Extended Erythropoietin Treatment Prevents Chronic Executive Functional and Microstructural Deficits Following Early Severe Traumatic Brain Injury in Rats

Abstract

Survivors of infant traumatic brain injury (TBI) are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high-dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose × 6d) to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12) controlled-cortical impact (CCI) model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI). Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI.

Neonatal Hypoxic-Ischemic Encephalopathy Yields Permanent Deficits in Learning Acquisition: A Preclinical Touchscreen Assessment

“…Both groups performed at equivalent levels during reversal sessions when performance was low and perseveration high (i.e., <50%), while HIE mice committed more trials and errors during sessions when performance was largely learning related (i.e., >50%). This deficit is in contrast to previously published touchscreen assessments in animal models of perinatal brain injury (38,41,57). Specifically, adult rats perinatal brain injury secondary to chorioamnionitis have a perseverative phenotype and significant deficit in cognitive control defined by a reversal deficit (38).…”

“…Specifically, adult rats perinatal brain injury secondary to chorioamnionitis have a perseverative phenotype and significant deficit in cognitive control defined by a reversal deficit (38). Similarly, adult rats suffering severe traumatic brain injury in infancy perseverate, lack cognitive flexibility and struggle to pass reversal learning criteria (41). The extensive white matter brain injury and orbitofrontocortical decoupling observed in both chorioamnionitis and traumatic brain injury may partially explain these findings.…”

“…Pairwise discrimination and reversal was tested as previously described (38)(39)(40)(41). Briefly, mice were first trained to discriminate 2 novel, approximately equally-luminescent stimuli, presented in the center of each window in a spatially pseudorandomized (left/right) manner, over 30-trial sessions (5-s inter-trial interval) using their nose (21,42).…”

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

“…In the last 20 years, erythropoietin (EPO) has emerged as a potential candidate for neuroprotective and neuroregenerative treatment in injury and disease of the nervous system (Sargin et al, 2010 ). Interestingly, EPO improves cognitive performance in healthy animals and humans and in disease, including in MS (Ehrenreich et al, 2007 ; Robinson et al, 2018 ; Li et al, 2018 ). Although the mechanism is still largely unknown, we and others showed that EPO acts directly on OLs to increase myelination in vitro and in vivo (Sugawa et al, 2002 ; Cervellini et al, 2013 ; Hassouna et al, 2016 ; Gyetvai et al, 2017 ).…”

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…Finally, DTI-MRI has been used as read-out of treatment efficacy in rodents' models of TBI. In particular, DTI has revealed the beneficial effect on white matter integrity of activation of mitochondrial calcium fluxes (Parent et al, 2020 ), of autophagy modulators (Medina et al, 2017 ; Yin et al, 2018 ), estrogens (Kim et al, 2015 , 2017 ), metamphetamine (Ding et al, 2013 ), erythropoietin (Robinson et al, 2016 , 2018 ), tissue plasminogen activator (in mice; Xia et al, 2018 ), mGluR5 (in mice; Byrnes et al, 2012 ), and dietary modulations (Shultz et al, 2015 ; Schober et al, 2016 ; Tan et al, 2016 ). Notably, the detrimental effect of alcohol in TBI was also investigated by DTI (Kong et al, 2013 ).…”