Evaluation of the Therapeutic Benefit of Delayed Administration of Erythropoietin following Early Hypoxic-Ischemic Injury in Rodents

Abstract

Hypoxia-ischemia (HI) and associated brain injuries are seen in premature as well as term infants with birth complications. The resulting impairments involve deficits in many cognitive domains, including language development. Poor rapid auditory processing is hypothesized to be one possible underlying factor leading to subsequent language delays. Mild hypothermia treatment for HI injuries in term infants is widely used as an intervention but can be costly and time consuming. Data suggest that the effectiveness of hypothermia treatment following HI injury declines beyond 6 h following injury. Consequently, the availability of a therapeutic alternative without these limitations could allow doctors to treat HI-injured infants more effectively and thus reduce deleterious cognitive and language outcomes. Evidence from both human studies and animal models of neonatal HI suggests that erythropoietin (Epo), an endogenous cytokine hormone, may be a therapeutic agent that can ameliorate HI brain injury and preserve subsequent cognitive development and function. The current study sought to investigate the therapeutic effectiveness of Epo when administered immediately after HI injury, or delayed at intervals following the injury, in neonatal rodents. Rat pups received an induced HI injury on postnatal day 7, followed by an intraperitoneal injection of Epo (1,000 U/kg) immediately, 60 min, or 180 min following induction of injury. Subjects were tested on rapid auditory processing tasks in juvenile (P38-42) and adult periods (P80-85). Ventricular and cortical size was also measured from post mortem tissue. Results from the current study show a therapeutic benefit of Epo when given immediately following induction of HI injury, with diminished benefit from a 60-min-delayed injection of Epo and no protection following a 180-min-delayed injection. The current data thus show that the effectiveness of a single dose of Epo in ameliorating auditory processing deficits following HI injury decreases precipitously as treatment is delayed following injury. These data may have important implications for experimental human neonatal intervention with Epo.

Effects of inter-alpha inhibitor proteins on neonatal brain injury: Age, task and treatment dependent neurobehavioral outcomes

“…Specifically, McClure et al (McClure, et al, 2007) showed that P7 neonatal HI rats, but not HI animals treated with erythropoietin (Epo), were impaired in both spatial and non-spatial learning as compared to sham treated control counterparts, when tested as adults (P60+). Similarly, others have observed deficits in neonatal HI injured animals on spatial and non-spatial water maze paradigms (similar to those used in the present studies; (Alexander, et al, 2012, Hill, et al, 2011)). However, these studies assessed performance only in adult subjects (P83+), which resulted in residual questions regarding the influence of age at assessment on task performance.…”

“…Previous studies from our group and others have assessed both spatial and non-spatial learning across multiple models of developmental brain injury, including models of neocortical microgyria and neonatal hypoxia-ischemia (Alexander, et al, 2012, Hill, et al, 2011, Hyde, et al, 2002, McClure, et al, 2007, Threlkeld, et al, 2012). Specifically, McClure et al (McClure, et al, 2007) showed that P7 neonatal HI rats, but not HI animals treated with erythropoietin (Epo), were impaired in both spatial and non-spatial learning as compared to sham treated control counterparts, when tested as adults (P60+).…”

Partial white and grey matter protection with prolonged infusion of recombinant human erythropoietin after asphyxia in preterm fetal sheep

“…5 Critically, repeated injection with 5000 IU/kg rEpo daily for three days, started immediately after HI, was more neuroprotective after seven days recovery, than either a single dose of 5000 IU/kg or three injections of 30,000 IU/kg, 9 but neuroprotection was largely lost when treatment was delayed for 1 to 3 h after HI. 10 This finding parallels the experience with mild induced hypothermia that optimal neuroprotection after acute HI injury is seen when cooling is started within the first 6 h and continued until secondary events such as seizures have resolved, after approximately three days. 11 This suggests that continued exposure to rEpo during this critical phase will be needed for optimal outcomes after acute HI.…”

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

“…Although physical cooling had been used in pre-clinical and clinical practice, challenges hinder clinical feasibilities may include disruptions of coagulation system (Mohr, et al, 2013), cardiac function (Egginton, et al, 2013), and fluid pH (Groger, et al, 2013). Moreover, conventional methods in physical cooling processes are costly and time-consuming (Alexander, et al, 2012). We show in previous and current investigations that our NTR compounds effectively reduce the brain temperature and do not show the adverse effects seen with physical cooling (Choi, et al, 2012, Lee, et al, 2014, Wei, et al, 2013).…”