Concurrent Erythropoietin and Hypothermia Treatment Improve Outcomes in a Term Nonhuman Primate Model of Perinatal Asphyxia

Abstract

Background: Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat: 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury and promotes glial cell survival and angiogenesis. We hypothesized that HT and concurrent Epo will be safe and effective, improve survival, and reduce moderate-severe cerebral palsy (CP) in a term nonhuman primate model of perinatal asphyxia. Methodology: Thirty-five Macacanemestrina were delivered after 15-18 min of umbilical cord occlusion (UCO) and randomized to saline (n = 14), HT only (n = 9), or HT+Epo (n = 12). There were 12 unasphyxiated controls. Epo (3,500 U/kg × 1 dose followed by 3 doses of 2,500 U/kg, or Epo 1,000 U/kg/day × 4 doses) was given on days 1, 2, 3, and 7. Timed blood samples were collected to measure plasma Epo concentrations. Animals underwent MRI/MRS and diffusion tensor imaging (DTI) at <72 h of age and again at 9 months. A battery of weekly developmental assessments was performed. Results: UCO resulted in death or moderate-severe CP in 43% of saline-, 44% of HT-, and 0% of HT+Epo-treated animals. Compared to non-UCO control animals, UCO animals exhibit poor weight gain, behavioral impairment, poor cerebellar growth, and abnormal brain DTI. Compared to UCO saline, UCO HT+Epo improved motor and cognitive responses, cerebellar growth, and DTI measures and produced a death/disability relative risk reduction of 0.911 (95% CI -0.429 to 0.994), an absolute risk reduction of 0.395 (95% CI 0.072-0.635), and a number needed to treat of 2 (95% CI 2-14). The effects of HT+Epo on DTI included an improved mode of anisotropy, fractional anisotropy, relative anisotropy, and volume ratio as compared to UCO saline-treated infants. No adverse drug reactions were noted in animals receiving Epo, and there were no hematology, liver, or kidney laboratory effects. Conclusions/Significance: HT+Epo treatment improved outcomes in nonhuman primates exposed to UCO. Adjunctive use of Epo combined with HT may improve the outcomes of term human infants with HIE, and clinical trials are warranted.

Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses

“…However, in a primate HIE model, only the combination of TH and exogenous Epo resulted in a significantly lower rate of death or moderate to severe cerebral palsy and improved long-term motor and cognitive responses [18], while high-dose exogenous Epo has also been found to improve neurodevelopmental outcome in term infants with HIE, both before the TH era [4,11] and in combination with TH [19]. …”

“…Hypoxia-ischaemia stimulates Epo production [10] while TH modifies the inflammatory cascade and apoptotic cell death and reduces brain injury [8,18]. It is difficult to be certain what effect TH has on endogenous Epo levels without looking at serum levels in infants randomized to TH versus normothermia, which to our knowledge has not been performed.…”

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

“…EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection 8, 9, 10, 11. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models,12, 13 and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants 8, 14, 15, 16, 17.…”

Modern Methods of Perinatal Hypoxic-Ischemic Brain Injury Modeling in Vivo

“…Исследования различных аспектов перинатально-го гипоксически-ишемического поражения ЦНС прово-дят на приматах, свиньях, овцах, кроликах и грызунах [7][8][9][10][11]. Учитывая достаточно большое сходство крово-снабжения головного мозга и нейробиологии грызунов и высших млекопитающих, а также практические и эко-номические преимущества экспериментальных моделей гипоксически-ишемического поражения ЦНС, модели с использованием грызунов (мыши, крысы, морские свинки) в настоящее время используют чаще, чем моде-ли с задействованием крупных животных [12][13][14].…”