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Abstract
Perinatal hypoxic-ischemic (HI) brain injury remains a major cause of newborn mortality and morbidity. Preconditioning with mild hypoxia can protect the brain against HI insults, while it has recently been shown that mild hypoxia administered after a brain injury (postconditioning) can protect the adult mouse brain. Furthermore, pre-injury treatment with compounds that mimic the effects of hypoxia (hypoxia-mimetics) can protect the brain against HI. The neuroprotective effects of hypoxic preconditioning, postconditioning and post-injury treatment with the hypoxia mimetics desferoxamine (DFX, 200mg/kg), cobalt chloride (CoCl2, 60mg/kg) and ethyl-3,4-dihydroxybenzoate (EDHB, 200mg/kg) were examined in a neonatal rat model of HI brain injury, at 7 days post-injury. Hypoxic treatments consisted of either 3 hr of 8% oxygen performed 24 hr prior to injury (preconditioning); or 1 hr of 8% oxygen 24 hr post-injury, performed once a day for 5 days (postconditioning). HI reduced ipsilateral brain tissue, while hypoxic preconditioning, postconditioning, DFX, CoCl2 and EDHB treatment, were all able to reduce the extent of brain damage to the ipsilateral hemisphere. NeuN immunohistochemistry in regional brain areas was performed to examine neuronal loss after HI injury. Hypoxic preconditioning reduced cortical, hippocampal and striatal neuronal loss, while hypoxic postconditioning reduced cortical and striatal loss. Treatment with DFX reduced neuronal loss in the cortex and striatum, whereas EDHB reduced cortical and hippocampal neuronal loss. The long-term neuroprotective actions of hypoxic postconditioning and EDHB treatment were also examined (37d post-injury), with sensorimotor and memory assessments following HI. Hypoxic postconditioning and EDHB treatment prevented long-term brain damage, after HI. Furthermore, behavioural testing (35d post-injury) revealed that both hypoxic postconditioning and EDHB treatment improved memory function in the novel object recognition test, whilst hypoxic postconditioning was also able to increase forearm muscle strength and improve fore/hindlimb placement in a grid-walking test after HI injury. The ability for hypoxic postconditioning and EDHB treatment to enhance tissue repair was also examined through post-injury neovascularisation and cell proliferation; however, evidence that hypoxic postconditioning or EDHB treatment could stimulate a reparative response through these mechanisms, after HI brain injury was not observed.