Abstract
Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.
Highlights
Traumatic brain injury (TBI) is a major cause of death and disability in humans
TBI: A Complex and Chronic Disorder. Both human and animal studies have indicated that TBI leads to chronic biochemical events that play a significant role in exacerbating head injury-induced tissue loss and neurological deficits
Cyclo-L-glycyl-L-2-allylproline (NNZ 2591), improved functional recovery and histological outcomes, and attenuated apoptotic pathways and microglial activation in rats after hypoxic-ischemic brain injury [74]. 35b treatment reduced the expression of multiple cell cycle members, as well as calpain and cathepsin, while increasing expression of two potent endogenous neuroprotective factors-brain derived neurotrophic factor (BDNF) and heat shock protein (HSP) 70 [95]
Summary
Traumatic brain injury (TBI) is a major cause of death and disability in humans. The incidence of TBI in the United States is at least 1.7 million annually with an estimated 5 million patients experiencing long-term complications (Centers for disease control and prevention (CDC), facts about. Potential caveats about animal modeling include questions about how well they simulate clinical pathophysiology, especially diffuse axonal injury; use of anesthetics resulting in potential drug-drug interaction issues; failure in most cases to demonstrate that proposed preclinical mechanisms reflect those in humans, use of genetically identical subjects and failure to address gender, injury severity, species, strain or age-related differences in most pre-clinical evaluations; and choice of outcomes that differ from those used clinically. Another major methodological issue has been the historical focus on using treatments directed toward single injury mechanisms, clearly secondary injury is multi-factorial.
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