dextromethorphan and Ischemic-Attack--Transient

Topics: Animals; Benzazepines; Body Temperature; Brain; Brain Injuries; Brain Ischemia; Calcium Channel Blockers; Dextromethorphan; Dizocilpine Maleate; Drug Therapy, Combination; Humans; Ischemic Attack, Transient; N-Methylaspartate

Experimental ischemia models have shown the antitussive dextromethorphan to be an N-methyl-D-aspartate antagonist with neuroprotective properties. We treated 10 patients with a history of recent stroke or transient ischemic attack with oral dextromethorphan (60 mg q.i.d.) for 3 weeks in a placebo-controlled, double-blind, crossover tolerance study. We documented no clinical evidence of toxicity attributable to dextromethorphan in this preliminary study.

Topics: Administration, Oral; Aged; Brain Ischemia; Cerebrovascular Disorders; Dextromethorphan; Double-Blind Method; Humans; Ischemic Attack, Transient; Middle Aged; Risk Factors

Cell death after cerebral ischemia is mediated by a massive release of excitatory amino acids, generation of free radicals, and - a crucial step - calcium influx into cells. We examined the hypothesis that concurrent administration of drugs ameliorating brain damage via different mechanisms would result in a synergistic neuroprotective effect. The neuroprotective efficacy of two clinically available drugs - the N-methyl-D-aspartate and calcium-channel antagonist dextromethorphan (DM) and the antioxidant tirilazad - were studied in monotherapy and in combination in a rat model of transient focal ischemia. Male Sprague-Dawley rats were subjected to 90 min of middle-cerebral-artery occlusion by an intraluminal filament technique. The animals were randomly assigned to one of four treatments (n=10 each): (1) vehicle-treated controls, (2) DM, (3) tirilazad, (4) DM+tirilazad. Drugs or vehicles were administered 15 min before ischemia and at reperfusion. Local cerebral blood flow (LCBF) was bilaterally recorded by continuous laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed planimetrically after 7 days. DM prevented post-ischemic hypoperfusion. Tirilazad did not influence LCBF. Monotherapy with DM or tirilazad improved neurological function and reduced infarct volume by 45% and 48%, respectively. Combination therapy failed to influence neurological recovery and infarct volume. Although, from pharmacological point of view, a synergistic neuroprotective effect is expected, combination of dextromethorphan and tirilazad may lead to mutual inhibition or potentiate adverse effects.

Topics: Animals; Calcium Channel Blockers; Cerebral Infarction; Dextromethorphan; Drug Evaluation, Preclinical; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Neuroprotective Agents; Pregnatrienes; Rats; Rats, Sprague-Dawley; Treatment Outcome; Weight Gain

To study the effects of dextromethorphan (Dex) on photochemically-induced focal cerebral ischemia in rats.. Anesthetized rats undergone 10-min light irradiation on exposed skull after rose bengal injection were pretreated with saline and Dex at 3 doses (12.5, 25, and 50 mg.kg-1, i.p., 15 min before ischemia). The alteration of volume of lesioned cortical region, regional cerebral blood flow (CBF), bcl-2 and bax expression at penumbra area were studied.. Dex dose-dependently decreased the infarcted volume (17%, 26%, and 50% reduction, respectively). Pretreatment with Dex at a dose of 50 mg.kg-1 improved the postischemic hypoperfusion compared with the control at 20 and 30 min after lesion (both 31% increase), and also upregulated the expression of anti-apoptosis gene bcl-2.. Dex protects against ischemic neuronal damage in this model and its effects on CBF and bcl-2 expression may contribute to its neuroprotective action.

Topics: Animals; Dextromethorphan; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Light; Male; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Rose Bengal

Dextromethorphan (DM) has been observed to afford neuroprotection in a variety of in vitro and in vivo experimental models of CNS injury. We have evaluated the neuroprotective activity of DM following both transient (2 h) and permanent focal cerebral ischemia in the rat. Middle cerebral artery occlusion (MCAO) was produced in male Sprague-Dawley rats using the intraluminal filament technique. Animals were dosed s.c with 20 mg/kg DM at 0.5, 1, 2, 4, and 6 hours post occlusion. Analysis of brain injury was performed 24 hours after permanent occlusion or reperfusion. Following transient MCAO, vehicle treated rats exhibited a total infarct volume of 203 +/- 33 mm3. DM produced a 61% reduction in infarct volume to 79 +/- 13 mm3. Permanent MCAO produced a larger infarct volume (406 +/- 44 mm3) which was not significantly reduced in size by treatment with DM (313 +/- 58 mm3). Infarcted hemispheric oedema was not different in vehicle treated rats following transient or permanent MCAO and was not reduced by DM in either group. Following transient MCAO, rectal temperature was elevated 1,2 and 5 hours post occlusion. While not inducing hypothermia or altering physiological parameters such as blood pressure and blood gases, DM attenuated this injury-related increase in temperature, an effect which appeared to correlate with its ability to protect neurons in temperature regulating hypothalamic centres. The DM-induced reduction in infarction demonstrated in our model of transient focal cerebral ischemia provides further support for the in vivo neuroprotective activity of this compound. Importantly, these data demonstrate the limited neuroprotective efficacy of DM when attempting to combat more severe focal ischemic injuries and imply that drug-induced hypothermia is not ultimately responsible for its protective action.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Dextromethorphan; Disease Models, Animal; Hypothermia; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury

To study the effect of dextromethorphan (DM) in focal cerebral ischemia.. The c-fos protein was detected immunohistochemically in the brain of rats after focal cerebral ischemia (induced by placing a nylon thread in the lumen of the internal carotid artery) with and without treatment with DM.. Focal cerebral ischemia induced c-fos protein expression outside the core territory of the middle cerebral artery (MCA) and neuronal damage in the core territory of the MCA. There was an evident expression of c-fos protein in the ipsilateral regions outside the MCA territory (e.g. cingulate cortices, piriform cortices and entorhinal cortices), and in the contralateral regions of hippocampus after 4-h reperfusion following 1-h MCA occlusion. But morphological results showed severe edema and neuronal damage in the core territory and the ipsilateral hippocampus. DM blocked both the c-fos protein induction and neuronal damage in all regions.. DM reduced c-fos protein expression and blocked the neuronal damage after focal cerebral ischemia.

Topics: Animals; Cerebral Cortex; Dextromethorphan; Ischemic Attack, Transient; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

To study the neuroprotective effects of dextromethorphan against transient cerebral ischemia/reperfusion injury.. Transient cerebral ischemia/reperfusion injury in gerbils was produced by temporarily clamping the common carotid arteries (CCA) for 10 min.. Intrahippocampal (ih) injection of 2.0 microL dextromethorphan (DM, 100 mumol.L-1) 5 min before ischemia quickened the recovery of EEG changes, the total power spectra of EEG, and the power of dominant frequency following reperfusion. The total power of EEG was increased to 92 +/- 30 (P < 0.01) at 240 min following reperfusion. DM substantially reduced the severe ischemic neuronal damage (SIND) after 10 min of cerebral ischemia and 24 h of reperfusion.. DM has neuroprotective effects against transient cerebral ischemia and reperfusion injury in gerbils.

Topics: Animals; Dextromethorphan; Electroencephalography; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Microinjections; Neurons; Reperfusion Injury

The effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on regional cerebral blood flow (rCBF) and cerebral injury were studied in a rabbit model of transient focal ischemia. Anesthetized rabbits underwent 2 h occlusion of the left internal carotid, middle cerebral and anterior cerebral artery, followed by 4 h of reperfusion. Ten minutes after the onset of ischemia they were treated with either i.v. DM 20 mg/kg followed by 10 mg/kg/h (n = 6) or normal saline (NS, n = 5). Control rabbits received DM (n = 3) or NS (n = 2) infusion without arterial occlusion. DM attenuated the sharp, post-ischemic rise in rCBF seen during reperfusion within the ischemic core of NS controls (DM 31% pre-ischemic value, NS 92%). DM also improved the delayed post-ischemic hypoperfusion compared with controls. DM infusion without arterial occlusion did not change rCBF values. Compared with NS controls, DM treated animals demonstrated recovery of the somatosensory evoked potential (DM 96% pre-ischemic values, NS 24%), 76% reduction in cortical edema and 92% decrease in cortical ischemic neuronal damage. We conclude that DM's effect on CBF may contribute to its neuroprotective action.

Topics: Animals; Brain; Brain Edema; Cerebrovascular Circulation; Dextromethorphan; Electric Stimulation; Evoked Potentials, Somatosensory; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Neurons; Rabbits; Reperfusion

Using proton and phosphorus magnetic resonance spectroscopy, we evaluated the metabolic effects of preischemic administration of the N-methyl-D-aspartate antagonist dextromethorphan (50 mg/kg i.p.) during global forebrain ischemia and subsequent reperfusion in rats. Dextromethorphan-treated animals (n = 10) showed less lactate formation during ischemia than untreated animals (n = 11, p less than 0.001). During reperfusion, the lactate level in the treated group was reduced (p less than 0.05). Tissue pH declined less in the treated group during ischemia (p less than 0.01). There was no difference in the phosphocreatine/inorganic phosphate peak height ratio between groups. During ischemia, the N-acetylaspartate resonance peaks decreased in both groups. Histologic damage assessed in the hippocampal CA1 region 7 days after the ischemic insult was more severe in the untreated group (p less than 0.05). There was a significant correlation between end-ischemic tissue pH and hippocampal damage (r = -0.73, p less than 0.05). In the dextromethorphan-treated animals, 90% of the rats survived compared with 47% of the untreated animals (p less than 0.05). These results support findings in previous studies that dextromethorphan attenuates ischemic damage.

Topics: Animals; Brain; Dextromethorphan; Energy Metabolism; Hippocampus; Hydrogen-Ion Concentration; Ischemic Attack, Transient; Lactates; Magnetic Resonance Spectroscopy; Male; Pyramidal Tracts; Rats; Rats, Inbred Strains; Reperfusion

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

The effects of dextromethorphan (DM) were tested in an in vivo model of incomplete global cerebral ischemia. Anesthetized rats were divided into 4 groups: Group 1 (saline); Group 2 (DM pre-treatment, 20 mg/kg i.v. bolus followed by 10 mg/kg/h DM infusion); Group 3 (DM post-treatment, 2 mg/kg i.v. bolus followed by 10 mg/kg/h DM infusion at the onset of post-ischemic hypoperfusion); and Group 4 (sham-operated, drug-treated). Groups 1-3 underwent 15 min of 4-vessel occlusion followed by 3 h of reperfusion. Administration of DM in sham-operated animals (Group 4) had no effect on cerebral blood flow or electroencephalographic (EEG) activity. In contrast, when compared to the Group 1 saline controls, significant attenuation of post-ischemic hypoperfusion and EEG dysfunction was demonstrated in ischemic rats treated with DM (both pre- and post-treatment), suggesting an ability of DM to improve cerebral blood flow (CBF) and brain function in cerebral ischemia.

Topics: Animals; Antitussive Agents; Cerebrovascular Circulation; Dextromethorphan; Electroencephalography; Female; Ischemic Attack, Transient; Levorphanol; Rats; Rats, Inbred Strains

The dextrorotatory morphinan dextromethorphan (DM), a clinically tested antagonist of the N-methyl-D-aspartate (NMDA) receptor-channel complex, was tested in an in vivo model of acute transient focal cerebral ischemia. Rabbits were randomly assigned to pretreatment with a 20 mg/kg i.v. bolus followed by 10 mg/kg/h of 0.4% DM in normal saline (NS), or with an equivalent volume of NS alone. They then underwent 1 h occlusion of the left internal carotid artery an anterior cerebral artery followed by 4 h of reperfusion. DM-treated animals showed a significant decrease in the percentage of severe neocortical ischemic neuronal damage (10.5%), as compared to NS-treated animals (49.6%).

Topics: Animals; Cerebral Cortex; Dextromethorphan; Disease Models, Animal; In Vitro Techniques; Ischemic Attack, Transient; Levorphanol; Male; Rabbits