title: Inhibition of Endocannabinoid Degradation Improves Outcomes from Mild Traumatic Brain Injury: A Mechanistic Role for Synaptic Hyperexcitability.
abstract: Traumatic brain injury (TBI) is an increasingly prevalent condition affecting soldiers, athletes, and motor vehicle accident victims. Unfortunately, it 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 synaptic changes, altered neuronal signaling, and, ultimately, behavioral changes. Previously we showed that preventing degradation of the endocannabinoid (EC) 2-acylglycerol (2-AG) with JZL184 after mild TBI attenuated neuroinflammation and improved recovery of neurobehavioral function during the early 24 h post-TBI period. The aim of this study was to extend the timeline of observations to 2 weeks post-injury and to investigate JZL184's impact on synaptic transmission, which we view as a potential mechanism for TBI-induced cellular and behavioral pathology. Adult male rats underwent mild TBI (mTBI) followed by a single intraperitoneal injection of JZL184 or vehicle 30 min post-injury. JZL184 administered-TBI animals showed improved neurobehavioral recovery compared with vehicle-injected TBI animals beginning 24 h post-injury and persisting for 2 weeks. JZL184-treated animals had significantly diminished gray and white matter astrocyte activation when compared with vehicle-treated animals at day 7 post-TBI. JZL184 administration significantly attenuated the increased pGluR1S845/GluR1 and pERK 1/2/ERK and the increases in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude observed in layer 5 pyramidal neurons at 10 days post-TBI. These results suggest a neuroprotective role for ECs in ameliorating the TBI-induced neurobehavioral, neuroinflammatory, and glutamate dyshomeostasis from mTBI. Further studies elucidating the cellular mechanisms involved are warranted.
authors.affiliation: 1 Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mayeux
authors.affiliation: 1 Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Paige
authors.initials: P
authors.lastname: Katz
authors.affiliation: 1 Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Scott
authors.initials: S
authors.lastname: Edwards
authors.affiliation: 2 Department of Cell Biology and Anatomy, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Middleton
authors.affiliation: 1 Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Molina
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D001924:Brain Concussion / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D063388:Endocannabinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D052117:Benzodioxoles; D063388:Endocannabinoids; C534333:JZL 184; D010880:Piperidines
keywords: 2-AG; MAGL; TBI; endocannabinoids; neuroinflammation