dextromethorphan and Nerve-Degeneration

Dextromethorphan (DM) has been well-characterized as a neuroprotective agent in experimental models of CNS injury. The goal of this study was to determine the neuroprotective profile of DM in a military-relevant model of penetrating ballistic-like brain injury (PBBI). In an acute (3 day) dose-response study, anesthetized male Sprague-Dawley rats were exposed to a unilateral frontal PBBI with DM (0.156-10 mg/kg) or vehicle delivered as an i.v. bolus from 30 min to 48 h post-injury. In a follow-up (7 day) experiment, the 10-mg/kg bolus injections of DM were administered in conjunction with a 6-h infusion (5 mg/kg/h). DM bolus injections alone produced a dose-dependent improvement in motor recovery on a balance beam task at 3 days post-injury. However, more rapid recovery (24 h) was observed on this task when the bolus injections were combined with the 6-h infusion. Moreover, the DM bolus/infusion treatment regimen resulted in a significant (76%) improvement in cognitive performance in a novel object recognition (NOR) task at 7 days post-injury. Although post-injury administration of DM (all doses) failed to reduce core lesion size, the maximum dose of DM (10 mg/kg) was effective in reducing silver-stained axonal fiber degeneration in the cortical regions adjacent to the injury.

Topics: Analysis of Variance; Animals; Behavior, Animal; Brain Injuries; Cognition; Dextromethorphan; Diffuse Axonal Injury; Dose-Response Relationship, Drug; Frontal Lobe; Head Injuries, Penetrating; Image Processing, Computer-Assisted; Male; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Time Factors

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Topics: Adrenergic alpha-Antagonists; Animals; Avoidance Learning; Behavior, Animal; Dextromethorphan; Ethylenediamines; Immunohistochemistry; Learning Disabilities; Maze Learning; Memory; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Phencyclidine; Receptors, sigma; Seizures; Sigma-1 Receptor; Trimethyltin Compounds

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM), a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS) -induced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-alpha, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM's failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These findings suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenerative diseases.

Topics: Animals; Astrocytes; Cell Death; Cells, Cultured; Coculture Techniques; Dextromethorphan; Dinoprostone; Dopamine; Embryo, Mammalian; Female; Inflammation; Lipopolysaccharides; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Nerve Degeneration; Neuroglia; Neurons; Neuroprotective Agents; Nitric Oxide; Nitrites; Parkinson Disease; Pregnancy; Rats; Rats, Inbred F344; Reactive Oxygen Species; Superoxides; Tritium; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1-10 micro M) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or beta-amyloid peptide (1-42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenylpyridinium; Amyloid beta-Peptides; Animals; Cells, Cultured; Dextromethorphan; Drug Interactions; Inflammation; Lipopolysaccharides; Microglia; Nerve Degeneration; Neurons; Neuroprotective Agents; Rats; Rats, Inbred F344; Receptors, Dopamine; Superoxides; Xanthine; Xanthine Oxidase

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a transient locomotor hyperactivity and a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of dextromethorphan, an antagonist at the N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. Dextromethorphan was administered 20 min before induction of ischemia at a dose of 10 or 50 mg/kg. Before and on day 1, 3 and 5 after operation the spontaneous locomotor activity was measured. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damage was assessed. Treatment with 50 mg/kg of dextromethorphan reduced the increase in locomotor activity observed on day 1 and 3 after ischemia. In the water maze dextromethorphan reduced the increase in escape latency and in swim distance induced by 4VO. Furthermore, the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial was increased by treatment with dextromethorphan. Neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum produced by 4VO was significantly attenuated by dextromethorphan. The present results demonstrate that protective effects on neuronal damage may be related to an attenuation of deficits in spatial leaning and memory following global ischemia.

Topics: Animals; Behavior, Animal; Brain Ischemia; Dextromethorphan; Male; Maze Learning; Memory; Motor Activity; N-Methylaspartate; Nerve Degeneration; Neurons; Neuroprotective Agents; Rats; Rats, Wistar

Dextromethorphan (DM), a widely used antitussive agent, has been shown to possess both anticonvulsant and neuroprotective properties functionally related to its inhibitory effects on glutamate-induced neurotoxicity. The current study was designed to determine whether DM administration prevents delayed neuronal degeneration in central nervous system areas after global forebrain ischemia and whether this correlates with inhibition of induction of the immediate early gene c-fos.. Mongolian gerbils, anesthetized with 2% halothane in air at 37 degrees C, received either 0.9% sodium chloride (vehicle, n = 9) or 50 mg/kg DM in vehicle (n = 9) by intraperitoneal injection before bilateral carotid artery occlusion. After 1 h of reperfusion under anesthesia, the animals were killed and the brains removed. Immunohistochemistry was used to detect neurons expressing Fos protein. Computer-assisted image analysis quantified changes in the number of labeled neurons as a function of drug treatment. To determine the extent of delayed neuronal degeneration within the hippocampus, other animals were treated with either DM (n = 7) or vehicle (n = 6) before carotid artery occlusion and allowed to survive for 1 week.. Global forebrain ischemia produced consistent patterns of Fos-like immunoreactivity in the hippocampus and neocortex of vehicle-treated animals. DM inhibited the induction of c-fos from 65% to 91%. DM also protected against delayed neuronal degeneration in the CA1 region of the hippocampus (P < 0.001).. The induction of nuclear-associated Fos protein represents a sensitive marker of cellular responses to ischemia and a method to assay the effectiveness of pharmacologic interventions. DM markedly inhibited ischemia-induced Fos expression and prevented cell death in CA1. DM given before conditions of ischemia or decreased central nervous system perfusion may be highly beneficial.

Topics: Animals; Brain Ischemia; Cell Death; Dextromethorphan; Gerbillinae; Hippocampus; Immunohistochemistry; Male; Nerve Degeneration; Neurons; Proto-Oncogene Proteins c-fos