Frontiers in neurology
-
Frontiers in neurology · Jan 2015
ReviewBench-to-Bedside and Bedside Back to the Bench; Seeking a Better Understanding of the Acute Pathophysiological Process in Severe Traumatic Brain Injury.
Despite substantial investments, traumatic brain injury (TBI) remains one of the major disorders that lack specific pharmacotherapy. To a substantial degree, this situation is due to lack of understanding of the pathophysiological process of the disease. ⋯ The pathophysiology during the acute phase of severe TBI is especially poorly understood. In this Mini review, I discuss some of the incongruences between current clinical practices and needs versus information provided by experimental TBI research as well as the benefits of designing animal experiments with translation into clinical practice in mind.
-
Frontiers in neurology · Jan 2015
ReviewCathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.
There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. ⋯ Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington's disease, multiple sclerosis, and Alzheimer's disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.
-
Frontiers in neurology · Jan 2015
Biochemical response to hyperbaric oxygen treatment of a transhemispheric penetrating cerebral gunshot injury.
Hyperbaric oxygen (HBO) therapy has been suggested a treatment option in order to reduce the development of secondary insults succeeding traumatic brain injury. This case report studied the course of a 23-year-old gentleman with a close range transhemispheric gunshot wound. The biochemical parameters, using a multi-modal monitoring in the neuro-intensive care unit, improved following HBO treatment.
-
Frontiers in neurology · Jan 2015
ReviewVascular and inflammatory factors in the pathophysiology of blast-induced brain injury.
Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. ⋯ At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI.
-
Epigenetic mediators of gene expression are hypothesized to regulate transcriptomic responses to preconditioning ischemia and ischemic tolerance. Here, we utilized a methyl-DNA enrichment protocol and sequencing (ChIP-seq) to identify patterns of DNA methylation in an established model of ischemic tolerance in neuronal cultures (oxygen and glucose deprivation: OGD). ⋯ We detected a smaller cohort of hypermethylated regions following ischemic conditions, which were further analyzed revealing differential chromosomal localization of methylation, and a differential concentration of methylation on genomic regions. Together, these data show that the temporal profiles of DNA methylation with respect to chromatin hyper- and hypo-methylation following various ischemic conditions are highly dynamic, and may reveal novel targets for neuroprotection.