Comparative Assessment of the Proteolytic Stability and Impact of Poly-Arginine Peptides R18 and R18D on Infarct Growth and Penumbral Tissue Preservation Following Middle Cerebral Artery Occlusion in the Sprague Dawley Rat
Diego MilaniVince W. ClarkKirk W. FeindelDavid BlackerMichael ByneveltAdam B. EdwardsRyan S. AndertonNeville W. KnuckeyBruno P. Meloni
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Objective: To investigate whether quantitative apparent diffusion coefficient(ADC) measurements can be employed to predict the prognosis of infarction in acute ischemic stroke without intravenous contrast material.Methods: Thirty-three patients having acute stroke symptoms with verified infarction in magnetic resonance imaging(MRI) were included in this study.Their MRI studies were performed between 6 and 12 h after the onset of their symptoms and were repeated.The infarction volumes were calculated by using DWI and the patients were divided into two groups as the ones having an expansion in the infarction area(group I,n=22) and the others having no expansion in the infarction area(group II,n=11).The groups were compared in terms of the ADC values and areas obtained from DWI,referring to three points: the core of the infarction,ischemic penumbra and the contralateral nonischemic parenchymal tissue.Quantitative ADC values and the infarction area were estimated.P 0.05 were accepted to be statistically significant.Results: The internal mean infarction area during the times between 6 and 12 h and in the fourth day was calculated by DWI.A significant statistical result was demonstrated on the DWI between the two groups(P0.001) and there was no difference between the core of the infarction and parenchymal tissue(P0.05).The ADC values of ischemic penumbra between the groups were found to be highly significant(P0.001).Conclusion: We believe that ADC results obtained from the core and the penumbra of the infarction area without intravenous contrast material will be a feasible and practical in the estimation of the infarction prognosis and in the planning of a treatment protocol.
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Abstract Malignant middle cerebral artery [MMCA] infarction has a different topographic distribution that might confound the relationship between lesion volume and outcome. Retrospective study to determine the multivariable relationship between computerized tomographic [CT] infarct location, volume and outcomes in decompressive hemicraniectomy [DHC] for MMCA infarction. The MCA infarctions were classified into four subgroups by CT, subtotal, complete MCA [co-MCA], Subtotal MCA with additional infarction [Subtotal MCAAI] and co-MCA with additional infarction [Co-MCAAI]. Maximum infarct volume [MIV] was measured on the pre-operative CT. Functional outcome was measured by the modified Rankin Scale [mRS] dichotomized as favourable 0–3 and unfavourable ≥4, at three months. In 137 patients, from least favourable to favourable outcome were co-MCAAI, subtotal MCAAI, co-MCA and subtotal MCA infarction. Co-MCAAI had the worst outcome, 56/57 patients with additional infarction had mRS ≥ 4. Multiple comparisons Scheffe test showed no significant difference in MIV of subtotal infarction , co-MCA, Subtotal MCAAI but the outcome was significantly different. Multivariate analysis confirmed MCAAI [7.027 (2.56–19.28), p = 0.000] as the most significant predictor of poor outcomes whereas MIV was not significant [OR, 0.99 (0.99–01.00), p = 0.594]. Other significant independent predictors were age ≥ 55 years 12.14 (2.60–56.02), p = 0.001 and uncal herniation 4.98(1.53–16.19), p = 0.007]. Our data shows the contribution of CT infarction location in determining the functional outcome after DHC. Subgroups of patients undergoing DHC had different outcomes despite comparable infarction volumes.
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Abstract In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect stressed yet viable brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. Here, we hypothesized that neuronal activation might maintain or trigger the astrocyte-to-neuron lactate shuttle (ANLS), whereby lactate is released from astrocytes to support the energy requirements of ATP-starved hypoxic neurons, and this leads to the observed neuroprotection. We tested this by using a human cell based in vitro model of the ischemic penumbra and investigating whether lactate might be neuroprotective in this setting. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation. Furthermore, we showed that lactate exogenously administered before hypoxia correlated with neuroprotection in our cellular model. In addition, stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. To conclude, here we presented evidence that lactate transport into neurons contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.
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Early detection of infarction is important for early management to minimize the effects of infarctions on the patient. Hyperdense middle cerebral artery is an early sign for infarction. To determine the most accurate way and value for early detection of infarction using hyperdense MCA artery sign. 87 patients with suspected infarction underwent non enhanced CT brain, hyperdense MCA was subjectively determined, then maximum density was determined in the suspected affected side and contralateral side and ratio was made then, follow-up CT was done to detect MCA territory infarction. The HU range of the affected MCA ranged from 44 up to 58 HU (mean value 49.62 HU). The mean value of MCA ratio was 1.24–1.55. HU value >47 and MCA ratio >1.5 100% sensitivity is compared to subjective method that gives 56.3% only. The objective measurements of the MCA as regards HU value and MCA ratio had a sensitivity of 100%, and specificity 60%. Hyperdense middle cerebral artery sign is an accurate method for early detection of infarction.
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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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Premovement neuronal activity
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Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.
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Collateral circulation
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Prediction of the regions of the ischemic penumbra that are likely to progress to infarction is of great clinical interest. Whether lowered apparent diffusion coefficient (ADC) values were present in the ischemic penumbra of patients presenting with acute ischemic stroke and were specific to regions of the penumbra that proceeded to infarction was investigated.Nineteen patients with hemispheric stroke of less than 6 hours' onset and with acute scans showing a perfusion lesion greater than a diffusion lesion (ischemic penumbra) were studied. Scans also were performed subacutely (days 3 to 5) and at outcome (day 90). The outcome scan was used to identify regions of the penumbra that proceeded to infarction.The ADC ratios were significantly reduced (P <.00001) in regions of the penumbra that progressed to infarction on the outcome scan compared with those that remained normal. In regions that showed transition to infarction, the mean ADC ratios were typically 0.75 to 0.90.Intermediate ADC values are present in the ischemic penumbra and are indicative of tissue at risk of infarction.
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Objective To investigate the relationship between the expression of Fas mRNA and neuron apoptosis in adult rats following permanent middle cerebral artery occlusion. Methods The rats models of focal cerebral ischemia were established by permanent middle cerebral artery occlusion (MCA) and brain tissue were collected at different time.In situ RT PCR and in situ end labeling (TUNEL) methods were used to analyze the expression of Fas mRNA and neuron apoptosis in ipsilateral cerebral hemisphere respectively.Results The expression of Fas mRNA in penumbra began at 12h,peaked at 24h,decreased to lower level at 48h and 72h and returned to baselines at 120h.TUNEL positive cells were present at 72h and 120h.All TUNEL positive cells localized at penumbra.Conclusion Focal cerebral ischemia induced the expression of Fas mRNA.Fas gene may be the promoter for cell apoptosis following cerebral ischemia.
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