The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines.
Endocannabinoids are involved in neuroprotection through numerous biochemical pathways. We have shown that the endocannabinoid 2-arachidonoyl glycerol (2-AG) is released in mouse brain after closed head injury (CHI), and treatment with exogenous 2-AG exerts neuroprotection via the central cannabinoid receptor CB1. This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF-kB. The present study was designed to examine the effect of 2-AG on the blood-brain barrier (BBB) and the possible inhibition of the early expression of proinflammatory cytokines, which are implicated in BBB disruption. We found that 2-AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines: TNF-alpha, IL-1beta and IL-6. It also augmented the levels of endogenous antioxidants. We suggest that 2-AG exerts neuroprotection in part by inhibition of the early (1-4 h) inflammatory response and augmentation of the brain reducing power.
Panikashvili
David
D
Department of Pharmacology, Faculty of Medicine, School of Pharmacy, The Hebrew University School of Jerusalem, Jerusalem 91120, Israel.
Shein
Na'ama A
NA
Mechoulam
Raphael
R
Trembovler
Victoria
V
Kohen
Ron
R
Alexandrovich
Alexander
A
Shohami
Esther
E
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D063388:Endocannabinoids; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016489:Head Injuries, Closed / Q000150:complications* / Q000503:physiopathology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
D000975:Antioxidants; D001095:Arachidonic Acids; D016207:Cytokines; D063388:Endocannabinoids; D005989:Glycerides; D007375:Interleukin-1; D015850:Interleukin-6; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C094503:glyceryl 2-arachidonate