dextromethorphan and Cerebral-Infarction

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.

Topics: Animals; Antitussive Agents; Brain; Cerebral Infarction; Dextromethorphan; Drug Design; Dysuria; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Molecular Targeted Therapy; Piperidines; Rats; Serotonin; Urinary Bladder, Overactive

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

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

We assessed the cerebral protective effects of the noncompetitive N-methyl-D-aspartate antagonist dextromethorphan (DM; 10-35 mg/kg i.p.) in 8-day-old rats that were subjected to brain hypoxia-ischemia by tying one carotid artery and placing them in 8% O2-92% N2 for 2 h. Light microscopic examination of brains perfused one week after the insult revealed that all control animals developed a frank infarction with cavitation and brain shrinkage in the middle cerebral artery territory. There was a highly significant decrease in the incidence of frank infarction in DM-pre-treated pups vs saline-treated littermates, although there was no clear relationship between drug dose and the degree of brain protection. DM and its active metabolite dextrorphan may prove to be clinically useful in protecting against hypoxia-ischemia.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Dextromethorphan; Dose-Response Relationship, Drug; Female; Levorphanol; Male; Rats; Rats, Inbred Strains