorphine did not. Infarct size was not altered by any treatment administered. These findings confirm previous work suggesting that, with the appropriate methodology, treatment with opiate antagonists partially reverses neurological deficits. They also show that opiate antagonists prolong survival in certain conditions of acute and subacute focal cerebral ischemia without altering the area of infarcted tissue.

Topics: Animals; Brain Ischemia; Cats; Cerebrovascular Disorders; Consciousness; Diprenorphine; Disease Models, Animal; Male; Morphinans; Movement; Naloxone; Naltrexone; Pupil; Sensation