Effect of ganaxolone in a rodent model of cerebral hematoma

• Published in: Stroke (1970) 2000-01, Vol.31 (1), p.169-175
• Main Authors: Lyden, P, Shin, C, Jackson-Friedman, C, Hassid, S, Chong, A, Macdonald, R L
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - administration & dosage; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - physiopathology; Collagenases - toxicity; gamma-Aminobutyric Acid - physiology; Injections, Intravenous; Male; Pregnanolone - administration & dosage; Pregnanolone - analogs & derivatives; Rats; Rats, Sprague-Dawley
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.STR.31.1.169

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. 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. 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