High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.

Elucidating novel mechanisms of brain injury following subarachnoid hemorrhage: an emerging role for neuroproteomics.

Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant patient morbidity and death. Since the first demonstration of cerebral vasospasm nearly 60 years ago, the preponderance of research has focused on strategies to limit arterial narrowing and delayed cerebral ischemia following SAH. However, recent clinical and preclinical data indicate a functional dissociation between cerebral vasospasm and neurological outcome, signaling the need for a paradigm shift in the study of brain injury following SAH. Early brain injury may contribute to poor outcome and early death following SAH. However, elucidation of the complex cellular mechanisms underlying early brain injury remains a major challenge. The advent of modern neuroproteomics has rapidly advanced scientific discovery by allowing proteome-wide screening in an objective, nonbiased manner, providing novel mechanisms of brain physiology and injury. In the context of neurosurgery, proteomic analysis of patient-derived CSF will permit the identification of biomarkers and/or novel drug targets that may not be intuitively linked with any particular disease. In the present report, the authors discuss the utility of neuroproteomics with a focus on the roles for this technology in understanding SAH. The authors also provide data from our laboratory that identifies high-mobility group box protein-1 as a potential biomarker of neurological outcome following SAH in humans.

Technical note: Resolution of spontaneous electromyographic discharge following disk-space distraction during lateral transpsoas interbody fusion.

PURPOSE: The lateral transpsoas interbody fusion (LTIF) is an increasingly popular minimally invasive technique for lumbar interbody fusion. Although a posterior approach to the lumbar spine has traditionally been favored for the treatment of canal stenosis and neural foraminal stenosis, a growing body of evidence suggests that indirect decompression of the spinal canal and neural foramen can be achieved using a lateral transpsoas approach to the lumbar spine. We present 2 cases that may suggest a role for spontaneous electromyography (s-EMG) monitoring in assessing the adequacy of decompression during LTIF. METHODS: The 2 cases presented in this technical note illustrate resolution of s-EMG firing during LTIF, following distraction across the disk space. Removal of the distracting device produced the return of s-EMG firing. Both of these cases were operated at the L2-3 level. RESULTS: In the first case, s-EMG firing was noted in the bilateral tibialis anterior leads. Resolution of EMG firing may suggest indirect decompression of the canal via ligamentotaxis as the L5 root traverses the L2-3 disk space. In the second case, s-EMG firing was noted in the left abductor hallucis and resolved with distraction of the L2-3 disk space. Again, this may be explained by canal decompression via ligamentotaxis as the S1 root traverses the L2-3 disk space. CONCLUSION: In both cases, distraction across the disk space resulted in resolution of s-EMG discharges-this correlated with an improvement in symptoms. These findings may suggest a role for s-EMG as a marker for adequacy of decompression in a select subset of patients undergoing LTIF. Further study is needed to determine if resolution of s-EMG is a useful measure of indirect decompression during LTIF.