title: Low-dose GYKI-52466: prophylactic preconditioning confers long-term neuroprotection and functional recovery following hypoxic-ischaemic brain injury.
abstract: Experimental preconditioning provides beneficial outcomes in conditions such as cardiac surgery, brain surgery and stroke. Here we evaluated the protective effects of low-dose subcutaneous GYKI-52466 preconditioning in a rat model of hypoxic-ischaemic (HI) brain injury. Male Sprague-Dawley rats (postnatal day 26) were administered saline or GYKI-52466 (GYKI; 3-mg/kg, 90 min; 1-mg/kg, twice in 120 min; or 0.5-mg/kg, thrice in 180 min) prior to left common carotid artery occlusion. Animals were allowed to recover for 2h, and then placed in a hypoxia chamber (8% O₂/92% N₂; 33 ± 1°C) for 1h. A sham surgery group received saline without HI. Seizure activity was scored during hypoxia and sensorimotor tests performed before surgery and at 1, 7, 14 and 90 days post-HI. On days 14 and 90 brains were fixed and sectioned for the assessment of infarct size and ventricular enlargement. Low-dose GYKI-52466 preconditioning significantly reduced infarct volume and ventricular enlargement relative to saline-treated controls at day 14 after HI. On day 90, tissue loss was significantly reduced by GYKI 3-mg/kg compared to saline. Foot-faults, paw use asymmetry, and postural reflex scores were significantly improved in all GYKI treatment groups. Our results show that GYKI-52466 is effective at doses well-below, and at pre-administration intervals well-beyond previous studies, and suggest that a classical blockade of ionotropic AMPA receptors does not underlie its neuroprotective effects. Low-dose GYKI-52466 preconditioning represents a novel, prophylactic strategy for neuroprotection in a field almost devoid of effective pharmaceuticals.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, Dunedin, New Zealand.
authors.forename: P K
authors.initials: PK
authors.lastname: Nayak
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, Dunedin, New Zealand. Electronic address: steve.kerr@otago.ac.nz.
authors.forename: D S
authors.initials: DS
authors.lastname: Kerr
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases; D017536:Carotid Artery, Common; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011187:Posture; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000517:prevention & control
chemical_list: D018696:Neuroprotective Agents; C061950:GYKI 52466; D001569:Benzodiazepines