Medical therapy for intracerebral hematoma with the gamma-aminobutyric acid-A agonist muscimol.
OBJECTIVE
No therapy has been rigorously proven effective for intracerebral hematoma, although surgery is frequently used for some types of lobar hemorrhages. Since intracerebral mass causes significant ischemia in surrounding brain, we reasoned that anti-ischemia therapy might improve outcome after experimental hematoma.


METHODS
We stereotaxically injected varying doses of bacterial collagenase into the caudate nucleus of rats. Four hours later we administered intravenously 2 mg/kg muscimol, a potent agonist of the gamma-aminobutyric acid-A receptor (n = 20); 1 mg/kg MK-801, an antagonist of the N-methyl-D-aspartate receptor (n = 17); or saline (n = 28). Forty-eight hours after collagenase injection we rated each animal using a standard rodent neurological examination. The ratings were compared with the amounts of injected collagenase by the quantal bioassay procedure. Brains were then prepared for histomorphometry and brain volumes estimated.


RESULTS
We found that the ED50 for collagenase (amount of enzyme that renders 50% of the subjects abnormal) was 0.77 +/- 0.09 U in saline-treated subjects. Treatment with muscimol significantly increased the ED50 to 1.2 +/- 0.21 U, for a potency ratio of 1.55 +/- 0.34 (t = 1.7, P < .05). MK-801 did not affect outcome. Volume of hematoma was significantly correlated with amount of injected collagenase (n = 33, r = .64, P < .001). Volumes of basal ganglia and white matter were significantly reduced by hemorrhage, and muscimol partially ameliorated this.


CONCLUSIONS
We conclude that muscimol significantly improves neurological outcome after intracerebral hematoma.
Lyden
P D
PD
Neurology and Research Services of the San Diego Veterans Administration Medical Center, USA.
Jackson-Friedman
C
C
Lonzo-Doktor
L
L
D000818:Animals; D002421:Caudate Nucleus / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017364:Collagenases / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D018756:GABA Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists; D006406:Hematoma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009118:Muscimol / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D018696:Neuroprotective Agents; D009118:Muscimol; D017364:Collagenases