Delayed erythropoietin therapy improves histological and behavioral outcomes after transient neonatal stroke

Abstract

Background and purpose: Stroke is a major cause of neonatal morbidity, often with delayed diagnosis and with no accepted therapeutic options. The purpose of this study is to investigate the efficacy of delayed initiation of multiple dose erythropoietin (EPO) therapy in improving histological and behavioral outcomes after early transient ischemic stroke. Methods: 32 postnatal day 10 (P10) Sprague-Dawley rats underwent sham surgery or transient middle cerebral artery occlusion (tMCAO) for 3 h, resulting in injury involving the striatum and parieto-temporal cortex. EPO (1000 U/kg per dose × 3 doses) or vehicle was administered intraperitoneally starting one week after tMCAO (at P17, P20, and P23). At four weeks after tMCAO, sensorimotor function was assessed in these four groups (6 vehicle-sham, 6 EPO-sham, 10 vehicle-tMCAO and 10 EPO-tMCAO) with forepaw preference in cylinder rearing trials. Brains were then harvested for hemispheric volume and Western blot analysis. Results: EPO-tMCAO animals had significant improvement in forepaw symmetry in cylinder rearing trials compared to vehicle-tMCAO animals, and did not differ from sham animals. There was also significant preservation of hemispheric brain volume in EPO-tMCAO compared to vehicle-tMCAO animals. No differences in ongoing cell death at P17 or P24 were noted by spectrin cleavage in either EPO-tMCAO or vehicle-tMCAO groups. Conclusions: These results suggest that delayed EPO therapy improves both behavioral and histological outcomes at one month following transient neonatal stroke, and may provide a late treatment alternative for early brain injury.

Keywords

• Neonatal stroke
• Ischemia
• Erythropoietin
• Brain injury
• Neuroprotection