Ethyl pyruvate improves white matter remodeling in rats after traumatic brain injury

Abstract

Background: Severe traumatic brain injury (TBI) results in long-term neurological deficits associated with white matter injury (WMI). Ethyl pyruvate (EP) is a simple derivative of the endogenous energy substrate pyruvate with neuroprotective properties, but its role in recovery from WMI has not been explored. Aims: This study examines the effect of EP treatment on rats following TBI using behavioral tests and white matter histological analysis up to 28 days post-injury. Materials and Methods: Anaesthetised adult rats were subjected to TBI by controlled cortical impact. After surgery, EP or Ringers solution (RS) was administrated intraperitoneally at 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Sensorimotor deficits were evaluated up to day 21 after TBI by four independent tests. Immunofluorescence and transmission electron microscopy (TEM) were performed to assess white matter injury. Microglia activation and related inflammatory molecules were examined up to day 14 after TBI by immunohistochemistry or real-time PCR. Results: Here, we demonstrate that EP improves sensorimotor function following TBI as well as improves white matter outcomes up to 28 d after TBI, as shown by reduced myelin loss. Furthermore, EP administration during the acute phase of TBI recovery shifted microglia polarization toward the anti-inflammatoryM2 phenotype, modulating the release of inflammatory-related factors. Conclusion: EP treatment may protect TBI-induced WMI via modulating microglia polarization toward M2.