Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Abstract

BackgroundAcute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential.MethodsInduction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2.ResultsHere, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult.ConclusionsOur results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1166-9) contains supplementary material, which is available to authorized users.

Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice

“…In light of previous studies showing that CB1 agonists improve survival and outcome in TBI patients and reduce neuroinflammation and neuronal excitotoxicity in rodent TBI models 25 , 71 – 73 , the observed lasting loss of endocannabinoids discloses an underlying mechanism, and supports the idea that inhibition of FAAH, the enzyme catalyzing the breakdown of AEA, OEA and PEA, could be a novel therapeutic approach. In rodent models, FAAH inhibitors attenuated TBI-evoked inflammatory markers in association with better performance in balance beam walking and Morris water maze 27 , 28 .…”

Peripheral inflammation and blood–brain barrier disruption: effects and mechanisms

“…On the other hand, IL‐1β led to a discontinuous distribution of claudin‐5 along the plasma membrane of brain endothelial cells 75 . Apart from claudin‐5, LPS‐induced systemic inflammation was also associated with degradation of occludin 82 . Another recent study showed that peripheral cytokines reduced expression of ZO‐1 in mice with pre‐existing tumors 83 …”

Intracellular transport and regulation of transcytosis across the blood–brain barrier

“…Inflammation drives the activation of the neurovasculature, thus disrupting the integrity of the BBB and substantially inducing its permeability as reported in several neurodegenerative diseases. Inhibition of MAGL activity, and, therefore, modulation of PGs expression were recently shown to prevent an inflammation-driven increase in BBB permeability [112] suggesting a dual role of the AA pathway controlling neuro-vascular coupling and BBB integrity/permeability. However, it should be stressed that changes to the BBB upon immune challenges are not restricted to intracellular transport but also affect paracellular transport and immune cell transmigration.…”