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 delay ed edema, necrosis and impaired function. Harmful mediators are accumu lating in the brain after injury and recently, the role of cytokines i n the pathophysiology of brain injury has been suggested. We have deve loped an experimental model for closed head injury (CHI), in which ede ma, blood-brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of I L-1, IL-6 and TNF-alpha gene mRNA transcription and of TNF-alpha and I L-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 an tagonist and is an effective cerebroprotecant. We report here that HU- 211 is a novel inhibitor of TNF-alpha production at a post-transcripti onal stage. HU-211, pentoxyfilline and TNF-binding protein improved th e outcome of CHI. We suggest that TNF-alpha is a primary mediator of n eurotoxicity 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.