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Traumatic brain injury (TBI) consists of two phases: an immediate phase in which damage is caused as a direct result of the mechanical impact; and a late phase of altered biochemical events that results in delayed tissue damage and is therefore amenable to therapeutic treatment. Because the molecular mechanisms of delayed post-traumatic neuronal cell death are still poorly understood, we investigated whether apoptosis-inducing factor (AIF), a pro-apoptotic mitochondrial molecule and the key factor in the caspase-independent, cell death signaling pathway, plays a causal role in neuronal death following TBI. Using an in vitro model of neuronal stretch injury, we demonstrated that AIF translocated from mitochondria to the nucleus of neurons displaying axonal disruption, chromatin condensation, and nuclear pyknosis in a caspase-independent manner, whereas astrocytes remained unaffected. Similar findings were observed following experimental TBI in mice, where AIF translocation to the nucleus coincided with delayed neuronal cell death in both cortical and hippocampal neurons. Down-regulation of AIF in vitro by siRNA significantly reduced stretch-induced neuronal cell death by 67%, a finding corroborated in vivo using AIF-deficient harlequin mutant mice, where secondary contusion expansion was significantly reduced by 44%. Hence, our current findings demonstrate that caspase-independent, AIF-mediated signaling pathways significantly contribute to post-traumatic neuronal cell death and may therefore represent novel therapeutic targets for the treatment of TBI.

__Einleitung__ Das leichte Schadel-Hirn-Trauma (leichtes SHT, engl. „minor traumatic brain injury, mTBI”) wird im Sport oft bagatellisiert. Definiert ist das leichte SHT hauptsachlich als eine klinisch transiente globale Hirnfunktionsstorung durch aussere Krafteinwirkung unter Abwesenheit von fokalen neurologischen Ausfallen und spezifischen neurologischen Befunden. Die wesentlichen Merkmale sind Bewusstseinsverlust fur maximal 20-30 Minuten, ein Glasgow Coma Scale (GCS) Score von 13-15, keine intrakranialen Abnormalitaten in der Computertomographie des Schadels, sowie Verwirrung und/oder Amnesie fur weniger als 24 Stunden. Der behandelnde Arzt geht meist davon aus, dass es sich hierbei um eine nicht-strukturelle Hirnverletzung handelt, die in jedem Fall eine blande Prognose hat. Im folgenden Artikel wird aufgezeigt, dass es sich auch beim leichten Schadel-Hirn-Trauma um eine behandlungsbedurftige strukturelle Hirnschadigung mit potentiell akut lebensbedrohlichen Folgen handelt. __Methodik__ Dieser Kurzbericht basiert auf dem „First International Meeting on Minor Traumatic Brain Injury” vom 28. Februar bis 4. Marz 2005 in Samedan/Schweiz unter der Leitung von Dr. Biasca. __Ergebnisse__ Das leichte SHT ist eine Verletzungsform, die bei allen Sportarten, bei welchen Geschwindigkeit und Kraft zusammenwirken, insbesondere durch Beschleunigung mit abrupten Rotationsbewegungen vorkommen kann. Die typischen sZeichen sind Verwirrtheit und Amnesie. Der Bewusstseinsverlust ist nicht obligatorisch. Warnsymptome sind Kopfschmerz, Schwindel oder Ubelkeit. Der Schweregrad eines leichten SHTs kann klinisch am besten anhand dem Auftreten und der Lange einer Amnesie beurteilt werden. Jegliche Form einer retrograden Amnesie ist mit einem 10-fach hoheren Risiko eines schlechteren Krankeitsverlaufs assoziiert. Dagegen scheint kein Pradilektionswert fur den Bewusstseinsverlust im Hinblick auf die Prognose nach einer mTBI vorzuliegen.

Dementia in humans following traumatic brain injury (TBI) has been well documented in clinical populations, either after a single TBI or repeated mild TBI (rMTBI). In most cases, trauma-induced dementia follows a slow, chronic time-course, and in many cases mild injuries accumulate over time. Both single TBI and rMTBI have been modeled experimentally in vivo, most often in rodents, and various treatment strategies have been studied in order to reduce brain damage after injury. Here, we review the recent literature with regard to currently used in vivo models of TBI in animals, and studies conducted with them to investigate the link between TBI and the development of dementia-like pathology, such as that associated with Alzheimer’s disease (AD). We also discuss the potential use of in vitro models of trauma for investigating a link between trauma and dementia.

Summary Undetected brain injury in sports: minor traumatic brain injury and its consequences. Part 1 Minor traumatic brain injury (mTBI) in sport must be regarded as an injury to the brain which requires treatment. All mTBIs sustained earlier must be duly recorded and taken into consideration in drawing up a treatment plan. Therapy should follow precisely defined guidelines, e.g. the stepwise protocol of the IOC/FIFA/IIHF Concussion in Sports (CIS) Group. Sports activities should be resumed only when all physical, and also cognitive, symptoms have subsided.

Traumatic brain injury (TBI) involves direct mechanical damage, which may be aggravated by secondary insults such as ischemia. We utilized an in vitro model of stretch-induced injury to investigate the effects of mechanical and combined mechanical/ischemic insults to cultured mouse cortical cells. Stretch injury alone caused significant neuronal loss and increased uptake of the dye, propidium iodide, suggesting cellular membrane damage to both glia and neurons. Exposure of cultures to ischemic conditions for 24 h, or a combination of stretch and 24 h of ischemia, caused greater neuronal loss compared to stretch injury alone. Next, we tested the neuroprotective effects of superoxide dismutase (SOD), and the nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NINA) and lubeluzole. In general, these agents decreased neuronal loss following stretch injury alone, but were relatively ineffective against the combined injury paradigm. A combination of SOD with 7-NINA or lubeluzole offered no additional protection than single drug treatment against stretch alone or combined injury. These results suggest that the effects of primary mechanical damage and secondary ischemia to cortical neurons are cumulative, and drugs that scavenge superoxide or reduce NO production may not be effective for treating the secondary ischemia that often accompanies TBI.

Recent studies in vivo have shown that cells of the cerebellum, and particularly Purkinje neurons (PNs), are susceptible to damage following traumatic brain injury (TBI). To investigate more closely the effects of TBI at the cellular level, we subjected cerebellar cell cultures to injury using an in vitro model of stretch-induced mechanical trauma and found increased cell damage and neuronal loss with increasing levels of injury and time post-injury. The release of neuron-specific enolase and S-100 beta were also elevated after injury. Compared to our previous findings in hippocampal cells, S-100 beta levels were much higher in cerebellar cultures after injury, suggesting that cells from different brain regions show variable responses to mechanical trauma. Lastly, the addition of exogenous S-100 beta to uninjured cerebellar cells caused no overt change in cell viability or overall neuronal number; there were, however, fewer calbindin-positive PNs, similar to findings after stretch injury.

Summary An interesting hypothesis in the study of neurotrauma is that repeated traumatic brain injury may result in cumulative damage to cells of the brain. However, postinjury sequelae are difficult to address at the cellular level in vivo. Therefore, it is necessary to complement these studies with experiments conducted in vitro .I n this report, the effects of single and repeated traumatic injury in vitro were investigated in cultured mouse hippocampal cells using a well characterized model of stretch-induced injury. Cell damage was assessed by the level of propidium iodide (PrI) uptake and retention of fluorescein diacetate (FDA). Uninjured control wells displayed minimal PrI uptake and high levels of FDA retention. Mild, moderate and severe levels of stretch caused increasing amounts of PrI uptake, respectively, when measured at 15 min and 24 h post-injury, indicating increased cellular damage with increasing amounts of stretch. For repeated injury studies, cultures received a second injury 1 h after the initial insult. Repeated mild injury caused a slight increase in PrI uptake compared with single injury at 15 min and 24 h post-injury, which was evident primarily in glial cells. However, the neurites of neurones in cultures that received repeated insults showed signs of damage that were not evident after a single mild injury. The release of neurone-specific enolase (NSE) and S-100b protein, two common clinical markers of CNS damage, was also measured following the repeated injuries paradigm. When measured at 6 h post-injury, both NSE and S-100b were found to be elevated after repeated mild injuries when compared with the single injury group. These results suggest that cells of the hippocampus may be susceptible to cumulative damage following repeated mild traumatic insults. Both glial cells and neurones appear to exhibit increased signs of damage after repetitive injury. To our knowledge, this study represents the first report on the effects of repeated mechanical insults on specific cells of the brain using an in vitro model system. The biochemical pathways of cellular degradation following repeated mild injuries may differ considerably from those that are activated by a single mild insult. Therefore, we hope to use this model in order to investigate secondary pathways of cellular damage after repeated mild traumatic injury, and as a rapid and economical means of screening possibilities for treatment strategies, including pharmaceutical intervention.