Christopher Sy

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

Background and Purpose— Normobaric oxygenation (NBO) and ethanol both provide neuroprotection in stroke. We evaluated the enhanced neuroprotective effect of combining these 2 treatments in a rat stroke model. Methods— Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Reperfusion was then established and followed by treatment with either (1) an intraperitoneal injection of ethanol (1.0 g/kg), (2) NBO treatment (2-hour duration), or (3) NBO plus ethanol. The extent of brain injury was determined by infarct volume and motor performance. Oxidative metabolism was determined by ADP/ATP ratios, reactive oxygen species levels, nicotinamide adenine dinucleotide phosphate oxidase activity, and pyruvate dehydrogenase activity. Protein expression of major nicotinamide adenine dinucleotide phosphate oxidase subunits (p47phox, gp91phox, and p67phox) and the enzyme pyruvate dehydrogenase was evaluated through Western immunoblotting. Results— NBO and ethanol monotherapies each demonstrated reductions as compared to stroke without treatment in infarct volume (36.7% and 37.9% vs 48.4%) and neurological deficits (score of 6.4 and 6.5 vs 8.4); however, the greatest neuroprotection (18.8% of infarct volume and 4.4 neurological deficit) was found in animals treated with combination therapy. This neuroprotection was associated with the largest reductions in ADP/ATP ratios, reactive oxygen species levels, and nicotinamide adenine dinucleotide phosphate oxidase activity, and the largest increase in pyruvate dehydrogenase activity. Conclusions— Combination therapy with NBO and ethanol enhances the neuroprotective effect produced by each therapy alone. The mechanism behind this synergistic action is related to changes in cellular metabolism after ischemia reperfusion. NBO plus ethanol is attractive for clinical study because of its ease of use, tolerability, and tremendous neuroprotective potential in stroke.

Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps

Abstract Conclusions: Our results indicate that chronic rhinosinusitis without nasal polyps (CRSsNP) is characterized by the down-regulation of a Toll-like receptor (TLR)-mediated signaling pathway and such a deficiency within the innate immune system may contribute to the inflammatory process of CRSsNP. In contrast, the inflammatory process found in CRS with nasal polyps (CRSwNP) is characterized by an excessively activated TLR-mediated signaling pathway, which may contribute to the formation of nasal polyps. This study suggests that the pathophysiologic mechanism of CRSsNP and CRSwNP is different. Objective: The nasal mucosa expresses a variety of TLRs that serve in recognizing microorganisms. We investigated the gene expression of a TLR-mediated signaling pathway within two distinctive patient subgroups: CRSwNP and CRSsNP. Methods: Nasal mucosal tissue was obtained from 78 subjects with CRS and 23 control subjects. qRT-PCR and immunohistochemistry were used to investigate tissues for the expression of TLR2, TLR4, TLR7, their downstream signaling components, MyD88 and TRIF, and associated cytokines, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10. Results: TLR2, TLR4, TLR7, and IL-4 were significantly increased in CRSwNP patients when compared with either CRSsNP patients or control subjects, whereas TLR4 and TLR7, and downstream MyD88 were significantly decreased in CRSsNP patients versus patients from CRSwNP and control subjects.

Rodent models of ischemic stroke lack translational relevance... are baboon models the answer

Abstract Rodent models of ischemic stroke are associated with many issues and limitations, which greatly diminish the translational potential of these studies. Recent studies demonstrate that significant differences exist between rodent and human ischemic stroke. These differences include the physical characteristics of the stroke, as well as changes in the subsequent inflammatory and molecular pathways following the acute ischemic insult. Non-human primate (NHP) models of ischemic stroke, however, are much more similar to humans. In addition to evident anatomical similarities, the physiological responses that NHPs experience during ischemic stroke are much more applicable to the human condition and thus make it an attractive model for future research. The baboon ischemic stroke model, in particular, has been studied extensively in comparison to other NHP models. Here we discuss the major shortcomings associated with rodent ischemic stroke models and provide a comparative overview of baboon ischemic stroke models. Studies have shown that baboons, although more difficult to obtain and handle, are more representative of ischemic events in humans and may have greater translational potential that can offset these deficiencies. There remain critical issues within these baboon stroke studies that need to be addressed in future investigations. The most critical issue revolves around the size and the variability of baboon ischemic stroke. Compared to rodent models, however, issues such as these can be addressed in future studies. Importantly, baboon models avoid many drawbacks associated with rodent models including vascular variability and inconsistent inflammatory responses – issues that are inherent to the species and cannot be avoided.

Dynamic metabolic changes after permanent cerebral ischemia in rats with/without post-stroke exercise: a positron emission tomography (PET) study.

Abstract Objectives: Recent studies have suggested that rehabilitation therapy can accelerate functional recovery after a stroke. Although often overlooked, the cortical hemisphere contralateral to an infarction plays an important role. This study investigates alterations in metabolism of both the damaged (‘ipsilateral’) as well as the undamaged (‘contralateral’) hemisphere using 18F-fluorodeoxyglucose (FDG)-micro-positron emission tomography (PET) in a rat permanent stroke model (with or without post-injury exercise) in order to elucidate the relative importance of either hemisphere to the recovery process following stroke. Methods: Thirty-six adult, male Sprague-Dawley rats were divided into four groups before subsequent surgery: sham controls with or without exercise, and ischemic (‘stroke’) groups with or without exercise. Fluorodeoxyglucose micro-PET imaging was performed at 7, 14, and 21 days after the designated procedure according to group assignment. The imaging data was analyzed by ANOVA using SPMratIHEP software. Results: Both exercise and ischemia have measurable effects on the motor cortex as well as on the striatum, the effects of which notably include the contralateral hemisphere. To that end, regions of the contralateral motor cortex and striatum have been found to be in a hypermetabolic state following exercise. We further observed that exercise reversed the hypometabolism caused by ischemia back to control levels from day 7 through day 21 on the ipsilateral side. Its effect on the contralateral hemisphere, notably, bolsters an already vigorous response observed after ischemic insult. Thus, the beneficial effect of exercise, as inferred by an increase in metabolic activity, is evident in both hemispheres. Discussion: These findings suggest that the contralateral hemisphere can compensate for the damaged cortex by remodeling neuronal activity. Thus, clinical treatments specifically targeted to the ‘intact’ hemisphere following stroke may provide a complimentary strategy for promoting recovery of functional deficits and for improving quality of life in stroke patients.

Thrombolysis and reperfusion: advanced understanding of early management strategies in acute ischemic stroke

Abstract Currently, intravenous (IV) thrombolysis within 3 hours from stroke onset is the only approved treatment in acute ischemic stroke (AIS). Although effective, the definition of therapeutic time window and appropriate patient selection still remains controversial. Notably, early endovascular treatment strategies may serve as an adjunct therapy for time window extension in AIS. In this article, we review the safety and efficacy of IV thrombolysis in AIS as it pertains to the optimal time window, the selection of eligible patients, and in combination with endovascular treatment. Combined clinical application of IV thrombolysis and endovascular therapy may improve the therapeutic outcomes for AIS patients.

Reduced cerebral monocarboxylate transporters and lactate levels by ethanol and normobaric oxygen therapy in severe transient and permanent ischemic stroke.

OBJECTIVES Neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO) were previously demonstrated in transient and permanent ischemic stroke. Here we sought to identify whether the enhanced lactic acidosis and increased expression of monocarboxylate transporters (MCTs) observed after stroke might be attenuated by single and/or combined EtOH and NBO therapies. METHODS Sprague-Dawley rats (n=96) were subjected to right middle cerebral artery occlusion (MCAO) for 2 or 4h (transient ischemia), or 28 h (permanent ischemia) followed by 3, 24h, or no reperfusion. Rats received: (1) either an intraperitoneal injection of saline (sham treatment), one dose of EtOH (1.5 g/kg), two doses of EtOH (1.5 g/kg at 2h of MCAO, followed by 1.0 g/kg 2h after 1st dose), or (2) EtOH+95% NBO (at 2h of MCAO for 6h in permanent ischemia). Lactate levels were detected at 3 and 24h of reperfusion. Gene and protein expressions of MCT-1, -2, -4 were assessed by real-time PCR and western blotting. RESULTS A dose-dependent EtOH neuroprotection was found in transient ischemia. Following transient ischemia, a single dose of EtOH (in 2h-MCAO) or a double dose (in 4h-MCAO), significantly attenuated lactate levels, as well as the mRNAs and protein expressions of MCT-1, MCT-2, and MCT-4. However, while two doses of EtOH alone was ineffective in permanent stroke, the combined therapy (EtOH+95% NBO) resulted in a more significant attenuation in all the above levels and expressions. CONCLUSIONS Our study demonstrates that acute EtOH administration attenuated lactic acidosis in transient or permanent ischemic stroke. This EtOH-induced beneficial effect was potentiated by NBO therapy in permanent ischemia. Because both EtOH and NBO are readily available, inexpensive and easy to administer, their combination could be implemented in the clinics shortly after stroke.

Impact of regional white matter lesions on cognitive function in subcortical vascular cognitive impairment

Abstract Objectives: Exact characterization and localization of white matter lesions (WMLs) as they relate and contribute to vascular cognitive impairment is highly debated. The purpose of this study was to investigate the impact of WML on cognitive function by using a new anatomy-based classification method. Methods: We detected WML accurately by using a three-dimensional fluid-attenuated inversion recovery (3D FLAIR) imaging technique and subsequently segmented WMLs by using an anatomy-based method. Participants included 56 consecutive patients diagnosed with subcortical vascular cognitive impairment (SubVCI). The volume of WMLs in different anatomic regions was measured. The volume of the hippocampus, the corpus callosum (CC), any lacunar infarcts, total gray matter (GM), and total brain volumes were also calculated. Results: Hippocampal (P  =  0·005) as well as temporal WML volumes (P  =  0·039) were both independently associated with mini-mental state examination (MMSE) score. Only the parietal WML volume (P  =  0·000) was independently associated with Montreal Cognitive Assessment (MoCA) score. Frontal WMLs were independently correlated with executive function. Occipital WMLs were independently associated with visuospatial and recall function. Language impairment was independently correlated with both parietal GM and parietal WML volume. Functions related to orientation were independently associated with parietal WML volume. Discussion: The volume of WMLs in the temporal region as well as in the hippocampus were both independently associated with MMSE score. For the MoCA score, however, only parietal WML volumes were independently correlated. White matter lesions within different anatomic regions were separately correlated with different subdomains of cognitive function.

Animal Stroke Model: Ischemia–Reperfusion and Intracerebral Hemorrhage

Stroke is a major health issue worldwide-one with serious financial and public health implications. As a result, ongoing clinical research on novel and improved stroke therapies is not only pertinent but also paramount. Due to the complexity of a stroke-like event and its many sequelae, devising usable methods and experimental models are necessary to study and better understand the pathophysiological processes that ensue. As it stands, animal models that simulate stroke-like events have proven to be the most logical and effective options in regards to experimental studies. A number of animal stroke models exist and have been demonstrated in previous studies on ischemic as well as hemorrhagic stroke. Considering the efficiency and reproducibility of animal models, here, we introduce an ischemic stroke model induced by middle cerebral artery occlusion (MCAO) and an intracerebral hemorrhagic stroke model induced by collagenase injection. The models outlined here have been proven to demonstrate the clinical relevance desired for use in continued research on stroke pathophysiology and the study of future therapeutic options.