HIGH-DOSE BACLOFEN IS NEUROPROTECTIVE BUT ALSO CAUSES INTRACEREBRAL HEMORRHAGE - A QUANTAL BIOASSAY STUDY USING THE INTRALUMINAL SUTURE OCCLUSION METHOD

Agonists of the GABA-A receptor are neuroprotective after experimental stroke, but studies of GABA-B agonists have contradicted each other. To further investigate whether GABA-B agonists may be neuroprotective, we devised a quantal bioassay using the intraluminal occlusion method of inducing reversible cerebral ischemia. Subjects underwent middle c erebral artery occlusion for varying amounts of time, ranging hom 5 to 90 min. Behavioral outcome was measured 48 h later with a quantal obs ervational scale: score of abnormal given for any one of asymmetric fo repaw flexion on tail lift, asymmetric grip, circling, reduced explora tion, seizures, or death. To the grouped response data the logistic eq uation was used to find the ED50, the duration of occlusion that cause d one-half of the subjects to be abnormal. To find the potency ratio f or each drug, we divided the ED50 for treatment by that for vehicle. W e administered baclofen, a GABA-B agonist, intraperitoneally 5 min aft er the onset of ischemia, Baclofen (20 mg/kg) was neuroprotective (pot ency ratio of 3.0, P < 0.05), but a lower dose (10 mg/kg) was not. How ever, both doses of baclofen caused significantly more intracerebral h emorrhages than control. Ln awake animals, both baclofen doses caused significant increases in mean arterial pressure, but no changes in oth er cardiorespiratory variables. The glutamate antagonist MK-801, the G ABA-A agonist muscimol, and hypothermia were all protective using the bioassay (potency ratios ranging from 1.5 to 3.0). We conclude that al though baclofen (20 mg/kg) may be neuroprotective, its utility is comp licated by postischemic hypertension and cerebral hemorrhages. (C) 199 7 Academic Press.