Endocannabinoid Degradation Inhibition Improves Neurobehavioral Function, Blood–Brain Barrier Integrity, and Neuroinflammation following Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is an increasingly frequent and poorly understood condition lacking effective therapeutic strategies. Inflammation and oxidative stress (OS) are critical components of injury, and targeted interventions to reduce their contribution to injury should improve neurobehavioral recovery and outcomes. Recent evidence reveals potential protective, yet short-lived, effects of the endocannabinoids (ECs), 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine (AEA), on neuroinflammatory and OS processes after TBI. The aim of this study was to determine whether EC degradation inhibition after TBI would improve neurobehavioral recovery by reducing inflammatory and oxidative damage. Adult male Sprague-Dawley rats underwent a 5-mm left lateral craniotomy, and TBI was induced by lateral fluid percussion. TBI produced apnea (17 -5 sec) and a delayed righting reflex (479 -21 sec). Thirty minutes post-TBI, rats were randomized to receive intraperitoneal injections of vehicle (alcohol, emulphor, and saline; 1:1:18) or a selective inhibitor of 2-AG ( JZL184, 16 mg/kg) or AEA (URB597, 0.3 mg/kg) degradation. At 24 h post-TBI, animals showed significant neurological and -behavioral impairment as well as disruption of blood-brain barrier (BBB) integrity. Improved neurological and -behavioral function was observed in JZL184-treated animals. BBB integrity was protected in both JZL184-and URB597-treated animals. No significant differences in ipsilateral cortex messenger RNA expression of interleukin (IL)-1b, IL-6, chemokine (C-C motif) ligand 2, tumor necrosis factor alpha, cyclooxygenase 2 (COX2), or nicotinamide adenine dinucleotide phosphate oxidase (NOX2) and protein expression of COX2 or NOX2 were observed across experimental groups. Astrocyte and microglia activation was significantly increased post-TBI, and treatment with JZL184 or URB597 blocked activation of both cell types. These findings suggest that EC degradation inhibition post-TBI exerts neuroprotective effects. Whether repeated dosing would achieve greater protection remains to be examined.

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

“…Very recently, enhancement of 2-AG signaling by inhibition of its major hydrolytic enzyme MAGL is also shown to attenuate neuroinflammation and neurodegeneration in the mouse model of mild traumatic brain injury (Katz et al, 2015;Zhang et al, 2015). In our previous studies, we have shown that a selective ABHD6 inhibitor WWL70 at 10 mg/kg has a better effect in blocking TBI-induced deficits in fine motor movement and motor coordination than WWL70 at 5 mg/kg (Tchantchou and Zhang, 2013).…”

Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting

“…Because post-TBI alcohol exposure is detrimental to overall recovery through sustained neuroinflammation and excitatory glutamate signaling (Mayeux, Teng, Katz, Gilpin, & Molina, 2015), Dr. Molina’s overall aim is to understand the underlying mechanisms leading to escalation in alcohol drinking post TBI. It has been previously shown that modulation of endocannabinoid tone by systemic administration of JZL184, a monoacylglycerol lipase inhibitor that prevents degradation of the endocannabinoid 2-Arachidonoylglycerol (2-AG), is sufficient to attenuate neuroinflammation and improve neurobehavioral recovery (Katz et al, 2015). Therefore, Dr. Molina’s group tested the hypothesis that post-TBI endocannabinoid degradation inhibition would improve neurobehavioral outcomes, including escalation of alcohol drinking.…”

Elevation of arachidonoylethanolamide levels by activation of the endocannabinoid system protects against colitis and ameliorates remote organ lesions in mice

“…A dye tracer extravasation method was applied for the detection of BBB integrity (20). Evans blue (2%, 2 ml/kg, intravenously) was administered 30 min prior to euthanasia.…”

“…Activation of the ECS decreased pro-inflammatory cytokine levels in mouse models of inflammation and sepsis (15,16), and also ameliorated neural inflammation and attenuated behavioral alterations in mice with Huntington's disease (17). Furthermore, elevation of endogenous arachidonoylethanolamide (AEA, also known as anandamide) levels via the inhibition of FAAH protected rats against aging-associated inflammatory responses in the hippocampus (18), attenuated Toll-like receptor 3-induced neural inflammatory responses (19), and ameliorated posttraumatic brain injury in mice (20). This evidence strongly suggests a neural protective role of the ECS.…”