Effect of ganaxolone in a rodent model of cerebral hematoma.
OBJECTIVE
Therapy with gamma-aminobutyric acid (GABA) agonists appears to improve outcome after experimental hematoma but with unacceptable side effects. We looked to synthetic GABA agonists, or positive GABA modulators, widely developed as anticonvulsants and anxiolytics, to find compounds that may be effective. Ganaxolone is a synthetic neuroactive steroid that positively modulates GABA. We sought to determine whether ganaxolone was beneficial using a model of intracerebral hematoma.


METHODS
We stereotaxically injected varying doses of bacterial collagenase into the caudate nucleus of rats to induce blood-brain barrier failure and hematoma formation. Four hours later, we administered intravenously 15 or 30 mg/kg ganaxolone (n=23 each group), 20 mg/kg pregnanolone (n=21), or vehicle (n=30). 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 using the quantal bioassay procedure. Other sets of animals were tested later for visuospatial learning. Brains were then prepared for histomorphometry, and brain volumes were estimated.


RESULTS
We found that ganaxolone 30 mg/kg significantly increased the ED(50) in the bioassay, for a potency ratio of 1.8+/-0.41 compared with vehicle (P<0.05). Ganaxolone 15 mg/kg and pregnanolone did not affect neurological outcome. Ganaxolone 30 mg/kg did not clearly improve visuospatial learning several weeks after hemorrhage. Ganaxolone exhibited a weak effect on cerebral volumes 48 hours after stroke, but 3 months after hemorrhage no such effect could be detected.


CONCLUSIONS
Ganaxolone improves neurological outcome 48 hours after intracerebral hematoma but not visuospatial learning several weeks after intracerebral hematoma. Histological evidence of damage was reduced at 48 hours but not at 3 months.
Lyden
P
P
Department of Neurosciences, University of California at San Diego School of Medicine, San Diego, California, USA.
Shin
C
C
Jackson-Friedman
C
C
Hassid
S
S
Chong
A
A
Macdonald
R L
RL
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017364:Collagenases / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D011280:Pregnanolone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; C105051:ganaxolone; D011280:Pregnanolone; D017364:Collagenases