Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency

Abstract

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury

“…To determine if both sexes responded to the infantile treatment with EPO + MLT, gait metrics were analyzed separately for males and females as a preliminary assessment. Similar to prior studies of preterm brain injury in Sprague-Dawley rats [39, 52], in this study male rats exhibited more severe deficits in gait metrics than females (Table 1). Overall, the study was not sufficiently powered with EPO + MLT-treated rats to fully assess the impact of sex on every functional outcome; however, a similar pattern in amelioration of gait metrics is apparent (Table 1).…”

“…EPO and its mimetics have been tested in multiple clinical trials in the neonatal period to mitigate perinatal brain injury for preterm [27, 28, 34] and term infants [4]. While EPO as monotherapy restores gait [20, 39, 42, 62] and spatial memory [52] after preterm CNS injury in preclinical models, neither EPO alone nor MLT alone as monotherapy in a neonatal regimen improved motor inhibition nor cognitive flexibility in adult animals [20]. Notably, only a cocktail of neonatal EPO + MLT after preterm CNS injury improved executive function in adult animals [20], suggesting that the two endogenous hormones work in concert to restore cognition.…”

Understanding and Modeling the Pathophysiology of Hydrocephalus: In Search of Better Treatment Options

“…Another anti-inflammatory treatment that is currently being investigated is erythropoietin and melatonin (EPO + MLT). EPO alone has shown to help improve cognitive function in cases of brain injury in rats [43]. In pre-clinical trials, EPO + MLT were able to reduce ventriculomegaly in induced hemorrhage neonatal rats [44].…”

Understanding and Modeling the Pathophysiology of Hydrocephalus: In Search of Better Treatment Options

“…An example of this is a cocktail of erythropoietin and melatonin (EPO + MLT). EPO alone has been shown to help improve cognitive function in many forms of brain injury [36]. In preclinical studies of PHHP, EPO + MLT were able to reduce ventriculomegaly and macrocephaly [37].…”