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

Abstract

Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT) could improve this trajectory. Thus, we administered EPO+MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ~25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ~1 year, rats were randomized to receive either a regimen of EPO+MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO+MLT were restored compared to vehicle-treated rats (p<0.05), and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

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

“…In pre-clinical trials, EPO + MLT were able to reduce ventriculomegaly in induced hemorrhage neonatal rats [44]. In another study, EPO + MLT was used to restore gait in adult rats that previously had induced prenatal injury [45]. The results from these studies are very promising and are moving into clinical trials for preterm infants with severe intraventricular hemorrhage [46].…”

Melatonin as a Therapy for Preterm Brain Injury: What Is the Evidence?

“…Overall, the ideal treatment would be capable of combating various noxious insults that comprise the multiple-hit pathology [ 26 ] in the progression of EoP. Melatonin, which has a broad range of potential as a neuroprotective and neurorestorative agent [ 7 , 8 , 52 , 53 , 54 , 55 , 56 , 57 ], seems highly promising in this context.…”

“…In a subsequent study from the same group, using the same rodent model but starting melatonin at P15 (equivalent to a human infant one year of age) and continuing once daily until P20, melatonin normalized multiple gait metrics investigated, even in mature/adult animals, indicating an extended neuroreparative effect of this treatment strategy [ 56 ]. The underlying cellular and molecular processes behind the neuroregenerative effects of combined EPO + melatonin regimens remain unknown.…”

Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods

“…The associated signal transduction and specific molecules have been identified as therapeutic targets ( Robinson et al, 2018a ; Jantzie et al, 2018 ; Yellowhair et al, 2018 ; Yellowhair et al, 2019a ; Yellowhair et al, 2019b ; Kitase et al, 2021 ; Gall et al, 2022 ). For example, therapies such as erythropoietin (EPO) and melatonin (MLT) have been studied individually, and as a cocktail, in preterm infants ( Yawno et al, 2017 ; Robinson et al, 2018a ; Robinson et al, 2018b ; Lee et al, 2019 ; Juul et al, 2020 ; Song et al, 2021 ; Wood et al, 2021 ; Jantzie et al, 2022 ). As monotherapy, both have been investigated in clinical trials to ameliorate CNS injury ( Juul et al, 2008 ; Ohls et al, 2014 ; Fauchère et al, 2015 ; Ohls et al, 2016 ; Wu et al, 2016 ; Carloni et al, 2017 ).…”

“…We also evaluated SIRT1, HIF1α and HIF2α as upstream signaling partners and molecular convergence points between EPO and MLT pathways. ( Chavez et al, 2006 ; Hou et al, 2011 ; Chen et al, 2012 ; Jantzie et al, 2022 ). We aimed to define changes in the expression of these important developmental regulators in the placenta-fetal-brain axis following injury.…”