Effects of acute alcoholic intoxication on the progression of neuropathologic sequelae following moderate traumatic brain injury

In the United States, head injury is the number one killer of persons under the age of 44 and kills more people under the age of 34 than all other diseases combined. The prevalence of alcohol-related traumatic brain injuries (TBIs) in recent years has predominately involved young adults consuming beer while driving. Therefore, we developed a model of acute alcohol intoxication designed to mimic the consumption of a "six pack" of beer both in fluid volume and alcohol content prior to moderate TBI. Time course experiments were performed to examine the effects of acute alcohol intoxication on the temporal and regional progression of neuropathological events after injury. First, impaired cognition was assessed using a complex task, the radial arm maze, which revealed deficits in working memory up to 35 days after injury in non-intoxicated TBI animals but only up to 7 days for intoxicated TBI animals. Next, alterations in regional cerebral blood flow (rCBF) resulting from this injury were measured by a modified indicator fractionation technique in conscious, unrestrained animals. An acute reduction in rCBF was maximal at 45 min for non-intoxicated TBI animals which was attenuated in intoxicated TBI animals. However, non-intoxicated TBI animals returned to uninjured levels by 6 hrs while intoxicated TBI animals had reduced rCBFs. Thirdly, blood-brain barrier permeability (rPS) was also assessed by regional uptake of a diffusion limited radiolabeled tracer. Non-intoxicated TBI animals had maximal rPS measurements by 2 hrs post-injury which was accelerated to 45 min in regions closest to the impact site for intoxicated TBI animals. Finally, alterations in the expression of genes in brain regions near the impact site were analyzed by Northern blot analysis. Immediate early genes were significantly elevated following injury in a regional specific manner. The inductions were greatest close to the impact site and returned to control levels by 6 hrs post-injury and prior intoxication had no effect. Astrocytes showed a temporal transcriptional activation with maximal inductions of glial fibrillary acidic protein expression levels at 24 hrs post-injury which was significantly inhibited by prior intoxication, particularly in more distal brain regions. From these studies, valuable information about the complication of pathologic events resulting from intoxication prior to moderate TBI can be utilized to establish a therapeutic window of opportunity far the development of effective therapeutic interventions to minimize subsequent functional deficits.