131 Neonatal Treatment with Endogenous Repair Agents Reverses Abnormal Thermal Sensation in a Preclinical Model of Cerebral Palsy

Abstract

Abstract INTRODUCTION Patients with cerebral palsy are prone to chronic pain. Discovery of effective interventions for this population necessitates understanding mechanisms of pain, and their potential reversibility. Pain circuits undergo perinatal maturation, and are thus vulnerable to early CNS insults. We hypothesized that neonatal treatment could mitigate abnormal pain circuit maturation. METHODS Using an established preclinical model of cerebral palsy, chorioamnionitis was induced on embryonic day 18. Rat pups were born at term (E22, ∼30 weeks human gestation). On postnatal day 1 (P1) rats were randomized to treatment (erythropoietin 2000 U/kg/dayx5d plus melatonin 20 mg/kg/dayx5d) or vehicle. Adult rats of both sexes were tested for mechanical and thermal sensation. Lumbar spinal cord assays were performed with immunoblotting, and serum with multiplex electrochemiluminscence. Groups were compared with two-way ANOVA and post-hoc correction, with P < 0.05 significant. RESULTS >Rats exposed to prenatal injury (injury-vehicle) showed hindpaw allodynia with mechanical non-nociceptive testing using von Frey at P30 compared to shams (P < 0.01), that was less pronounced at P60 (P = 0.07), perhaps due to delayed A-fiber maturation after injury. Treatment did not alter responses. By contrast, injury-vehicle rats exhibited c-fiber hypersensitivity to thermal tail immersion with maturation, compared to shams (P < 0.01). The thermal deficit was fully repaired by neonatal treatment (injury-vehicle versus injury-treatment, P < 0.01). CXCL1 is implicated in calpain-mediated degradation of KCC2 in neuropathic pain. Injury-vehicle rats had elevated serum CXCL1 and lumbar cord KCC2 degradation products compared to shams (both P < 0.01). Neonatal treatment normalized serum CXCL1 on P7 (P < 0.01). CONCLUSION Using a prenatal CNS injury that mimics gait abnormalities of cerebral palsy, our initial results show for the first time that prenatal injury also produces complex abnormalities in maturation of lumbar spinal cord sensation. Moreover, hypersensitivity to thermal stimuli appears to be normalized after neonatal treatment with endogenous neuroreparative agents that are currently in clinical trials for preterm infants.