Neuroprotective Effects of an Edible Pigment Brilliant Blue FCF against Behavioral Abnormity in MCAO Rats
Jingyang LeXiao XiaoDifan ZhangYi FengZhuoying WuYuechun MaoChenye MouYanfei XieXiaowei ChenHao LiuWei Cui
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Abstract:
Ischemic stroke leads to hypoxia-induced neuronal death and behavioral abnormity, and is a major cause of death in the modern society. However, the treatments of this disease are limited. Brilliant Blue FCF (BBF) is an edible pigment used in the food industry that with multiple aromatic rings and sulfonic acid groups in its structure. BBF and its derivatives were proved to cross the blood-brain barrier and have advantages on the therapy of neuropsychiatric diseases. In this study, BBF, but not its derivatives, significantly ameliorated chemical hypoxia-induced cell death in HT22 hippocampal neuronal cell line. Moreover, protective effects of BBF were attributed to the inhibition of the extracellular regulated protein kinase (ERK) and glycogen synthase kinase-3β (GSK3β) pathways as evidenced by Western blotting analysis and specific inhibitors. Furthermore, BBF significantly reduced neurological and behavioral abnormity, and decreased brain infarct volume and cerebral edema induced by middle cerebral artery occlusion/reperfusion (MCAO) in rats. MCAO-induced increase of p-ERK in ischemic penumbra was reduced by BBF in rats. These results suggested that BBF prevented chemical hypoxia-induced otoxicity and MCAO-induced behavioral abnormity via the inhibition of the ERK and GSK3β pathways, indicating the potential use of BBF for treating ischemic stroke.Keywords:
Hypoxia
Penumbra
The concept of an ischaemic penumbra, surrounding a focal cerebral lesion, is now widely accepted, although no universal definition of the 'penumbra' exists. In the present review, we consider the penumbra as that volume of brain tissue at the periphery of a focal, irreversibly damaged area that is threatened by recruitment into necrosis. Implicit to such a definition are several secondary concepts. First, the penumbra is both spatial, in that it surrounds the densely ischaemic core, but it is also temporal, in that its evolution toward infarction is a relatively progressive phenomenon. The pertinent literature is summarized. Second, penumbral tissue is potentially salvageable; the most recent animal studies are reviewed. Third, because electrically silent and pathologically damaged tissues have identical functional characteristics, it is evident that most clinical rating scales, be they neurological, behavioural, or psychological, are poorly adapted to address the problem of the penumbra. Finally, the penumbral tissue is remarkably and intensively 'active': multiple processes of cell death and repair occur and involve molecular mechanisms, electrophysiology and the vasculature.
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The ischaemic penumbra has been documented in the laboratory animal as a severely hypoperfused, non-functional, but still viable cortex surrounding the irreversibly damaged ischaemic core; with elapsing time, more penumbra gets recruited into the core, while tissue reperfusion is able to stop this deleterious process until a certain point in time. As saving the penumbra should improve clinical outcome, it should constitute the main target of acute stroke therapy. In a series of PET studies performed 5–18 h after stroke onset, we were able to (i) document, for the first time in man, the existence of tissue fulfilling operational criteria for penumbra in about one third of the cases; (ii) show that long-term neurological recovery is proportional to the volume of penumbra that eventually escapes infarction, and (iii) detect penumbral tissue as late as 16 h after symptom onset in occasional patients, suggesting the therapeutic window may be protracted in such cases. Mapping the penumbra in the individual patient with neuroimaging procedures should allow to formulate a pathophysiological diagnosis, and thus to design a rational management of the stroke patient and to improve the selection of candidates for therapeutic trials.
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Abstract We prospectively tested the hypothesis that early recovery after ischemic stroke depends on the ultimate survival of functionally impaired, critically ischemic (i.e., “penumbral”) tissue. From a series of 26 consecutive patients studied with positron emission tomography within 18 hours of first‐ever stroke in the middle cerebral artery territory, all 11 survivors to the 2‐month end point who exhibited increased oxygen extraction fraction were declared eligible. The positron emission tomographic images were compared to ultimate infarction defined by computed tomography performed during the chronic stage. The penumbra (operationally defined by increased oxygen extraction fraction and divided outcome despite uniformly reduced cerebral blood flow) was individually detected in 10 of the 11 patients; cerebral blood flow ranged from 7 to 17 ml/100 gm·min, consistent with that found in monkey studies. The volume of the penumbra that escaped infarction was highly correlated with neurological recovery ( p <0.04 to p <0.0001, depending on the scale used). This longitudinal study is the first to characterize the penumbra in humans and to document one mechanism strongly influencing recovery; the surviving penumbra may offer opportunities for secondary perifocal neuronal reorganization. Therapeutic measures to prevent infarction of the penumbra (up to 16 hours in this series) may have reduced residual neurological impairment. Mapping the extent of the penumbra, according to prospective criteria, may allow one to predict each patient's potential for recovery, and to select the most appropriate candidates for therapeutic trials.
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It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of "good" outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach.
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Summary In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. However, the biological mechanisms underlying the benefit from neuronal activation are unknown. We hypothesized that neuronal activation might trigger the astrocyte-to-neuron lactate shuttle, whereby lactate is released from astrocytes to support the energy requirements of hypoxic neurons, and this leads to the observed neuroprotection. We tested this by establishing a human cell based in vitro model of the ischemic penumbra. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation, that lactate exogenously administered before hypoxia correlated with neuroprotection, and that stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. We presented evidence that lactate contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.
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Background The glycogen synthase kinase -3β (GSK-3β) is a multifunctional Ser/Thr kinase involved in a variety of metabolic processes,and is abundant in central nervous system.Recent studies revealed that the dysfunction of GSK-3β is associated with numerous pathophysiologic processes. Objective We analysized and summarized the role of modulation of GSK-3β activity in neuroprotection with its related mechanism. Content This article described the basic structure and modulation of GSK-3β,the neuroprotection of GSK-3β inhibitor against cerebral ischemia reperfusion injury and related mechanism. Trend The neuroprotective effect of GSK-3β inhibitor against cerebral ischemia reperfusion injury demonstrated the therapeutic prospective of development of isoform-specific inhibitors or gene silencing.
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Glycogen synthase kinase-3β; Neuroprotection; Cerebral ischemia/reperfusion injury
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Patient selection for acute stroke therapy based on physiology rather than on time may lead to expansion of the therapeutic window, improved outcomes, and fewer side effects than currently achieved. This approach requires early determination of both irreversible (core) and reversible (penumbra) ischemia in acute stroke.Using established perfusion thresholds, we characterized the relationship among core, penumbra, and brain tissue perfused above penumbral thresholds (non-core/non-penumbra [NC/NP]) in 36 patients with middle cerebral artery (MCA) stem occlusion who underwent quantitative cerebral blood flow (CBF) assessment with xenon-enhanced CT within 6 hours of symptom onset.While great variability in the mean+/-SD percentage of core (37.6+/-18.7) and NC/NP (30.3+/-16.6) was observed, the percentage of penumbra was relatively constant from individual to individual, constituting approximately one third of the cortical MCA territory (32.1+/-7). In univariable and multivariable analyses, percent core and not percent penumbra was significantly associated with outcome.In acute MCA occlusion, penumbra is consistently present within a relatively narrow range, despite great variability in the size of core. This may explain why the core and not the penumbra is the main determinant of outcome in our group of patients. Recanalization therapy in acute MCA occlusion should ideally be guided by diagnostic methods capable of rapidly and reliably identifying irreversible ischemia.
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P51 Background and Purpose: The ischemic penumbra is composed of neurons that are functionally impaired but structurally intact, and thus potentially salvageable. Identifying the penumbra and its relationship with the ischemic core may lead to a more physiologic selection of patients who might benefit from recanalization therapy. We sought to explore the core/penumbra relationship by quantitatively measuring cerebral blood flow (CBF) in patients with acute M1 occlusion. Methods: 19 patients with M1 occlusion proven by CT angiography or conventional cerebral angiography underwent a Xe-CT/CBF study within 6 hours of symptoms onset. Mean CBF values were measured in the ipsilateral cortical MCA territory. The core was defined as areas with CBF< 8 ml/100g/min and the penumbra was defined as areas with CBF 9–20 ml/100g/min. Findings were correlated with the admission NIH stroke scale (NIHSS). Results: In 6/19 patients (31.5%)(group 1), the size of the penumbra was greater than twice the size of the core. In 8/19 patients (42.1%) (group 2), the size of the penumbra was approximately equal the size of the core. In 5/19 patients (26.8%)(group 3) the size of the penumbra was less than half the size of the core. The median core volumes for each of the three groups, expressed as percentage of core relative to ipsilateral cortical MCA territory, increased from group 1 to group 3. While there was a trend towards a correlation between the admission NIHSS and the combined core and penumbral volumes, no such correlation could be established between admission NIHSS and core or penumbral volumes alone. Conclusions: In the first 6 hours after M1 occlusion, penumbral volumes that are larger than or equal to core volumes are present in 14 out of 19 patients. A smaller core volume is associated with an increased penumbra to core ratio. The admission NIHSS in patients with M1 occlusion correlates with the combined volumes of core and penumbra.
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Abstract: Acute ischemic stroke is one of the leading causes of disability and death worldwide. The brain tissue adjacent to the central necrotic core was first defined as ischemic penumbra characterized by reduced cerebral blood flow (CBF) with electrical failure but maintained ionic homeostasis and transmembrane electrical potentials. Since then, the evolving concepts of the ischemic penumbra have been proposed based on energy metabolism, CBF thresholds and protein synthesis, which provide insight for the diagnosis and treatment of acute ischemic stroke. This paper summarizes the recent advances in the understanding of ischemic penumbra, from its discovery to the diagnosis methods based on imaging techniques and biomarkers, finally some of the treatments developed. In addition, we discussed future perspectives on therapeutic targets beyond ischemic penumbra to develop a treatment for acute ischemic stroke.
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