Endocannabinoid System of the Blood-Brain Barrier: Current Understandings and Therapeutic Potentials

Overview

Journal Cannabis Cannabinoid Res

Specialty Pharmacology

Date 2021 Dec 17

PMID 34918950

Citations 7

Authors

Kofi Hagan

Panayiotis Varelas

HaiAn Zheng

Affiliations

Soon will be listed here.

Abstract

The endocannabinoid system (ECS) has been found at the blood-brain barrier (BBB), as Cannabinoid receptors were characterized in human brain microvascular endothelial cells and astrocytes. In several and studies, cannabinoids decreased BBB permeability and enhanced membrane integrity, which may be achieved through endothelial tight junctions and other mechanisms. These permeability regulation effects of cannabinoids suggested that the ECS may protect the brain by enhancing barrier integrity. Related questions about cannabinoid-drug interaction and drug distribution across the BBB are also raised. Specifically, can cannabinoids significantly reduce drug bioavailability to the brain? More in-depth and systematic investigations are needed to characterize and quantify these effects of cannabinoids on brain microvasculature physiopathology. Therefore, this review summarizes literatures from different disciplines to promote more research on assessing the therapeutic benefits and risks of using cannabinoids to protect BBB from dysfunctions or breakdown, and to avoid consequent brain damages due to inflammation, neurodegenerations, hemorrhage, ischemia, or other causes.

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References

Bachur N, UDENFRIEND S . Microsomal synthesis of fatty acid amides. J Biol Chem. 1966; 241(6):1308-13. View

Klegeris A, Bissonnette C, McGeer P . Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003; 139(4):775-86. PMC: 1573900. DOI: 10.1038/sj.bjp.0705304. View

Munro S, Thomas K . Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993; 365(6441):61-5. DOI: 10.1038/365061a0. View

Nagayama T, Sinor A, Simon R, Chen J, Graham S, Jin K . Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999; 19(8):2987-95. PMC: 6782289. View

Harhaj N, Antonetti D . Regulation of tight junctions and loss of barrier function in pathophysiology. Int J Biochem Cell Biol. 2004; 36(7):1206-37. DOI: 10.1016/j.biocel.2003.08.007. View

Vendel E, de Lange E . Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med. 2014; 16(3):620-42. DOI: 10.1007/s12017-014-8314-x. View

Vorbrodt A, Dobrogowska D . Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist's view. Brain Res Brain Res Rev. 2003; 42(3):221-42. DOI: 10.1016/s0165-0173(03)00177-2. View

Amenta P, Jallo J, Tuma R, Elliott M . A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J Neurosci Res. 2012; 90(12):2293-305. DOI: 10.1002/jnr.23114. View

Wolburg H, Lippoldt A . Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul Pharmacol. 2003; 38(6):323-37. DOI: 10.1016/s1537-1891(02)00200-8. View

10.

Shigetomi K, Ono Y, Inai T, Ikenouchi J . Adherens junctions influence tight junction formation via changes in membrane lipid composition. J Cell Biol. 2018; 217(7):2373-2381. PMC: 6028530. DOI: 10.1083/jcb.201711042. View

11.

Tao-Cheng J, Nagy Z, Brightman M . Tight junctions of brain endothelium in vitro are enhanced by astroglia. J Neurosci. 1987; 7(10):3293-9. PMC: 6569185. View

12.

Nunez-Lumbreras M, Castaneda-Cabral J, Valle-Dorado M, Sanchez-Valle V, Orozco-Suarez S, Guevara-Guzman R . Drug-Resistant Temporal Lobe Epilepsy Alters the Expression and Functional Coupling to Gαi/o Proteins of CB1 and CB2 Receptors in the Microvasculature of the Human Brain. Front Behav Neurosci. 2021; 14:611780. PMC: 7854549. DOI: 10.3389/fnbeh.2020.611780. View

13.

Tomkins O, Friedman O, Ivens S, Reiffurth C, Major S, Dreier J . Blood-brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. Neurobiol Dis. 2006; 25(2):367-77. DOI: 10.1016/j.nbd.2006.10.006. View

14.

Long J, Li W, Booker L, Burston J, Kinsey S, Schlosburg J . Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2008; 5(1):37-44. PMC: 2605181. DOI: 10.1038/nchembio.129. View

15.

Hind W, England T, OSullivan S . Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br J Pharmacol. 2015; 173(5):815-25. PMC: 4761095. DOI: 10.1111/bph.13368. View

16.

Kho D, Glass M, Graham E . Is the Cannabinoid CB Receptor a Major Regulator of the Neuroinflammatory Axis of the Neurovascular Unit in Humans?. Adv Pharmacol. 2017; 80:367-396. DOI: 10.1016/bs.apha.2017.03.009. View

17.

Fujii M, Sherchan P, Soejima Y, Hasegawa Y, Flores J, Doycheva D . Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats. Exp Neurol. 2014; 261:396-403. PMC: 4194247. DOI: 10.1016/j.expneurol.2014.07.005. View

18.

Tietz S, Engelhardt B . Brain barriers: Crosstalk between complex tight junctions and adherens junctions. J Cell Biol. 2015; 209(4):493-506. PMC: 4442813. DOI: 10.1083/jcb.201412147. View

19.

Piscitelli F, Carta G, Bisogno T, Murru E, Cordeddu L, Berge K . Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice. Nutr Metab (Lond). 2011; 8(1):51. PMC: 3154144. DOI: 10.1186/1743-7075-8-51. View

20.

Shi Y, Zhang L, Pu H, Mao L, Hu X, Jiang X . Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury. Nat Commun. 2016; 7:10523. PMC: 4737895. DOI: 10.1038/ncomms10523. View