Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Abstract

Background: Both hypothermia and erythropoietin (ePO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (hI). We investigated a possible additive effect of the use of a combination of hypothermia-ePO in a rat model of neonatal hI. Methods: at postnatal day 7, rats were subjected to hI and then randomized to 3 h of hypothermia, ePO, or both. sensorimotor function was assessed by the cylinder-rearing test (cRT) at 2 and 5 wk after hI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. results: Multivariable analysis using general linear modeling showed that hypothermia, ePO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after hI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the cRT. Maximal improvement in males was 26% after combined treatment with hypothermia and ePO. histological outcome was improved by hypothermia only with no additional effect of ePO or gender. conclusion: hypothermia after hI improved sensorimotor function in females more than in males. There was a borderline additive effect of ePO when combined with hypothermia. histology of brain lesion volume and white matter damage was improved only by hypothermia.P erinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury and is associated with long-term neurological sequelae such as cognitive dysfunction, developmental delay, seizures, and sensory and/or motor impairment (1,2). Several studies in newborn rodents indicate that reduction of brain temperature by 2-5 °C even for 3 h, when started within 6 h after HI, provides neuroprotection and improved behavioral outcome (3-6).The neuroprotective effects of hypothermia of mildly asphyxiated newborns have been demonstrated, but in clinical practice, morbidity and mortality remain considerable (30-45%) (7,8). The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10-13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO,.The aim of the present study was to test whether the addition of EPO to hypothermia has additive neuroprotective effects as compared with a single treatment and to examine possible gender effects. Results HypothermiaSham-treated rats did not show a paw preference in the cylinder-rearing test (CRT) (paw preference < ±5%, data not shown). A significant paw preference of the unimpaired forepaw in the normothermia groups was observed at both 2 and 5 wk after HI (Figure 1). Differences between males and females in the normothermia group were not statistically significant. In fema...

Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood

“…Other neuroprotective studies in both rats and humans have shown that long-term functional outcome was improved despite no effect on brain infarct volume per se (30-32) after stroke. An improved function despite a nonsignificant improvement in brain volume has also been observed in the same rat model with erythropoietin treatment (33,34). Additionally, other studies have shown that xenon provides neuroprotection in different preclinical models.…”

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

“…Despite other animal studies showing improvements with EPO, especially in stroke models [13], 2 studies on rats treated with hypothermia and EPO showed no added improvement of EPO over hypothermia only [34, 35]. Much of the work showing improvement with EPO in HI has been in the P7 rat model [15, 36, 37].…”

Time Is Brain: Starting Therapeutic Hypothermia within Three Hours after Birth Improves Motor Outcome in Asphyxiated Newborns

“…The most promising ones are xenon [19,20], erythropoietin [21,22,23] and melatonin [18,24], which are currently undergoing preclinical studies, feasibility studies or small randomized controlled studies [21,25]. Whatever the outcome from combination therapy, it is important to further optimize HT used as the sole intervention.…”