Dextrorphan is a dextrorotatory
morphinan and a noncompetitive
N-methyl-D-aspartate (
NMDA) receptor antagonist. We studied the dose response characteristics of
dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal
cerebral ischemia. Thirty-three rabbits, anesthetized with
halothane, 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
ischemia, they were treated with an i.v. infusion of varying
dextrorphan doses or
normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of
dextrorphan, correlating plasma with brain
dextrorphan levels. Twenty-six additional
dextrorphan unanesthetized, nonischemic rabbits received infusions of
dextrorphan to correlate behavioral side effects with
dextrorphan dose and levels. Compared with controls,
dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The
dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6).
Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of
dextrorphan was correlated with plasma free
dextrorphan levels (r = -0.50, p less than 0.02 for ischemic neuronal damage; r = -0.66, p less than 0.001 for ischemic MRI high signal). All the rabbits with plasma levels greater than 2,000 ng/ml had less than 12% cortical ischemic neuronal damage and less than 34% MRI high signal. All rabbits with plasma levels greater than 3,000 ng/ml showed less than 7% ischemic neuronal damage and less than 11% MRI high signal. Plasma levels of approximately 2,500 ng/ml correlated with brain
dextrorphan levels of approximately 6,000 ng/g. Unanesthetized rabbits with plasma levels of approximately 2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with
dextrorphan after 1 h focal
ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of
dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent
glutamate or
NMDA-induced injury in neuronal culture.