The effects of hypoxic postconditioning and prolyl hydroxylase inhibitors on brain repair after stroke

Abstract

Ischaemic stroke remains a major cause of death and adult disability in the world. Post stroke treatment with mild hypoxic postconditioning (HPC) and prolyl hydroxylase (PHD) inhibitors, which are compounds that mimic the effects of hypoxia, have shown to be neuroprotective in adult rats. However, there are limited studies showing functional improvements following these treatments. The effects of HPC and PHD inhibitors, ethy-3, 4-dihydroxybenzoate (EDHB) and deferoxamine (DFX), on functional recovery and brain histology were examined using an endothelin-1-stroke model in adult rats. Stroke was induced in conscious rats by delivery of endothelin-1 onto the middle cerebral artery via intracranial injection. Animals were exposed to HPC, starting 24h after stroke in a hypoxic chamber (8% O2, 1h/d for 5d) or treated with EDHB (200mg/kg daily, for 3 day, i.p) or DFX (200mg/kg single dose, i.p) 6h after stroke. Sham animals were exposed to room air or injection with saline. Motor and sensory function tests were conducted and brains were collected at the end of each experiment for histological analyses. Stroke resulted in contralateral motor and sensory deficits with accompanying ipsilateral brain injury. HPC after stroke reversed some of the contralateral motor and sensory deficits in addition to reduced ipsilateral brain injury 6d after stroke. HPC also enhanced the astrocyte response and reduced neuronal injury in the cortex following stroke. Post-stroke treatment with DFX or EDHB reduced contralateral motor and sensory deficits up to 2 and 3 weeks respectively and reduced ipsilateral brain damage. This demonstrates that induction of hypoxia-induced adaptions by HPC, DFX or EDHB after stroke can promote brain repair. Further investigations of DFX-induced neuroprotection in hippocampal cultures revealed that protection is partially dependent on hypoxia inducible factor-1 and reduction of oxidative stress is also likely to be involved. HPC and PHD inhibitors have the potential to be a novel therapeutic approach that can enhance endogenous repair of the brain after stroke.