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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.
AuthorsP K Nayak, D S Kerr
JournalNeuroscience (Neuroscience) Vol. 232 Pg. 128-38 (Mar 01 2013) ISSN: 1873-7544 [Electronic] United States
PMID23246617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • Neuroprotective Agents
  • GYKI 52466
  • Benzodiazepines
Topics
  • Animals
  • Benzodiazepines (administration & dosage)
  • Brain (drug effects, pathology, physiopathology)
  • Carotid Artery Diseases
  • Carotid Artery, Common
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hypoxia-Ischemia, Brain (drug therapy, pathology, physiopathology)
  • Male
  • Motor Activity (drug effects, physiology)
  • Neuroprotective Agents (administration & dosage)
  • Posture
  • Rats, Sprague-Dawley
  • Recovery of Function (drug effects, physiology)
  • Reflex (drug effects, physiology)
  • Seizures (prevention & control)

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