Erythropoietin Reverses Cognitive Deficits Following Infantile Traumatic Brain Injury: A Translational Touchscreen Investigation

Abstract

Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for infants who are born healthy. No targeted treatment currently exists to actively promote repair after early TBI, despite the high incidence of chronic, debilitating deficits. EPO is a neuro‐reparative agent with multiple mechanisms of action that may benefit infants who suffer TBI. TBI in infants increases EPO receptor expression on neural cells, and extended EPO dosing reduces neuroinflammation and enhances survival and maturation of oligodendrocytes and neurons after injury. Using a translatable preclinical model of infant TBI, we hypothesized that EPO would reverse deficits of cognition as observed on a touchscreen paradigm. Controlled cortical impact (CCI) was performed on postnatal day 12 (P12) rats of both sexes. Anesthetized rats underwent left parietal craniectomy and 0.6mm impact. On post‐injury day (pid) 1, injured rats were randomized to 6 doses of intraperitoneal erythropoietin (EPO) 3000U/kg/dose or vehicle (sterile saline) over pid 1–8. Similar to the Cambridge Neuropsychological Test Automated Battery (CANTAB) in humans, a touchscreen platform was applied to assess multiple cognitive domains. Adult rats were trained on a touchscreen operant platform by blinded investigators. Following successful training, rats performed visual discrimination (VD) and reversal tasks to assess executive function and cognitive flexibility (n=6–8/group, two way ANOVA with Bonferroni correction). Results indicate that Sham, CCI and CCI‐EPO rats are able to successfully perform VD with each group requiring a similar number of sessions to passing criteria and committing similar numbers of discrimination errors. However, when assessing reversal learning, only 57.1% of CCI animals successfully passed criteria compared to 100% of Sham and 83.3% of CCI animals treated with EPO. Notably, CCI animals committed significantly more errors and required more correction trials (1114±132) compared to Sham (730±95) and CCI‐EPO (652±61, p<0.05 for all), concomitant with increased perseveration (all p<0.05). Taken together, EPO treatment ameliorates deficits from TBI on a touchscreen platform, including error reduction and perseveration, and restores cognitive flexibility. EPO, administered in an extended post‐injury dosing paradigm congruent with its mechanisms of action, proved efficacious in reversing functional impairment after TBI in developing rats.Support or Funding InformationDedicated health research funds from the University of New Mexico, Genise Goldenson Foundation and Boston Children's Hospital.