Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats
TL;DR: Treatment with recombinant osteopontin prevented a significant loss in body weight, neurologic impairment, brain edema, and blood–brain barrier disruption after subarachnoid hemorrhage.
Abstract: Objective
Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage (SAH) is not only cerebral arterial narrowing, but also early brain injury (EBI). Our objective was to determine the effect of recombinant osteopontin (r-OPN), a pleiotropic extracellular matrix glycoprotein, on post-SAH EBI in rats.
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TL;DR: It could be argued that the treatment of EBI may successfully attenuate some of the devastating secondary injuries and improve the outcome of patients with SAH and the reversal of vasospasm does not appear to improve patient outcome.
Abstract: Subarachnoid hemorrhage (SAH), predominantly caused by a ruptured aneurysm, is a devastating neurological disease that has a morbidity and mortality rate higher than 50%. Most of the traditional in vivo research has focused on the pathophysiological or morphological changes of large-arteries after intracisternal blood injection. This was due to a widely held assumption that delayed vasospasm following SAH was the major cause of delayed cerebral ischemia and poor outcome. However, the results of the CONSCIOUS-1 trial implicated some other pathophysiological factors, independent of angiographic vasospasm, in contributing to the poor clinical outcome. The term early brain injury (EBI) has been coined and describes the immediate injury to the brain after SAH, before onset of delayed vasospasm. During the EBI period, a ruptured aneurysm brings on many physiological derangements such as increasing intracranial pressure (ICP), decreased cerebral blood flow (CBF), and global cerebral ischemia. These events initiate secondary injuries such as blood-brain barrier disruption, inflammation, and oxidative cascades that all ultimately lead to cell death. Given the fact that the reversal of vasospasm does not appear to improve patient outcome, it could be argued that the treatment of EBI may successfully attenuate some of the devastating secondary injuries and improve the outcome of patients with SAH. In this review, we provide an overview of the major advances in EBI after SAH research.
394 citations
TL;DR: Physiological parameters, functional (motor, cognitive, and behavioral) outcomes, and underlying molecular mechanisms involved in inflammation measured in the brain over the 30 day post-blast period showed this model is capable of reproducing major neurological changes of clinical BINT.
271 citations
TL;DR: The authors characterise optically cleared tissue as an electrolyte gel and apply this knowledge to stain the entirety of thick tissue samples, offering advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.
Abstract: Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems. Tissue clearing has revolutionised histology, but limited penetration of antibodies and stains into thick tissue segments is still a bottleneck. Here, the authors characterise optically cleared tissue as an electrolyte gel and apply this knowledge to stain the entirety of thick tissue samples.
178 citations
TL;DR: OPN may increase MAPK phosphatase-1 that inactivates MAPKs, upstream and downstream of vascular endothelial growth factor-A, by binding to l-arginyl-glycyl-l-aspartate-dependent integrin receptors, suggesting a novel mechanism of OPN-induced post-SAH BBB protection.
Abstract: Background and Purpose— Osteopontin (OPN) is an inducible, multifunctional, extracellular matrix protein that may be protective against blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). However, the protective mechanisms remain unclear. Methods— We produced the endovascular perforation model of SAH in rats and studied the time course of OPN induction in brains by Western blotting and immunofluorescence (n=50). Then, 34 rats were randomly assigned to sham (n=3), sham+OPN small interfering RNA (siRNA, n=3), SAH+negative control siRNA (n=14), and SAH+OPN siRNA (n=14) groups, and 109 rats were allocated to sham+vehicle (n=17), sham+recombinant OPN (n=17), SAH+vehicle (n=33), SAH+recombinant OPN (n=31), and SAH+recombinant OPN+l-arginyl-glycyl-l-aspartate motif–containing hexapeptide (n=11) groups. The effects of OPN siRNA or recombinant OPN on BBB disruption and related proteins were studied. Results— OPN was significantly induced in reactive astrocytes and capillary endothelial cells,...
141 citations
TL;DR: The pathological mechanisms of early brain injury are reviewed, which may reveal new therapeutic avenues that can be exploited to serve as combination therapy with anti‐vasospasm medications in the future.
Abstract: Subarachnoid hemorrhage is a devastating disease that can be difficult to manage. Not only is the initial bleeding and rebleeding associated with high mortality, but a large fraction of patients also develop a delayed neurological deficit even when the aneurysm was successfully secured with clipping or coiling. Past research effort has traditionally been focused on vasospasm, which was conceived to be the sole factor for delayed neurological deficit. The failure of anti-vasospastic drugs to improve outcome in clinical trials has brought into focus the significance of early brain injury. The immediate events associated with subarachnoid hemorrhage, including increased intracranial pressure, decreased cerebral blood flow and global ischemia initiate a cascade of pathological changes that occur before the onset of delayed vasospasm. These pathological changes in the very early stage of the hemorrhage propagate and cause blood-brain barrier disruption, inflammation, oxidative stress and cell death. Focusing only on the treatment of vasospasm with complete disregard for early brain injury is insufficient for the management of subarachnoid hemorrhage. Instead, a therapeutic intervention has to aim at stopping the molecular cascades of early brain injury that may lead to long-term deficits in addition to vasospasm. We review the pathological mechanisms of early brain injury, which may reveal new therapeutic avenues that can be exploited to serve as combination therapy with anti-vasospasm medications in the future.
137 citations
Cites background from "Protective effects of recombinant o..."
...…cascade of EBI starts immediately after aneurysm rupture, which not only is responsible for the initial signs and symptoms of SAH, but also contributes to the delayed neurological deterioration and poor long-term outcome traditionally linked to vasospasm (Suzuki et al. 2010b; Sherchan et al. 2011)....
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...MMP-9 degrades extracellular matrix of cerebral microvessel basal lamina, including collagen IV, laminin, fibronectin and interendothelial tight junction proteins such as zona occludens-1 (Sehba et al. 2004; Yatsushige et al. 2007; Suzuki et al. 2010a)....
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...Inflammation The proinflammatory cytokines TNF-a, IL1-b and IL6 were found increased in experimental studies in the early period and were proposed to lead to BBB disruption (Sozen et al. 2009; Sugawara et al. 2009; Ersahin et al. 2010b; Suzuki et al. 2010c)....
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References
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TL;DR: A systematic literature review was conducted based on a search of MEDLINE to identify all relevant randomized clinical trials published between June 30, 1994, and November 1, 2006 to reevaluate the recommendations for management of aneurysmal SAH.
Abstract: Subarachnoid hemorrhage (SAH) is a common and frequently devastating condition, accounting for ≈5% of all strokes and affecting as many as 30 000 Americans each year.1,2 The American Heart Association (AHA) previously published “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.”3 Since then, considerable advances have been made in endovascular techniques, diagnostic methods, and surgical and perioperative management paradigms. Nevertheless, outcome for patients with SAH remains poor, with population-based mortality rates as high as 45% and significant morbidity among survivors.4–9 Several multicenter, prospective, randomized trials and prospective cohort analyses have influenced treatment protocols for SAH. However, rapid evolution of newer treatment modalities, as well as other practical and ethical considerations, has meant that rigorous clinical scientific assessment of the treatment protocols has not been feasible in several important areas.
To address these issues, the Stroke Council of the AHA formed a writing group to reevaluate the recommendations for management of aneurysmal SAH. A consensus committee reviewed existing data in this field and prepared the recommendations in 1994.3 In an effort to update those recommendations, a systematic literature review was conducted based on a search of MEDLINE to identify all relevant randomized clinical trials published between June 30, 1994, and November 1, 2006 (search terms: subarachnoid hemorrhage , cerebral aneurysm , trial ; Table 1). Each identified article was reviewed by at least 2 members of the writing group. Selected articles had to meet one of the following criteria to be included: randomized trial or nonrandomized concurrent cohort study. Case series and nonrandomized historical cohort studies were reviewed if no studies with a higher level of evidence were available for a particular topic covered in the initial guidelines. These were chosen on the basis of sample size and the relevance of the particular studies to subjects that …
1,629 citations
"Protective effects of recombinant o..." refers background in this paper
...Cerebral vasospasm has been believed to be a leading cause of mortality and morbidity (2)....
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TL;DR: It is suggested that OPN delivers an antiapoptotic “ECM-like” signal via multiple ligand-receptor interactions to cells, both adherent and nonadherent.
Abstract: OPN is a multifunctional cytokine and adhesion protein that contains an integrin-binding RGD sequence and additional sequences that interact with CD44v6/7 or other adhesive receptors. Its expression is increased in response to early proinflammatory cytokines and to mechanical strain in bone. The function of the secreted protein may be altered by extracellular enzymes, including thrombin and kinases. The study of OPN-null mice has revealed roles for OPN in a broad range of homeostatic (bone remodeling, tissue debridement) and pathologic (cellular immunity, wound healing, cancer metastasis) processes. While these processes seem disparate, they are linked by several common themes, including enhanced expression of OPN in response to stress or tissue injury, and stimulation of cell motility and cell survival pathways via interactions of OPN with adhesive receptors.
OPN is chemotactic for various cell types, notably monocytes/macrophages, which are attracted to sites of infection and inflammation. It is essential for cell-mediated immunity and a normal Th1 cytokine response during granuloma formation. OPN serves both to attach bone cells to bone matrix and to generate intracellular signals essential for normal osteoclast motility on bone; it may mediate osteocyte recognition of bone strain. OPN activates intracellular signaling pathways and regulates gene expression as a consequence of its interactions with its various receptors. The best-characterized is the integrin-stimulated FAK-Src-Rho pathway, which alters gelsolin function and podosome formation in osteoclasts. Identification and dissection of the signal transduction pathways and their targets are complicated by the fact that OPN can engage more than one type of receptor on the cell. For this reason, it is important to ascertain which receptors are in play in any given experimental system.
There is compelling evidence that soluble OPN can in a variety of situations help cells survive an otherwise lethal insult. Remarkably, this survival signaling is mediated by receptors that are generally considered to be receptors for ECM components. We suggest that OPN delivers an antiapoptotic “ECM-like” signal via multiple ligand-receptor interactions to cells, both adherent and nonadherent.
1,055 citations
"Protective effects of recombinant o..." refers background in this paper
...However, there is compelling evidence that OPN can, in a variety of situations, help cells survive an otherwise lethal insult (8)....
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TL;DR: In a study from 1950 it was concluded that 60% of patients with subarachnoid hemorrhage soon or later die from the lesion, while 20% become permanently disabled and only 20% have a chance of making a good recovery.
Abstract: Rupture of an intracranial aneurysm is the leading cause of subarachnoid hemorrhage not due to trauma. This review summarizes both the approach to establishing the diagnosis and treatment options, including the placement of intravascular coils to arrest the bleeding. Common management problems include vasospasm, hydrocephalus, and rebleeding.
841 citations
TL;DR: Recent advances in understanding the functional role of the OPN-induced signaling pathway in the regulation of cell migration and tumor progression and the implications for identifying novel targets for cancer therapy are focused on.
657 citations
"Protective effects of recombinant o..." refers background in this paper
...born aortic smooth muscle cells in the presence of platelet-derived growth factor-BB , as well as in many tumor cells (26, 28)....
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...OPN regulates the bioavailability of MMP, although the effects exerted by OPN on MMP differ depending on cell types, receptor interactions, post-translational modifications, and the phosphorylation state of OPN (7, 25, 26)....
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TL;DR: Clazosentan significantly decreased moderate and severe vasospasms in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed.
Abstract: Background and Purpose— This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage. Methods— Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks. Results— Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the...
573 citations