Inhibition of endocannabinoid degradation reduces neurological damage and blood brain barrier disruption following traumatic brain injury

Abstract

Traumatic brain injury (TBI) contributes to over a third of all injury‐related deaths in the United States. Initial damage following TBI involves acute neuroinflammation, oxidative stress and altered blood brain barrier (BBB) integrity. Recent studies suggest a neuroprotective role for the endocannabinoid (EC) system including 2‐arachidonoyl glycerol (2‐AG) and N‐arachidonoyl‐ethanolamine (AEA) following TBI. We hypothesized that reducing EC degradation would reduce inflammatory and oxidative tissue damage, improve neurological (NSS) and neurobehavioral (NBS) outcomes, and preserve blood brain barrier (BBB) integrity. Male Sprague‐Dawley rats underwent a 5mm craniotomy and female Leur lock placement over the left hemisphere and were recovered for 3 days. TBI induced by lateral fluid percussion (1.4 J; 30 ms) produced apnea of 15 ± 5 second duration and a 522 ± 83 second delay in righting reflex. The impact of pharmacological inhibitors of 2‐AG and AEA degradation (JZL184; 16 mg/kg and URB597 0.3 mg/kg, respectively; administered IP 30 min post‐TBI) was examined during the first 72 h post injury. TBI markedly impaired NSS and NBS function, and disrupted BBB integrity. Inhibition of 2‐AG degradation (JZL 184) effectively reduced NSS and NBS impairment and significantly attenuated BBB disruption. These findings provide additional support for the potential therapeutic benefit of EC modulation in attenuating the detrimental impact on both NSS and NBS function and BBB integrity following TBI. DOD‐W81XWH‐11–2‐0011, NIAAA‐7577, NIAA‐19587