David B. Kurland

Hemorrhagic Progression of a Contusion after Traumatic Brain Injury: A Review

The magnitude of damage to cerebral tissues following head trauma is determined by the primary injury, caused by the kinetic energy delivered at the time of impact, plus numerous secondary injury responses that almost inevitably worsen the primary injury. When head trauma results in a cerebral contusion, the hemorrhagic lesion often progresses during the first several hours after impact, either expanding or developing new, non-contiguous hemorrhagic lesions, a phenomenon termed hemorrhagic progression of a contusion (HPC). Because a hemorrhagic contusion marks tissues with essentially total unrecoverable loss of function, and because blood is one of the most toxic substances to which the brain can be exposed, HPC is one of the most severe types of secondary injury encountered following traumatic brain injury (TBI). Historically, HPC has been attributed to continued bleeding of microvessels fractured at the time of primary injury. This concept has given rise to the notion that continued bleeding might be due to overt or latent coagulopathy, prompting attempts to normalize coagulation with agents such as recombinant factor VIIa. Recently, a novel mechanism was postulated to account for HPC that involves delayed, progressive microvascular failure initiated by the impact. Here we review the topic of HPC, we examine data relevant to the concept of a coagulopathy, and we detail emerging data elucidating the mechanism of progressive microvascular failure that predisposes to HPC after head trauma.

Inhibition of the Sur1-Trpm4 Channel Reduces Neuroinflammation and Cognitive Impairment in Subarachnoid Hemorrhage

Background and Purpose— Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. Methods— We used Förster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Förster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis &agr; overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19. Results— Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis &agr; overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls. Conclusions— Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.

Complications Associated with Decompressive Craniectomy: A Systematic Review

Decompressive craniectomy (DC) has been used for many years in the management of patients with elevated intracranial pressure and cerebral edema. Ongoing clinical trials are investigating the clinical and cost effectiveness of DC in trauma and stroke. While DC has demonstrable efficacy in saving life, it is accompanied by a myriad of non-trivial complications that have been inadequately highlighted in prospective clinical trials. Missing from our current understanding is a comprehensive analysis of all potential complications associated with DC. Here, we review the available literature, we tabulate all reported complications, and we calculate their frequency for specific indications. Of over 1500 records initially identified, a final total of 142 eligible records were included in our comprehensive analysis. We identified numerous complications related to DC that have not been systematically reviewed. Complications were of three major types: (1) Hemorrhagic (2) Infectious/Inflammatory, and (3) Disturbances of the CSF compartment. Complications associated with cranioplasty fell under similar major types, with additional complications relating to the bone flap. Overall, one of every ten patients undergoing DC may suffer a complication necessitating additional medical and/or neurosurgical intervention. While DC has received increased attention as a potential therapeutic option in a variety of situations, like any surgical procedure, DC is not without risk. Neurologists and neurosurgeons must be aware of all the potential complications of DC in order to properly advise their patients.

Mechanisms of Astrocyte-Mediated Cerebral Edema

Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4-dependent edema formation.

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.

Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke

Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.

The Protective Effect of Glibenclamide in a Model of Hemorrhagic Encephalopathy of Prematurity

We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35–49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences.

The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia

BackgroundHarmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca2+-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca2+ influx, we hypothesized that, in activated microglia, Sur1-Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2.MethodsWe studied microglia in vivo and in primary culture from adult rats, and from wild type, Abcc8−/− and Trpm4−/− mice, and immortalized N9 microglia, following activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), using in situ hybridization, immunohistochemistry, co-immunoprecipitation, immunoblot, qPCR, patch clamp electrophysiology, calcium imaging, the Griess assay, and chromatin immunoprecipitation.ResultsIn microglia in vivo and in vitro, LPS activation of TLR4 led to de novo upregulation of Sur1-Trpm4 channels and CN/NFAT-dependent upregulation of Nos2 mRNA, NOS2 protein, and NO. Pharmacological inhibition of Sur1 (glibenclamide), Trpm4 (9-phenanthrol), or gene silencing of Abcc8 or Trpm4 reduced Nos2 upregulation. Inhibiting Sur1-Trpm4 increased the intracellular calcium concentration ([Ca2+]i), as expected, but also decreased NFAT nuclear translocation. The increase in [Ca2+]i induced by inhibiting or silencing Sur1-Trpm4 resulted in phosphorylation of Ca2+/calmodulin protein kinase II and of CN, consistent with reduced nuclear translocation of NFAT. The regulation of NFAT by Sur1-Trpm4 was confirmed using chromatin immunoprecipitation.ConclusionsSur1-Trpm4 constitutes a novel mechanism by which TLR4-activated microglia regulate pro-inflammatory, Ca2+-sensitive gene expression, including Nos2.

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood–CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4–NF-κB signaling or the SPAK–NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.

Biomarkers as outcome predictors in subarachnoid hemorrhage – a systematic review

Abstract Context: Subarachnoid hemorrhage (SAH) has a high fatality rate and many suffer from delayed neurological deficits. Biomarkers may aid in the identification of high-risk patients, guide treatment/management and improve outcome. Objective: The aim of this review was to summarize biomarkers of SAH associated with outcome. Methods: An electronic database query was completed, including an additional review of reference lists to include all potential human studies. Results: A total of 298 articles were identified; 112 were reviewed; 55 studies were included. Conclusion: This review details biomarkers of SAH that correlate with outcome. It provides the basis for research investigating their possible translation into the management of SAH patients.