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 cerebral artery occlusion for varying amounts of time, ranging from 5 to 90 min. Behavioral outcome was measured 48 h later with a quantal observational scale: score of abnormal given for any one of asymmetric forepaw flexion on tail lift, asymmetric grip, circling, reduced exploration, seizures, or death. To the grouped response data the logistic equation was used to find the ED50, the duration of occlusion that caused one-half of the subjects to be abnormal. To find the potency ratio for each drug, we divided the ED50 for treatment by that for vehicle. We administered baclofen, a GABA-B agonist, intraperitoneally 5 min after the onset ofischemia. Baclofen (20 mg/kg) was neuroprotective (potency ratio of 3.0, P < 0.05), but a lower dose (10 mg/kg) was not. However, both doses of baclofen caused significantly more intracerebral hemorrhages than control. In awake animals, both baclofen doses caused significant increases in mean arterial pressure, but no changes in other cardiorespiratory variables. The glutamate antagonist MK-801, the GABA-A agonist muscimol, and hypothermia were all protective using the bioassay (potency ratios ranging from 1.5 to 3.0). We conclude that although baclofen (20 mg/kg) may be neuroprotective, its utility is complicated by postischemic hypertension and cerebral hemorrhages.
Jackson-Friedman
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C
Department of Neurosciences, School of Medicine, University of California, San Diego, USA.
Lyden
P D
PD
Nunez
S
S
Jin
A
A
Zweifler
R
R
D000818:Animals; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001681:Biological Assay; D002543:Cerebral Hemorrhage / Q000139:chemically induced*; D003080:Cold Temperature; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D009118:Muscimol / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013536:Suture Techniques
D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D018696:Neuroprotective Agents; D009118:Muscimol; D016291:Dizocilpine Maleate; D001418:Baclofen