dextromethorphan and Brain-Edema

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

While N-methyl-D-aspartate antagonists have been shown to attenuate neuronal damage in focal cerebral ischemia, few studies have examined whether continuous or multiple dose treatment is necessary for maximum efficacy. We studied the effect of a loading dose only or load plus maintenance infusion using several non-competitive N-methyl-D-aspartate antagonists (dextromethorphan, dextrorphan, MK-801) and the levorotatory enantiomer of dextromethorphan (levomethorphan) in a rabbit model of focal cerebral ischemia. Forty-seven anesthetized rabbits underwent occlusion of the left internal carotid, anterior cerebral and middle cerebral arteries for 2 h followed by 4 h of reperfusion. Drugs were administered 10 min after occlusion. Dextromethorphan and dextrorphan protected against ischemic edema only when given as load plus maintenance (29% and 31% reduction, respectively), while both load only and load plus maintenance of MK-801 protected against edema (26% and 31% reduction, respectively). Levomethorphan load plus maintenance also protected against ischemic edema (25% reduction). However, dextromethorphan and dextrorphan both required maintenance infusion to protect against ischemic neuronal damage (24% and 27% reduction in area of ischemic neuronal damage, respectively), while levomethorphan failed to protect against neuronal injury even when given as load plus maintenance. Administration of MK-801 as load plus maintenance reduced ischemic neuronal damage by 23%, but this difference was not quite statistically significant. These results suggest that processes of ischemic damage, such as excitotoxic injury, continue for several hours beyond the initial period of focal ischemia, and that non-competitive N-methyl-D-aspartate antagonists require more prolonged administration to achieve neuroprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Temperature; Brain Edema; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Dextromethorphan; Dextrorphan; Hydrogen-Ion Concentration; N-Methylaspartate; Neuroprotective Agents; Oxygen; Rabbits

Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits 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 ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.

Topics: Animals; Ataxia; Brain Chemistry; Brain Edema; Brain Ischemia; Dextromethorphan; Drug Evaluation, Preclinical; Magnetic Resonance Imaging; Male; Rabbits; Receptors, N-Methyl-D-Aspartate; Respiration Disorders

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