John R. Vender

Opposing roles for reactive astrocytes following traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Current medical therapies exhibit limited efficacy in reducing neurological injury and the prognosis for patients remains poor. While most research is focused on the direct protection of neuronal cells, non-neuronal cells, such as astrocytes, may exert an active role in the pathogenesis of TBI. Astrocytes, the predominant cell type in the human brain, are traditionally associated with providing only structural support within the CNS. However, recent work suggests astrocytes may regulate brain homeostasis and limit brain injury. In contrast, reactive astrocytes may also contribute to increased neuroinflammation, the development of cerebral edema, and elevated intracranial pressure, suggesting possible roles in exacerbating secondary brain injury following neurotrauma. The multiple, opposing roles for astrocytes following neurotrauma may have important implications for the design of directed therapeutics to limit neurological injury. As such, a primary focus of this review is to summarize the emerging evidence suggesting reactive astrocytes influence the response of the brain to TBI.

Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4?

J. Neurochem. (2010) 113, 637–648.

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. GLIA 2013;62:26–38

Activation of P2X7 Promotes Cerebral Edema and Neurological Injury after Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7−/− mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1β expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.

Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice

OBJECT Traumatic brain injury (TBI) induces significant neurological damage, including deficits in learning and memory, which contribute to a poor clinical prognosis. Treatment options to limit cognitive decline and promote neurological recovery are lacking, in part due to a poor understanding of the secondary or delayed processes that contribute to brain injury. In the present study, the authors characterized the temporal and spatial changes in the expression of postsynaptic density protein-95 (PSD-95), a key scaffolding protein implicated in excitatory synaptic signaling, after controlled cortical impacts in mice. Neurological injury, as assessed by the open-field activity test and the novel object recognition test, was compared with changes in PSD-95 expression. METHODS Adult male CD-1 mice were subjected to controlled cortical impacts to simulate moderate TBI in humans. The spatial and temporal expression of PSD-95 was analyzed in the cerebral cortex and hippocampus at various time points following injury and sham operations. Neurological assessments were performed to compare changes in PSD-95 with cognitive deficits. RESULTS A significant decrease in PSD-95 expression was observed in the ipsilateral hippocampus beginning on Day 7 postinjury. The loss of PSD-95 corresponded with a concomitant reduction in immunoreactivity for NeuN (neuronal nuclei), a neuron-specific marker. Aside from the contused cortex, a significant loss of PSD-95 immunoreactivity was not observed in the cerebral cortex. The delayed loss of hippocampal PSD-95 directly correlated with the onset of behavioral deficits, suggesting a possible causative role for PSD-95 in behavioral abnormalities following head trauma. CONCLUSIONS A delayed loss of hippocampal synapses was observed following head trauma in mice. These data may suggest a cellular mechanism to explain the delayed learning and memory deficits in humans after TBI and provide a potential framework for further testing to implicate PSD-95 as a clinically relevant therapeutic target.

Postoperative pain management after craniotomy: Evaluation and cost analysis

OBJECTIVE:Patients undergoing craniotomies have traditionally received opiates for the management of their postoperative pain. The use of narcotic pain medications can be costly, can decrease early walking, can lengthen hospital stay, and can alter a patients neurological examination results. The use of alternative pain medications such as cyclooxygenase-2 (COX-2) inhibitors may benefit patients by resolving many of these issues. Compared with traditional nonsteroidal anti-inflammatory drugs, these anti-inflammatory medications may be used safely in neurosurgical patients because of their selective inhibition of the COX-2 enzyme, which avoids the platelet dysfunction caused by other nonsteroidal anti-inflammatory drugs. METHODS:A randomized, single-blinded prospective study was used to evaluate the efficacy of alternative pain management strategies for patients who have undergone craniotomy. Twenty-seven patients were randomly assigned to a control group (n = 13) receiving narcotics alone or an experimental group (n = 14) receiving a COX-2 inhibitor in addition to narcotic pain medications. RESULTS:The narcotics group was noted to have statistically significantly higher visual analog scale scores, increased length of stay, and increased narcotic use compared with the COX-2 group. The narcotics group also had increased hospitalization costs when compared with the COX-2 group. CONCLUSION:The use of scheduled atypical analgesics, such as COX-2 inhibitors, in addition to narcotics for the management of postoperative pain after craniotomy may provide better pain control, may decrease side effects associated with narcotic pain medications, may encourage earlier walking, and may reduce total hospitalization costs.

Traumatic Cerebrospinal Fluid Leaks

This article discusses the epidemiology, diagnosis, and management of traumatic cerebrospinal fluid (CSF) leaks. An overview of traumatic CSF leaks is presented, and both conservative and operative therapies are reviewed. Management decisions are discussed based on the current literature. Controversial clinical topics are addressed, including the use of prophylactic antibiotics and the timing of surgical repair.

INHIBITION OF NFκB REDUCES CELLULAR VIABILITY IN GH3 PITUITARY ADENOMA CELLS

OBJECTIVE Adenomas of the pituitary gland are among the most common types of tumors of the adult brain. Although adenomas are histologically benign, they may be associated with significant morbidity and mortality, mostly because of their invasive growth pattern and hormone hypersecretion. Current medical therapies are suppressive, acting at a receptor level. Thus, there is a need to identify novel cellular and molecular targets for pituitary tumors. We investigated the possible role of the NFkappaB transcription factor in pituitary tumor cell growth. METHODS The effect of NFkappaB pathway inhibition on cellular viability was studied in the GH3 pituitary adenoma cell line, a well-characterized rat cell line that secretes growth hormone and prolactin. Cells were treated with mechanistically diverse pharmacological NFkappaB pathway inhibitors or with molecular inhibitors that were overexpressed in tumor cells before the assessment of cellular viability. NFkappaB activity was also assessed in GH3 cells using deoxyribonucleic acid binding assays. RESULTS GH3 cells exhibited constitutive NFkappaB activity, which contributed to increased cellular proliferation. Treatment with wedelolactone, an IkappaB kinase inhibitor, or overexpression of an IkappaB super-repressor reduced cell viability, further implicating NFkappaB in pituitary tumor cell growth. Pharmacological or molecular inhibition of Akt similarly reduced GH3 viability and NFkappaB binding, suggesting that constitutive activation of NFkappaB may be, at least in part, mediated by Akt. CONCLUSION Directed targeting of the Akt and NFkappaB signaling pathways may be a useful adjunct in the clinical management of pituitary tumors. Further elucidation of this pathway may yield novel information regarding the behavior of pituitary tumors in humans.

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.

Postoperative pain management with tramadol after craniotomy: evaluation and cost analysis

OBJECT Patients undergoing craniotomies have traditionally received opiates with acetaminophen for the management of their postoperative pain. The use of narcotic pain medications can be costly, decrease rates of early postoperative ambulation, lengthen hospital stays, and alter a patients neurological examination. The use of alternative pain medications such as tramadol may benefit patients by resolving many of these issues. METHODS The authors conducted a randomized, blinded prospective study to evaluate the efficacy of alternative pain management strategies for patients following craniotomies. Fifty patients were randomly assigned either to a control group who received narcotics and acetaminophen alone or an experimental group who received tramadol in addition to narcotic pain medications (25 patients assigned to each group). RESULTS The control group was noted to have statistically significant higher visual analog scale pain scores, an increased length of hospital stay, and increased narcotic use compared with the tramadol group. The narcotics and acetaminophen group also had increased hospitalization costs when compared with the tramadol group. CONCLUSIONS The use of scheduled atypical analgesics such as tramadol in addition to narcotics with acetaminophen for the management of postoperative pain after craniotomy may provide better pain control, decrease the side effects associated with narcotic pain medications, encourage earlier postoperative ambulation, and reduce total hospitalization costs.