Assessment of therapeutic window for poly-arginine-18D (R18D) in a P7 rat model of perinatal hypoxic-ischaemic encephalopathy

作者：Edwards, Adam B.^*; Anderton, Ryan S.; Knuckey, Neville W.; Meloni, Bruno P.

来源：Journal of Neuroscience Research, 2018, 96(11): 1816-1826.

DOI：10.1002/jnr.24315

• hypoxia
• hypoxia-ischaemia
• neonatal
• neuroprotection

Hypoxic-ischaemic encephalopathy (HIE) remains the leading cause of mortality and morbidity in neonates, with no available neuroprotective therapeutic agent. In the development of a therapeutic for HIE, we examined the neuroprotective efficacy of the poly-arginine peptide R18D (arginine 18 mer synthesised with D-arginine) in a perinatal model of hypoxia-ischaemia (HI; common carotid and external carotid occlusion + 8%O-2/92%N-2 for 2.5hr) in the P7 Sprague-Dawley rat. R18D was administered intraperitoneally 30min (doses 10, 30, 100, 300 and 1,000nmol/kg), 60min (doses 30 and 300nmol/kg) or 120min (doses 30 and 300nmol/kg) after HI. Infarct volumes and behavioural outcomes were measured 48hr after HI. When administered 30min after HI, R18D at varying doses reduced infarct volume by 23.7% to 35.6% (p=0.009 to < 0.0001) and resulted in improvements in the negative geotactic response and wire-hang times, at a dose of 30nmol/kg. When administered 60min after HI, R18D at the 30nmol/kg dose reduced total infarct volume by 34.2% (p=0.002), whilst the 300nmol/kg dose improved wire-hang time. When administered 120min after HI, R18D at the 30 and 300nmol/kg doses had no significant impact on infarct volume, but the 300nmol/kg dose improved the negative geotactic response. This study further confirms the neuroprotective properties of poly-arginine peptides, demonstrating that R18D can reduce infarct volume and improve behavioural outcomes after HI if administered up to 60min after HI and improve behavioural outcomes up to 2hr after HI.

• 出版日期2018-11