dextromethorphan and Brain-Injuries

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 evidence indicates a role of the N-methyl-D-aspartate receptor in the pathogenesis of brain injury occurring during cardiac surgery with cardiopulmonary bypass (CPB). Dextromethorphan is a noncompetitive antagonist of this receptor with a favorable safety profile. Thirteen children age 3-36 months undergoing cardiac surgery with expected CPB of 60 minutes or more were randomly assigned to treatment with dextromethorphan (36-38 mg/kg/day) or placebo administered by naso-gastric tube. Dextromethorphan was absorbed well and reached putative therapeutic levels in blood and cerebrospinal fluid. Adverse effects were not observed. Mild hemiparesis developed after operation in one child of each group, and severe encephalopathy in one of the placebo group. Sharp waves were recorded in postoperative continuous electroencephalography in all placebo (n = 7) but only in 2/6 dextromethorphan treated children (p = 0.02). Pre- and postoperative cranial magnetic resonance imaging (MRI) revealed less pronounced ventricular enlargement in the dextromethorphan group (not significant). An increase of periventricular white matter lesions was visible in two placebo-treated children only. No elevations of cerebrospinal fluid enzymes were observed in either group. Although children with dextromethorphan showed less abnormalities in electroencephalography and MRI, dissimilarities of the treatment groups by chance diminished conclusions to possible protective effects of dextromethorphan at this time.

Topics: Brain Chemistry; Brain Injuries; Cardiopulmonary Bypass; Child, Preschool; Dextromethorphan; Electroencephalography; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Pilot Projects; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

Topics: Animals; Brain Injuries; Carotid Artery, Common; Cognition; Cognition Disorders; Dementia, Vascular; Dextromethorphan; Heme Oxygenase-1; Hippocampus; Male; Maze Learning; Neostriatum; Neuroglia; Neurons; Neuroprotection; Optic Tract; Oxidative Stress; Rats, Sprague-Dawley; Up-Regulation; White Matter

Pathological laughing and crying, or pseudobulbar affect (PBA), has been described in patients with neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, and traumatic brain injury (TBI) since the 19th century (Schiffer 2005). The syndrome is characterized by inappropriate episodes of laughing or crying after minor stimuli. It was first coined a disinhibition of cortical control by Kinnier Wilson in 1924. It was observed in brain disease and seen with mild TBI. It can impair social and occupational function and is largely underrecognized in clinical settings. PBA is usually treated with antidepressants and dopaminergic agents. In this case we treated a military recruit with TBI with Nuedexta-a dextromethorphan/Quinidine derivative with a subsequent decrease in his episodes.

Topics: Adult; Affective Symptoms; Brain Concussion; Brain Injuries; Crying; Dextromethorphan; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Humans; Laughter; Male; Quinidine; Stress Disorders, Post-Traumatic

Traumatic brain injury (TBI) is caused by primary and secondary injury mechanisms. TBI induces a certain amount of inflammatory responses and glutamate excitotoxicity that are believed to participate in the pathogenesis of secondary injury. The non‑narcotic anti‑tussive drug dextromethorphan (DM) has been reported to have a high safety profile in humans and its neuroprotective against a variety of disorders, including cerebral ischemia, epilepsy and acute brain injury. However, few studies have explored the underlying mechanisms of the neuroprotective effects of DM in animals in the setting of TBI. The aim of the present study was to investigate the neuroprotective effects of DM on TBI and to determine the underlying mechanisms. Rats were subjected to a controlled cortical impact (CCI) injury and randomly divided into three groups: Sham‑operated, TBI and DM treatment groups. The DM treatment group was administered DM (30 mg/kg of body weight, intraperitoneally) immediately after injury. It was identified that DM treatment following TBI significantly reduced brain edema and neurological deficits, as well as increased neuronal survival. These effects correlated with a decrease of tumor necrosis factor α, interleukin‑1β (IL‑1β) and IL‑6 protein expression and an increase of glutamate/aspartate transporter and glutamate transporter‑1 in the cortex of the brain. These results provided in vivo evidence that DM exerts neuroprotective effects via reducing inflammation and excitotoxicity induced following TBI. The present study has shed light on the potential use of DM as a neuroprotective agent in the treatment of cerebral injuries.

Topics: Animals; Anti-Inflammatory Agents; Brain; Brain Edema; Brain Injuries; Dextromethorphan; Inflammation; Interleukin-1beta; Interleukin-6; Male; Neuroprotection; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation.

Topics: Animals; Animals, Newborn; Antitussive Agents; Apoptosis; Brain; Brain Injuries; Caspase 3; Cell Line; Cell Survival; Cytokines; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Gray Matter; Hyperoxia; Neuroprotective Agents; Oligodendroglia; Oxygen; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sigma-1 Receptor; White Matter

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