Different effects of high- and low-dose phenobarbital on post-stroke seizure suppression and recovery in immature CD1 mice

Abstract

Neonatal stroke presents with seizures that are usually treated with phenobarbital. We hypothesized that anticonvulsants would attenuate ischemic injury, but that the dose-dependent effects of standard anticonvulsants would impact important age-dependent and injury-dependent consequences. In this study, ischemia induced by unilateral carotid ligation in postnatal day 12 (P12) CD1 mice was immediately followed by an i.p. dose of vehicle, low-dose or high-dose phenobarbital. Severity of acute behavioral seizures was scored. 5-bromo-2’-deoxyuridine (BrdU) was administered from P18-P20, behavioral testing performed, and mice perfused at P40. Atrophy quantification and counts of BrdU/NeuN-labeled cells in the dentate gyrus were performed. Blood phenobarbital concentrations were measured. 30 mg/kg phenobarbital reduced acute seizures and chronic brain injury, and restored normal weight gain and exploratory behavior. By comparison, 60 mg/kg was a less efficacious anticonvulsant, was not neuroprotective, did not restore normal weight gain, and impaired behavioral and cognitive recovery. Hippocampal neurogenesis was not different between treatment groups. These results suggest a protective effect of lower-dose phenobarbital, but a lack of this effect at higher concentrations after stroke in P12 mice.

Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model

“…These findings support data both from our model and clinical reports where the when initial loading-dose of PB fails to curb seizures, additional PB doses do not help rescue the refractoriness (2,66). Additionally, given the toxicity of high-dose PB on neonatal brains such protocols may be counterproductive in the short and long-term (67)(68)(69).…”

Impact of trichostatin A and sodium valproate treatment on post-stroke neurogenesis and behavioral outcomes in immature mice

“…For each brain, hippocampal, and hemispherical atrophy scores from a series of equidistant sections were combined to calculate average atrophy scores as previously described (Markowitz et al, 2011). …”

Anesthesia in Experimental Stroke Research

“…The efficacy is often attributed solely to CMR reduction, although this has been disputed [91]. Barbiturates constitute a family of compounds, for which free radical scavenging [94], anticonvulsant properties [95], and attenuation of glutamate accumulation [54] have been reported. Ketamine has been widely studied as a non-competitive NMDA receptor antagonist with potential to limit excitotoxicity [96], but effects on ischemic outcome have been inconsistent [97-100], in part due to lack of brain temperature control [101, 102].…”