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Assessment of therapeutic window for poly‐arginine‐18D (R18D) in a P7 rat model of perinatal hypoxic‐ischaemic encephalopathy
Author(s) -
Edwards Adam B.,
Anderton Ryan S.,
Knuckey Neville W.,
Meloni Bruno P.
Publication year - 2018
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24315
Subject(s) - neuroprotection , medicine , encephalopathy , arginine , anesthesia , hypoxia (environmental) , hypoxic ischemic encephalopathy , therapeutic effect , pharmacology , endocrinology , chemistry , amino acid , biochemistry , oxygen , organic chemistry
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 2.5 hr) in the P7 Sprague‐Dawley rat. R18D was administered intraperitoneally 30 min (doses 10, 30, 100, 300 and 1,000 nmol/kg), 60 min (doses 30 and 300 nmol/kg) or 120 min (doses 30 and 300 nmol/kg) after HI. Infarct volumes and behavioural outcomes were measured 48 hr after HI. When administered 30 min 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 30 nmol/kg. When administered 60 min after HI, R18D at the 30 nmol/kg dose reduced total infarct volume by 34.2% ( p = 0.002), whilst the 300 nmol/kg dose improved wire‐hang time. When administered 120 min after HI, R18D at the 30 and 300 nmol/kg doses had no significant impact on infarct volume, but the 300 nmol/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 60 min after HI and improve behavioural outcomes up to 2 hr after HI.