dextrorphan and Ischemic-Attack--Transient

Previous studies have implicated both excitotoxicity and apoptosis in the pathogenesis of cerebral infarction induced by focal ischemic insults. Here we tested the possibility that the NMDA antagonist, dextrorphan, and the protein synthesis inhibitor, cycloheximide, would produce additive protective effects in a rodent model of focal ischemia-reperfusion. Transient focal cerebral ischemia was induced by a 90 min period of ligation of the right middle cerebral artery and both common carotid arteries. Administration of either 30 mg/kg dextrorphan or 0.5 mg/kg cycloheximide, given i.p. 15 min before ischemia, reduced infarct volume by about 65%. When optimal concentrations of each drug were given together, infarct volume was reduced by 87% as measured 14 days later. These observations support the idea that both excitotoxicity, and apoptosis dependent on new protein synthesis, contribute to cerebral infarction after transient focal ischemia in the rat.

Topics: Animals; Blood Glucose; Cerebral Arteries; Cerebral Infarction; Cycloheximide; Dextrorphan; Ischemic Attack, Transient; Male; Neuroprotective Agents; Protein Synthesis Inhibitors; Rats

Focal cerebral ischemia confined to the cerebral cortex in the right middle cerebral artery (MCA) territory was induced by temporary ligation of the MCA and both common carotid arteries (CCAs). Reperfusion was initiated by releasing all three arterial occlusions after 90 min of ischemia. Infarct volume was morphometrically measured after triphenyltetrazolium chloride staining 24 h postischemia. Blood-brain barrier breakdown was assessed 4 h postischemia by measuring vascular permeability to fluorescein isothiocyanate-conjugated dextran (FITC-D), a macromolecule tracer. Ischemic brain edema was measured based on percent water content, 24 h postischemia. Dextrorphan (DX) 20-10 mg/kg given ip 15 min before ischemia reduced infarct volume in a dose-dependent manner with an apparent U-shaped dose-response curve; best protection was observed at 30 mg/kg. Posttreatment at 30 min, but not 60 min, was still effective. DX (30 mg/kg, given 15 min before ischemia) also reduced the postischemic increase in vascular permeability and brain edema in the right MCA cortex. Results from this study support the idea that NMDA receptor activation contributes to blood-brain barrier breakdown and brain edema after ischemic insults

Topics: Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Blood-Brain Barrier; Brain Edema; Carbon Dioxide; Carotid Artery, Common; Cerebral Infarction; Cerebrovascular Circulation; Dextrorphan; Heart Rate; Ischemic Attack, Transient; Male; Neuroprotective Agents; Oxygen; Rats; Reperfusion; Time Factors

N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to protect against focal cerebral ischaemia when administered either before or soon after the onset of ischaemia. However, the precise therapeutic window for protection using these drugs remains to be defined. We studied dextrorphan administration delayed for 2 or 4 h after transient middle cerebral focal ischaemia in a rabbit model. With a 2h delay, the mid (12.5 mg kg-1 h-1) and high doses (17.5 mg kg-1 h-1) provided significant cortical neuroprotection (50% and 58% reduction, respectively), and the low dose (7.5 mg kg-1 h-1) protected against ischaemic damage in the basal ganglia (52% reduction). Animals having steady-state serum dextrorphan concentrations greater than 2000 ng ml-1 showed 50% cortical neuroprotection for the 2-h-delay group. No significant neuroprotection was seen in the 4-h-delay group, and the 4 h delay animals with dextrorphan levels greater than 2000 ng ml-1 had more severe ischaemic oedema than the saline controls. These results suggest a narrow temporal therapeutic window for neuroprotection, where delivery of drug delayed by 2 h was efficacious but treatment at 4 h after ischaemia onset was not beneficial and possibly harmful. These findings may have important implications for the treatment of clinical stroke.

Topics: Animals; Dextrorphan; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rabbits; Receptors, N-Methyl-D-Aspartate; Time Factors

A 5-min period of cerebral ischemia increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) assessed by the working memory procedure applied in a three-panel runway task. The selective and competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGS 19755 (3.2 and 10 mg/kg), administered i.p. immediately after blood flow reperfusion, significantly reduced the increase in errors expected to occur 24 h after 5 min of ischemia. CGS 19755 10 mg/kg had no effect on the increase in errors when injected 6 h after ischemia. The i.p. administration of the non-competitive NMDA antagonists dextrorphan 10 and 32 mg/kg and MK-801 1.0 mg/kg immediately after reperfusion decreased the increase of errors in the ischemic rats. The protective effects of NMDA antagonists suggest that the mechanism mediated by NMDA receptors during the early reperfusion phase plays a pivotal role in the postischemic impairment of working memory.

Topics: Animals; Dextrorphan; Dizocilpine Maleate; Ischemic Attack, Transient; Memory; N-Methylaspartate; Pipecolic Acids; Prosencephalon; Rats; Receptors, N-Methyl-D-Aspartate

Excessive activation of glutamate receptors, most notably the N-methyl-D-aspartate (NMDA) subtype, appears to be a crucial factor in the sequence of cellular events which lead to irreversible ischaemic damage to neurones. The ability of newly developed antagonists of the NMDA receptor to reduce ischaemic brain damage has been assessed in cat and rodent models of focal cerebral ischemia. Non-competitive NMDA receptor antagonists such as dizocilpine (CAS 77086-21-6) which act at a site within the receptor operated ion channel markedly reduce (by more than 50%) ischaemic brain damage when administered prior to the ischaemic episode or 2 h after the onset of ischaemia. Competitive NMDA receptor antagonists, such as D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid, which act at the neurotransmitter recognition site are equally effective in reducing the ischaemic brain damage when administered prior to the onset of the ischaemic episode. The clinical utility of competitive and non-competitive NMDA receptor antagonists in man will, however, be determined not by their tremendous anti-ischaemic efficacy, but by their profile of adverse effects. Careful selection of the therapeutic target for NMDA antagonists will be necessary if beneficial effects are to be established in man.

Topics: Animals; Cats; Cerebral Arteries; Dextrorphan; Dizocilpine Maleate; Hematoma, Subdural; Ischemic Attack, Transient; Kynurenic Acid; Phencyclidine; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate

Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = -0.50, p less than 0.02 for ischemic neuronal damage; r = -0.66, p less than 0.001 for ischemic MRI high signal). All the rabbits with plasma levels greater than 2,000 ng/ml had less than 12% cortical ischemic neuronal damage and less than 34% MRI high signal. All rabbits with plasma levels greater than 3,000 ng/ml showed less than 7% ischemic neuronal damage and less than 11% MRI high signal. Plasma levels of approximately 2,500 ng/ml correlated with brain dextrorphan levels of approximately 6,000 ng/g. Unanesthetized rabbits with plasma levels of approximately 2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral dam

Topics: Animals; Brain; Dextrorphan; Dose-Response Relationship, Drug; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; N-Methylaspartate; Nervous System Diseases; Rabbits

We studied the efficacy of postischemic, systemic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan and dextrorphan in a rabbit model of transient focal cerebral ischemia. Twenty-two rabbits underwent 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4.5 hours of reperfusion before sacrifice. One hour after the onset of ischemia, immediately after removing the arterial clips, the rabbits were blindly assigned to treatment with dextromethorphan (20 mg/kg i.v. loading dose followed by 10 mg/kg/hr maintenance infusion, n = 7), dextrorphan (15 mg/kg i.v. loading dose followed by 15 mg/kg/hr maintenance infusion, n = 7), or an equivalent volume of normal saline alone (n = 8). The maintenance infusion of drugs or saline was continued for the duration of the experiment. The formalin-fixed brains were analyzed with magnetic resonance imaging using coronal T2-weighted images, and ischemic neuronal damage was assessed on standard coronal hematoxylin-and- eosin-stained sections. The area of neocortical ischemic neuronal damage was significantly reduced in the groups treated with dextromethorphan (4.2%, p less than 0.01) and dextrorphan (6.1%, p less than 0.01) compared with the controls (36.2%). Magnetic resonance imaging demonstrated significantly smaller areas of cortical edema in the groups treated with dextromethorphan (14.6%, p less than 0.01) and dextrorphan (8.0%, p less than 0.01) compared with the controls (32.9%). These clinically tested antitussives with NMDA-antagonist properties may have therapeutic value in the treatment of human cerebrovascular disease.

Topics: Animals; Aspartic Acid; Cerebral Cortex; Corpus Striatum; Dextromethorphan; Dextrorphan; Ischemic Attack, Transient; Levorphanol; Magnetic Resonance Imaging; Male; Morphinans; N-Methylaspartate; Neurons; Rabbits

We studied the efficacy of systemic pre-treatment with dextrorphan (DX), a clinically tested N-methyl-D-aspartate (NMDA) antagonist, in a rabbit model of transient focal cerebral ischemia. Rabbits were treated with either a 24 mg/kg i.v. loading dose followed by 12 mg/kg/h i.v. infusion of 0.48% DX in normal saline (NS), or with an equivalent volume of NS alone. One and 1/2 h after starting the drug or NS, the rabbits underwent a 1 h occlusion of the left internal carotid and anterior cerebral arteries, followed by 4 h of reperfusion. The DX-treated rabbits had significantly less neocortical ischemic neuronal damage (7.4%) than the normal saline group (31.6%) and demonstrated a significant decrease in ischemic cortical edema. DX may prove useful in the treatment of clinical cerebrovascular disease.

Topics: Animals; Aspartic Acid; Brain; Brain Edema; Cerebral Cortex; Dextrorphan; Ischemic Attack, Transient; Magnetic Resonance Spectroscopy; Male; Morphinans; N-Methylaspartate; Neurons; Rabbits