Effect of Ganaxolone in a Rodent Model of Cerebral Hematoma

Abstract

Background and Purpose-Therapy with ␥-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 (nϭ23 each group), 20 mg/kg pregnanolone (nϭ21), or vehicle (nϭ30). 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 1.8Ϯ0.41 compared with vehicle (PϽ0.05). 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. (Stroke. 2000;31:169-175.)

Treatment of intracerebral hemorrhage in animal models: Meta‐analysis

“…We excluded 10 studies because ICH was not induced using collagenase or autologous blood injection,16–18 outcome data could not be extracted or obtained,19 variance values of zero precluded meta‐analysis,20, 21 or interventions were administered before the induction of ICH22–25 (although we included 3 of these studies in a post hoc sensitivity analysis24–26). After corresponding authors clarified the data in 2 studies,27, 28 we included 88 studies reporting 151 different treatment comparisons (87 of which had sham groups) that described the effects of nonsurgical interventions on neurobehavioral outcome in 2,616 treated or control rodents with ICH (Supporting Information Table 1) 26–113…”

Brain Genomics of Intracerebral Hemorrhage

“…In addition, a large number of genes related to potassium channels were downregulated, and if this downregulation were to act like mutations of potassium channel genes, the net result would likely be an increase in brain excitability (Elger, 2005) and presumably an increase in the risk for seizures. It is notable that several studies from Lyden and colleagues have shown that GABA agonists improve outcomes after experimental ICH (Lyden et al, 1997(Lyden et al, , 2000. The combined data suggest that GABA receptor function is decreased after ICH, and GABA receptor activation could be of benefit after ICH.…”

Neurosteroids: A novel promise for the treatment of stroke and post‐stroke complications

“…In the past few decades, more neurosteroids have been identified, including PREG and PREG sulfate, PROG and allopregnanolone, deoxycorticosterone, and tetrahydro deoxycorticosterone (THDOC) (Ratner et al, 2019). Although these steroids are supposed to play important pharmacological and physiological roles in the nervous system, some researchers have also studied synthetic neurosteroid analogs, such as alphaxolone (Barker et al, 1987; Granados et al, 2012; Harrison & Simmonds, 1984), ganaxolone (Lyden et al, 2000; Reddy, 2002), and minaxolone (Gourlay et al, 1980; Mitchell et al, 2007; Weir et al, 2004), and the potential therapeutic effects of these drugs on epilepsy and other brain diseases have aroused great interest (Reddy, 2010).…”