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.