Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile.
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.
Steinberg
G K
GK
Department of Neurosurgery, Stanford University School of Medicine, CA 94305.
Kunis
D
D
DeLaPaz
R
R
Poljak
A
A
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001923:Brain Chemistry; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D008279:Magnetic Resonance Imaging; D008297:Male; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012120:Respiration Disorders / Q000139:chemically induced
D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan