Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice.

BACKGROUND: The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage. METHODS: To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide. RESULTS: mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h. CONCLUSIONS: These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.

Tumor necrosis factor-α synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice.

Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-α), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-α levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-α and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 h and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 h prior to injury, or at 1 or 12 h post-injury. Together, these results implicate TNF-α as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment.

The influence of alcohol on behavioral recovery after mTBI in mice.

In the United States 258,000 people were injured in 2004 in motor vehicle accidents that were caused by drivers under the influence of alcohol. The majority of these drivers were binge drinkers, most notably young people who tend to drink heavily during the weekends, but rarely drink alcohol during the week. Since a large proportion of the injuries involved head injuries, the present study aimed at investigating the influence of binge alcohol drinking on mild traumatic brain injury (mTBI) in an animal model. Mice had access to 0%, 7.5%, 15%, or 30% alcohol solutions for 48 consecutive hours once a week for 4 weeks as the sole source of fluids (the remaining time they drank water). Three experiments were done. For the first one (alcohol-mTBI-alcohol) the animals were subjected to a controlled mTBI injury by applying a closed-head weight drop, or a sham procedure. After the mTBI/sham-mTBI the animals got alcohol and /water for the same regimen for 4 additional weeks. In the second experiment (alcohol only) after the 4 weeks of drinking blood samples were collected, at the same time as the animals that underwent sham-mTBI or mTBI procedures. In the third experiment (mTBI-alcohol) the mice were subjected to mTBI/sham-mTBI without any treatment, and after mTBI they had alcohol for 4 weeks in the same regimen as in the previous experiments. At the end of the pharmacological treatment all animals were assessed using different behavioral tests. mTBI mice exhibited lower memory ability in the Y-maze, higher anxiety in the elevated plus maze, and lower retention in the passive avoidance test than sham-mTBI animals. Alcohol reversed these effects at all doses. The results suggest that alcohol drinking before trauma might have a protective effect on recovery from brain trauma, but not if consumed after the trauma.