Inhibition of Endocannabinoid Degradation Improves Recovery of Neurobehavioral Function and Resolution of Neuroinflammation and Synaptic Hyperexcitability in a Rodent Model of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is an increasingly prevalent condition affecting soldiers, athletes, and motor vehicle accident victims. It is the most common cause of death for people under 30 and currently lacks effective therapeutic interventions. TBI is defined as a primary mechanical insult followed by a secondary cascade involving inflammation, apoptosis, release of reactive oxygen species, and excitotoxicity, all of which can cause neuronal death and poor recovery. Previously we showed that inhibition of monoacylglycerol lipase (MAGL), the enzyme involved in 2‐acylglycerol (2‐AG) degradation, with JZL184 following mild TBI attenuated neuroinflammation and improved recovery of neurobehavioral function during the early 72 h post‐TBI period. The aim of this study was to examine if common pathologies resulting from the injury, including inflammation, neurobehavioral disruption, and synaptic excitability, could be reversed during the acute recovery period up to 10 days post‐injury. Adult male Wistar rats underwent a 5‐mm left lateral craniotomy, and TBI was induced three days later by lateral fluid percussion. Thirty minutes post‐TBI, rats received intraperitoneal injections of vehicle (alcohol, emulphor, and saline; 1:1:18) or JZL184 (16 mg/kg). Neurobehavioral function, neuroinflammation (immunohistochemistry) and synaptic excitability (brain slice electrophysiological recordings) were assessed up to 10 days post‐TBI. JZL184 administered‐TBI animals had improved neurobehavioral recovery compared to vehicle‐injected TBI animals beginning 24 hours post‐injury and persisting for two weeks. JZL184 administration significantly improved both ipsilateral cortex (gray matter) and corpus callosum (white matter) neuroinflammation seven days post‐TBI. JZL184 administration significantly attenuated TBI‐induced increases in mEPSC frequency and amplitude at 10 days post‐TBI. Taken together these results show that EC degradation inhibition 30 minutes post‐TBI has potential therapeutic benefits that persist throughout the acute recovery period up to 10 days post‐injury. Current studies are investigating the mechanisms of EC degradation inhibition‐mediated improvements from TBI.Support or Funding InformationSupport T‐32 AA007577, DOD W81XWH‐11‐2‐0011