title: 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 to 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. 30mg/kg phenobarbital reduced acute seizures and chronic brain injury, and restored normal weight gain and exploratory behavior. By comparison, 60mg/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.
authors.affiliation: Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Markowitz
authors.affiliation: Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neuroscience, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neurology, Johns Hopkins Medicine, Baltimore, MD 21205, USA.
authors.forename: Shilpa D
authors.initials: SD
authors.lastname: Kadam
authors.affiliation: Neurogenetics and Behavior Center, Dept. of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Dani R
authors.initials: DR
authors.lastname: Smith
authors.affiliation: Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neuroscience, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neurology, Johns Hopkins Medicine, Baltimore, MD 21205, USA; Dept. of Pediatrics, Johns Hopkins Medicine, Baltimore, MD 21205, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neurology, Johns Hopkins Medicine, Baltimore, MD 21205, USA; Dept. of Pediatrics, Johns Hopkins Medicine, Baltimore, MD 21205, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Comi
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000627:therapeutic use*; D001284:Atrophy / Q000188:drug therapy / Q000209:etiology; D001835:Body Weight / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007839:Functional Laterality; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D010634:Phenobarbital / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects*; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology*; D020521:Stroke / Q000150:complications*
chemical_list: D000927:Anticonvulsants; D010634:Phenobarbital