Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant.
Traumatic brain injury triggers a cascade of events resulting in delayed edema, necrosis and impaired function. Harmful mediators are accumulating in the brain after injury and recently, the role of cytokines in the pathophysiology of brain injury has been suggested. We have developed an experimental model for closed head injury (CHI), in which edema, blood-brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of IL-1, IL-6 and TNF-alpha gene mRNA transcription and of TNF-alpha and IL-6 activity in rat brain after CHI are shown. Dexanabinol, HU-211, is a synthetic cannabinoid devoid of cannabimimetic effects; it exhibits pharmacological properties of N-methyl-D-aspartate (NMDA)-receptor antagonist and is an effective cerebroprotectant. We report here that HU-211 is a novel inhibitor of TNF-alpha production at a post-transcriptional stage. HU-211, pentoxyfilline and TNF-binding protein improved the outcome of CHI. We suggest that TNF-alpha is a primary mediator of neurotoxicity after CHI, as inhibition of TNF-alpha is associated with better clinical recovery. TNF-alpha modulating agents, if given within the early time window post-injury, may improve the final neurological outcome in victims of brain trauma.
Shohami
E
E
Department of Pharmacology, Hebrew University, School of Pharmacy, Jerusalem, Israel. esty@yam-suff.cc.huji.ac.il
Gallily
R
R
Mechoulam
R
R
Bass
R
R
Ben-Hur
T
T
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D016489:Head Injuries, Closed / Q000188:drug therapy* / Q000276:immunology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D016207:Cytokines; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D013759:Dronabinol; C062018:HU 211