Erythropoietin Improved Cognitive Function and Decreased Hippocampal Caspase Activity in Rat Pups after Traumatic Brain Injury

Schober, Michelle E.; Requena, Daniela F.; Block, Benjamin; Davis, Lizeth J.; Rodesch, Christopher K.; Casper, T. Charles; Juul, Sandra E.; Kesner, Raymond P.; Lane, Robert H.

doi:10.1089/neu.2013.2922

Cited by 32 publications

(28 citation statements)

References 76 publications

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“…In addition, in a toddler P17 model of TBI, EPO treatment restored memory testing novel object recognition in rats at 2 weeks after injury. 85 Here, EPO treatment restored motor performance, demonstrating that extended postinjury EPO treatment can induce sustained improvement following infant TBI.…”

Section: Discussionmentioning

confidence: 66%

“…In a preclinical model of toddler TBI in rats with CCI on P17, extended EPO dosing was effective in reducing neuronal apoptosis and improving novel object recognition at 14 days after injury. 85 A longer duration of EPO treatment provided additional functional improvement in adult CCI rats. 102 In the present study, the dosing regimen was designed to be extended and to use high neuro-reparative doses.…”

Section: Discussionmentioning

confidence: 95%

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Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Robinson

Winer

Berkner

et al. 2016

PED

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OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1–4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13–28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst–like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13–16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16–23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13–P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats. CONCLUSIONS Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial–compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 95%

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Robinson

Winer

Berkner

et al. 2016

PED

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“…In models of traumatic brain injury (70), Epo decreases white matter damage and decreases neuroinflammation in conditions of hypoxia (71, 72). Epo improves cognitive function and neuronal survival through changes seen in the hippocampus of traumatic brain injury rat pup models (73). Epo protects the vascular integrity of capillaries following injury through vascular endothelial growth factor (VEGF) (19, 74) and participates in preservation of the blood-brain barrier (6, 75).…”

Section: Epo For Neuroprotectionmentioning

confidence: 99%

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Rangarajan¹,

Juul²

2014

Pediatric Neurology

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108

106

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BACKGROUND In the last two decades, there has been considerable evolution in the understanding role of erythropoietin (Epo) in neuroprotection. Epo has both paracrine and autocrine functions in the brain. Epo binding results in neurogenesis, oligodendrogenesis, and angiogenesis. Epo and its receptor are upregulated by exposure to hypoxia and proinflammatory cytokines following brain injury. While Epo aids in recovery of locally injured neuronal cells, it provides negative feedback to glial cells in the penumbra, thereby limiting extension of injury. This forms the rationale for use of recombinant Epo and Epo mimetics in neonatal and adult injury models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage and neonatal hypoxic-ischemia. METHOD Review of published literature (Pubmed, Medline and Google scholar) RESULTS Preclinical neuroprotective data are reviewed and the rationale for proceeding to clinical trials is discussed. Results from Phase I/II trials are presented, as are updates on ongoing and upcoming clinical trials of Epo neuroprotection in neonatal populations. CONCLUSIONS The scientific rationale and preclinical data for Epo neuroprotection are promising. Phase II and III clinical trials are currently in process to determine the safety and efficacy of neuroprotective dosing of Epo for extreme prematurity and hypoxic ischemic encephalopathy in neonates.

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“…[28][29][30][31][32][33] We selected this age because rat brain maturation at P17 is comparable to that of the human infant/young toddler, the pediatric age group at highest risk for cognitive deficits after TBI. 7,8,[34][35][36] We tested DHA's effects on functional, histologic, and imaging outcomes in rat pups after CCI.…”

mentioning

confidence: 99%

Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury

Schober

Requena

Abdullah

et al. 2016

Journal of Neurotrauma

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Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children. Specific therapies to treat acute TBI are lacking. Cognitive impairment from TBI may be blunted by decreasing inflammation and oxidative damage after injury. Docosahexaenoic acid (DHA) decreases cognitive impairment, oxidative stress, and white matter injury in adult rats after TBI. Effects of DHA on cognitive outcome, oxidative stress, and white matter injury in the developing rat after experimental TBI are unknown. We hypothesized that DHA would decrease early inflammatory markers and oxidative stress, and improve cognitive, imaging and histologic outcomes in rat pups after controlled cortical impact (CCI). CCI or sham surgery was delivered to 17 d old male rat pups exposed to DHA or standard diet for the duration of the experiments. DHA was introduced into the dam diet the day before CCI to allow timely DHA delivery to the preweanling pups. Inflammatory cytokines and nitrates/nitrites were measured in the injured brains at post-injury Day (PID) 1 and PID2. Morris water maze (MWM) testing was performed at PID41-PID47. T2-weighted and diffusion tensor imaging studies were obtained at PID12 and PID28. Tissue sparing was calculated histologically at PID3 and PID50. DHA did not adversely affect rat survival or weight gain. DHA acutely decreased oxidative stress and increased anti-inflammatory interleukin 10 in CCI brains. DHA improved MWM performance and lesion volume late after injury. At PID12, DHA decreased T2-imaging measures of cerebral edema and decreased radial diffusivity, an index of white matter injury. DHA improved short-and long-term neurologic outcomes after CCI in the rat pup. Given its favorable safety profile, DHA is a promising candidate therapy for pediatric TBI. Further studies are needed to explore neuroprotective mechanisms of DHA after developmental TBI.

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Erythropoietin Improved Cognitive Function and Decreased Hippocampal Caspase Activity in Rat Pups after Traumatic Brain Injury

Cited by 32 publications

References 76 publications

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury

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