title: The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function.
abstract: To aid in development of chronic stage treatments for sensorimotor deficits induced by ischemic stroke, we investigated the effects of GABA antagonism on brain structure and fine skilled reaching in a rat model of focal ischemia induced via cortical microinjections of endothelin-1 (ET-1). Beginning 7 days after stroke, animals were administered a gamma-aminobutyric acid (GABAA) inverse agonist, L-655,708, at a dose low enough to afford α5-GABAA receptor specificity. A week after stroke, the ischemic lesion comprised a small hypointense necrotic core (6±1 mm(3)) surrounded by a large (62±11 mm(3)) hyperintense perilesional region; the skilled reaching ability on the Montoya staircase test was decreased to 34%±2% of the animals' prestroke performance level. On L-655,708 treatment, animals showed a progressive decrease in total stroke volume (13±4 mm(3) per week), with no change in animals receiving placebo. Concomitantly, treated animals' skilled reaching progressively improved by 9%±1% per week, so that after 2 weeks of treatment, these animals performed at 65%±6% of their baseline ability, which was 25%±11% better than animals given placebo. These data indicate beneficial effects of delayed, sustained low-dose GABAA antagonism on neuroanatomic injury and skilled reaching in the chronic stage of stroke recovery in an ET-1 rat model of focal ischemia.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Evelyn M R
authors.initials: EM
authors.lastname: Lake
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Chaudhuri
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Lynsie
authors.initials: L
authors.lastname: Thomason
authors.affiliation: Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Rafal
authors.initials: R
authors.lastname: Janik
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Milan
authors.initials: M
authors.lastname: Ganguly
authors.affiliation: Department of Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Hurvitz Brain Sciences Research, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.|Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Ottawa, Ontario, Canada.
authors.forename: Dale
authors.initials: D
authors.lastname: Corbett
authors.affiliation: Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Neurosurgery and Paediatric Neurosurgery, Medical University Lublin, Lublin, Poland.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Stanisz
authors.affiliation: Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Ottawa, Ontario, Canada.|Department of Neurosurgery and Paediatric Neurosurgery, Medical University Lublin, Lublin, Poland.|Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Stefanovic
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000523:psychology*; D019332:Endothelin-1 / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009048:Motor Skills / Q000187:drug effects*; D009336:Necrosis; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects; D056152:Respiratory Rate / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000523:psychology*; D013318:Stroke Volume / Q000187:drug effects
chemical_list: D019332:Endothelin-1; D018756:GABA Antagonists; D007093:Imidazoles; C105490:L 655,708; D011963:Receptors, GABA-A