Acute Ischemic Insult Research Articles

Spontaneous coronary artery dissection: new insights into diagnosis and treatment.

Spontaneous coronary artery dissection (SCAD) remains an infrequent, elusive, and challenging clinical entity of unknown etiology eight decades after its initial description. Our understanding of the pathophysiology of SCAD, initially limited to information from early pathological studies, case reports, and very short series, has been enriched recently by relatively large contemporary series of patients studied prospectively. The typical presentation involves a young woman without coronary risk factors suffering an acute coronary syndrome but, actually, most patients are middle-aged and have coronary risk factors. A high number of conditions have been related to SCAD, but fibromuscular dysplasia has shown a major intriguing association with potential pathophysiological implications. SCAD may present (a) with an intimal tear and the classic angiographic 'flap' leading to the appearance of two lumens (true and false), or (b) without an intimal rupture, as an intramural hematoma. An increased clinical awareness together with new diagnostic tools have led to a major surge in the diagnosis of SCAD. High-resolution intracoronary techniques provide unique diagnostic insights into the underlying pathophysiology and facilitate identification of the disease in patients misdiagnosed previously. After the initial acute ischemic insult, most patients stabilize and have a benign clinical course and eventually experience spontaneous healing of the vessel wall during follow-up. However, recurrences may still occur in up to 10-20% of cases. Accordingly, a conservative medical management (watchful waiting strategy) has been recommended as the initial approach. Revascularization remains particularly challenging and may be associated with suboptimal results, acute complications, and poor long-term outcome. Nevertheless, in patients with ongoing or refractory ischemia and adequate anatomy, revascularization should be attempted. Some novel and attractive coronary interventions have been proposed in this uniquely challenging anatomic scenario. This review aims to present a comprehensive and contemporary update on this elusive and intriguing clinical entity.

Differential spread of anoxic depolarization contributes to the pattern of neuronal injury after oxygen and glucose deprivation (OGD) in the Substantia Nigra in rat brain slices

Anoxic depolarization (AD) is an acute event evoked by brain ischemia, involving a profound loss of cell membrane potential and swelling that spreads over susceptible parts of the gray matter. Its occurrence is a strong predictor of the severity of neuronal injury. Little is known about this event in the Substantia Nigra, a midbrain nucleus critical for motor control. We tested the effects of oxygen and glucose deprivation (OGD), an in vitro model of brain ischemia, in rat midbrain slices. AD developed within 4min from OGD onset and spread in the Substantia Nigra pars reticulata (SNr), but not through the Substantia Nigra pars compacta (SNc). This differential effect involved a contrasting pattern of changes in membrane potential between dopamine-producing SNc and non-dopaminergic SNr neurons. A fast depolarization in SNr neurons was not followed by repolarization after the end of OGD, and was associated with swollen somata and beaded dendrites. In contrast, slowly developing depolarization of SNc neurons led to repolarization after OGD ended, and no changes in neuronal morphology were observed. The AD-resistance of the SNc involved smaller dysregulations of K+ and Ca2+ ions, and a slower loss of energy metabolites. Our results show that acute ischemia profoundly impairs the function and morphology of SNr neurons but not adjacent SNc neurons, and that the surprising higher tolerance of SNc neurons correlates with the resistance of the SNc region to AD. This differential response may affect the pattern of early neuronal injury that develops in the brainstem after acute ischemic insults.

Ischemic Hand Complications From Intra-Arterial Injection of Sublingual Buprenorphine/Naloxone Among Patients With Opioid Dependency.

Sublingual buprenorphine/naloxone, a common treatment for opioid dependence, is frequently abused by intravenous injection. Inadvertent intra-arterial injection of buprenorphine/naloxone can produce acute ischemic insult to the hand due to gelatin embolism. Our purpose was to review a series of these patients in order to describe the clinical entity, review the outcomes, and propose a rational treatment algorithm. Clinical records of all patients evaluated by the hand surgery team between 2011 and 2015 for ischemia of the hand after buprenorphine/naloxone injection were reviewed. Treatment, complications, and amount of tissue loss were recorded. Patients presenting within 48 hours of the injection were treated with intravenous heparin for 5 days, followed by oral aspirin and clopidogrel for 30 days. Those presenting after 48 hours were treated with aspirin and clopidogrel only. Ten patients presented during the review period. Average follow-up time was 13 weeks. Eight had ischemia of the radial side of the hand, 1 of the ulnar side, and 1 had bilateral ischemia. Three patients were treated with intravenous heparin and 5 with oral agents. Two presented with dry gangrene and did not receive anticoagulation. All patients experienced tissue loss. There was no difference in outcome regardless of treatment. With the increasing use of sublingual buprenorphine/naloxone in opioid dependency, ischemic hand injuries will be seen with greater frequency. Whereas outcomes did not vary with treatment modality in this series, further study is needed to determine the most effective treatment of these injuries.

Association between Leukoaraiosis and Poor Outcome is not due to Reperfusion Inefficiency after Intravenous Thrombolysis.

Leukoaraiosis (LA) is associated with structural and functional cerebrovascular impairment, which may compromise the capacity of ischemic tissue to maximize reperfusion after intravenous thrombolysis (IVT). We aimed to determine whether severe LA is correlated with reperfusion inefficiency, which contributes to infarct growth and poor functional outcome. We analyzed data from our consecutive acute ischemic stroke (AIS) patients who had acquired baseline and 24-h follow-up diffusion- and perfusion-weighted imaging. Reperfusion was defined as reduction of ≥70% of hypoperfusion lesion at 24h from baseline. Severe LA was defined as Fazekas score 2 or 3 on FLAIR images. We investigated the relationship between severity of LA and reperfusion status. Multivariate statistical analysis was carried out for modeling the independent predictors of reperfusion, infarct growth, and functional outcome. Finally, 79 patients were included, among them 30 (37.97%) had severe LA. Reperfusion was observed in 41 (51.89%) patients, the proportion of reperfusion was very similar in patients with and without severe LA (53.33 vs 51.02%, p = 1.000). Large artery occlusion was the only independent unfavorable predictor for reperfusion (OR = 0.202, 95% confidence interval, 0.060-0.673; p = 0.014). Multiple linear regression analysis revealed that severe LA was independently associated with infarct growth (standardized coefficients = 0.191, p = 0.040). Severe LA was also an independent predictor of poor outcome (mRS ≥ 3) (OR = 4.004, 95% confidence interval, 1.267-12.656, p = 0.018) after adjusting for reperfusion and baseline severity of stroke. Severe LA was associated with infarct growth and poor outcome independent of reperfusion status, which may expand the notion that LA contributes the intrinsic vulnerability of brain tissue to acute ischemic insults. The burden of LA may not serve as an imaging indicator of reperfusion inefficiency after IVT for AIS patients.

High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke

Estrogens have previously been shown to protect the brain against acute ischemic insults, by potentially augmenting cerebrovascular function after ischemic stroke. The current study hypothesized that treatment with sustained release of high-dose 17β-estradiol (E2) at the time of reperfusion from middle cerebral artery occlusion (MCAO) in rats would attenuate reperfusion injury, augment post-stroke angiogenesis and cerebral blood flow, and attenuate lesion volume. Female Wistar rats underwent ovariectomy, followed two weeks later by transient, two-hour right MCAO (tMCAO) and treatment with E2 (n=13) or placebo (P; n=12) pellets starting at reperfusion. E2 treatment resulted in significantly smaller total lesion volume, smaller lesions within striatal and cortical brain regions, and less atrophy of the ipsilateral hemisphere after six weeks of recovery. E2-treated animals exhibited accelerated recovery of contralateral forelimb sensorimotor function in the cylinder test. Magnetic resonance imaging (MRI) showed that E2 treatment reduced the formation of lesion cysts, decreased lesion volume, and increased lesional cerebral blood flow (CBF). Ktrans, a measure of vascular permeability, was increased in the lesions. This finding, which represents lesion neovascularization, was not altered by E2 treatment. Ischemic stroke-related angiogenesis and vessel formation was confirmed with immunolabeling of brain tissue and was not altered with E2 treatment. In summary, E2 treatment administered immediately following reperfusion significantly reduced lesion size, cyst formation, and brain atrophy while improving lesional CBF and accelerating recovery of functional deficits in a rat model of ischemic stroke.

Xenon Blocks Neuronal Injury Associated with Decompression.

Despite state-of-the-art hyperbaric oxygen (HBO) treatment, about 30% of patients suffering neurologic decompression sickness (DCS) exhibit incomplete recovery. Since the mechanisms of neurologic DCS involve ischemic processes which result in excitotoxicity, it is likely that HBO in combination with an anti-excitotoxic treatment would improve the outcome in patients being treated for DCS. Therefore, in the present study, we investigated the effect of the noble gas xenon in an ex vivo model of neurologic DCS. Xenon has been shown to provide neuroprotection in multiple models of acute ischemic insults. Fast decompression compared to slow decompression induced an increase in lactate dehydrogenase (LDH), a well-known marker of sub-lethal cell injury. Post-decompression administration of xenon blocked the increase in LDH release induced by fast decompression. These data suggest that xenon could be an efficient additional treatment to HBO for the treatment of neurologic DCS.

Preconditioning effect of (S)-3,5-dihydroxyphenylglycine on ischemic injury in middle cerebral artery occluded Sprague–Dawley rats

Glutamate receptors are the integral cellular components associated with excitotoxicity mechanism induced by the ischemic cascade events. Therefore the glutamate receptors have become the major molecular targets of neuroprotective agents in stroke researches. Recent studies have demonstrated that a Group I metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) preconditioning elicits neuroprotection in the hippocampal slice cultures exposed to toxic level of N-methyl-d-aspartate (NMDA). We further investigated the preconditioning effects of (S)-3,5-DHPG on acute ischemic stroke rats. One 10 or 100μM of (S)-3,5-DHPG was administered intrathecally to Sprague–Dawley adult male rats, 2h prior to induction of acute ischemic stroke by middle cerebral artery occlusion (MCAO). After 24h, neurological deficits were evaluated by modified stroke severity scores and grid-walking test. All rats were sacrificed and infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining. The serum level of neuron-specific enolase (NSE) of each rat was analyzed by enzyme-linked immunosorbent assay (ELISA). One and 10μM of (S)-3,5-DHPG preconditioning in the stroke rats showed significant improvements in motor impairment (P<0.01), reduction in the infarct volume (P<0.01) and reduction in the NSE serum level (P<0.01) compared to the control stroke rats. We conclude that 1 and 10μM (S)-3,5-DHPG preconditioning induced protective effects against acute ischemic insult in vivo.

A novel method to establish a rat ED model using internal iliac artery ligation combined with hyperlipidemia.

ObjectiveTo investigate a novel method, namely using bilateral internal iliac artery ligation combined with a high-fat diet (BCH), for establishing a rat model of erectile dysfunction (ED) that, compared to classical approaches, more closely mimics the chronic pathophysiology of human ED after acute ischemic insult.Materials and MethodsForty 4-month-old male Sprague Dawley rats were randomly placed into five groups (n = 8 per group): normal control (NC), bilateral internal iliac artery ligation (BIIAL), high-fat diet (HFD), BCH, and mock surgery (MS). All rats were induced for 12 weeks. Copulatory behavior, intracavernosal pressure (ICP), ICP/mean arterial pressure, hematoxylin-eosin staining, Masson's trichrome staining, serum lipid levels, and endothelial and neuronal nitric oxide synthase immunohistochemical staining of the cavernous smooth muscle and endothelium were assessed. Data were analyzed by SAS 8.0 for Windows.ResultsSerum total cholesterol and triglyceride levels were significantly higher in the HFD and BCH groups than the NC and MS groups. High density lipoprotein levels were significantly lower in the HFD and BCH groups than the NC and MS groups. The ICP values and mount and intromission numbers were significantly lower in the BIIAL, HFD, and BCH groups than in the NC and MS groups. ICP was significantly lower in the BCH group than in the BIIAL and HFD groups. Cavernous smooth muscle and endothelial damage increased in the HFD and BCH groups. Cavernous smooth muscle to collagen ratio, nNOS and eNOS staining decreased significantly in the BIIAL, HFD, and BCH groups compared to the NC and MS groups.ConclusionsThe novel BCH model mimics the chronic pathophysiology of ED in humans and avoids the drawbacks of traditional ED models.

Myocardial Infarction and Functional Outcome Assessment in Pigs

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One important prerequisite is a good understanding of all safety and efficacy aspects obtained in a large animal model that validly reflect the human scenario of myocardial infarction (MI). Pigs are widely used in this regard since their cardiac size, hemodynamics, and coronary anatomy are close to that of humans. Here, we present an effective protocol for using the porcine MI model using a closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. This approach is based on 90 min of myocardial ischemia, inducing large left ventricle infarction of the anterior, septal and inferoseptal walls. Furthermore, we present protocols for various measures of outcome that provide a wide range of information on the heart, such as cardiac systolic and diastolic function, hemodynamics, coronary flow velocity, microvascular resistance, and infarct size. This protocol can be easily tailored to meet study specific requirements for the validation of novel cardioregenerative biologics at different stages (i.e. directly after the acute ischemic insult, in the subacute setting or even in the chronic MI once scar formation has been completed). This model therefore provides a useful translational tool to study MI, subsequent adverse remodeling, and the potential of novel cardioregenerative agents.

Myocardial infarction and functional outcome assessment in pigs.

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One important prerequisite is a good understanding of all safety and efficacy aspects obtained in a large animal model that validly reflect the human scenario of myocardial infarction (MI). Pigs are widely used in this regard since their cardiac size, hemodynamics, and coronary anatomy are close to that of humans. Here, we present an effective protocol for using the porcine MI model using a closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. This approach is based on 90 min of myocardial ischemia, inducing large left ventricle infarction of the anterior, septal and inferoseptal walls. Furthermore, we present protocols for various measures of outcome that provide a wide range of information on the heart, such as cardiac systolic and diastolic function, hemodynamics, coronary flow velocity, microvascular resistance, and infarct size. This protocol can be easily tailored to meet study specific requirements for the validation of novel cardioregenerative biologics at different stages (i.e. directly after the acute ischemic insult, in the subacute setting or even in the chronic MI once scar formation has been completed). This model therefore provides a useful translational tool to study MI, subsequent adverse remodeling, and the potential of novel cardioregenerative agents.

Role of MIF in myocardial ischaemia and infarction: insight from recent clinical and experimental findings

First discovered in 1966 as an inflammatory cytokine, MIF (macrophage migration inhibitory factor) has been extensively studied for its pivotal role in a variety of inflammatory diseases, including rheumatoid arthritis and atherosclerosis. Although initial studies over a decade ago reported increases in circulating MIF levels following acute MI (myocardial infarction), the dynamic changes in MIF and its pathophysiological significance following MI have been unknown until recently. In the present review, we summarize recent experimental and clinical studies examining the diverse functions of MIF across the spectrum of acute MI from brief ischaemia to post-infarct healing. Following an acute ischaemic insult, MIF is rapidly released from jeopardized cardiomyocytes, followed by a persistent MIF production and release from activated immune cells, resulting in a sustained increase in circulating levels of MIF. Recent studies have documented two distinct actions of MIF following acute MI. In the supra-acute phase of ischaemia, MIF mediates cardioprotection via several distinct mechanisms, including metabolic activation, apoptosis suppression and antioxidative stress. In prolonged myocardial ischaemia, however, MIF promotes inflammatory responses with largely detrimental effects on cardiac function and remodelling. The pro-inflammatory properties of MIF are complex and involve MIF derived from cardiac and immune cells contributing sequentially to the innate immune response evoked by MI. Emerging evidence on the role of MIF in myocardial ischaemia and infarction highlights a significant potential for the clinical use of MIF agonists or antagonists and as a unique cardiac biomarker.

Susceptibility to focal and global brain ischemia of Alzheimer mice displaying aβ deposits: effect of immunoglobulin.

Cerebral ischemia is a risk factor for Alzheimer's disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.

Role of the TLR4 pathway in blood-spinal cord barrier dysfunction during the bimodal stage after ischemia/reperfusion injury in rats

BackgroundSpinal cord ischemia-reperfusion (I/R) involves two-phase injury, including an initial acute ischemic insult and subsequent inflammatory reperfusion injury, resulting in blood-spinal cord barrier (BSCB) dysfunction involving the TLR4 pathway. However, the correlation between TLR4/MyD88-dependent and TLR4/TRIF-dependent pathways in BSCB dysfunction is not fully understood. The aim of this study is to characterize inflammatory responses in spinal cord I/R and the events that define its clinical progression with delayed neurological deficits, supporting a bimodal mechanism of injury.MethodsRats were intrathecally pretreated with TAK-242, MyD88 inhibitory peptide, or Resveratrol at a 12 h interval for 3 days before undergoing 14-minute occlusion of aortic arch. Evan’s Blue (EB) extravasation and water content were detected at 6, 12, 18, 24, 36, 48, and 72 h after reperfusion. EB extravasation, water content, and NF-κB activation were increased with time after reperfusion, suggesting a bimodal distribution, as maximal increasing were detected at both 12 and 48 h after reperfusion. The changes were directly proportional to TLR4 levels determined by Western blot. Double-labeled immunohistochemical analysis was also used to detect the relationship between different cell types of BSCB with TLR4. Furthermore, NF-κB and IL-1β were analyzed at 12 and 48 h to identify the correlation between MyD88-dependent and TRIF-dependent pathways.ResultsRats without functional TLR4 and MyD88 attenuated BSCB leakage and inflammatory responses at 12 h, suggesting the ischemic event was largely mediated by MyD88-dependent pathway. Similar protective effects observed in rats with depleted TLR4, MyD88, and TRIF receptor at 48 h infer that the ongoing inflammation which occurred in late phase was mainly initiated by TRIF-dependent pathway and such inflammatory response could be further amplified by MyD88-dependent pathway. Additionally, microglia appeared to play a major role in early phase of inflammation after I/R injury, while in late responding phase both microglia and astrocytes were necessary.ConclusionsThese findings indicate the relevance of TLR4/MyD88-dependent and TLR4/TRIF-dependent pathways in bimodal phases of inflammatory responses after I/R injury, corresponding with the clinical progression of injury and delayed onset of symptoms. The clinical usage of TLR4 signaling inhibitors at different phases may be a therapeutic option for the prevention of delayed injury.

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

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.

Impact of Carotid Atherosclerosis Combined with Hypercholesterolemia on Cerebral Microvessels and Brain Parenchyma in a New Complex Rat Model

Most previous investigations about stroke caused by carotid atherosclerosis have focused on thromboembolism. There is a lack of knowledge about pathophysiology of the brain before ischemic insults. The objective of this study was to develop a new model of hypercholesterolemia plus carotid injury and to investigate the impact of carotid atherosclerosis combined with hypercholesterolemia in the rat brain. The complex rat model was developed by carotid injury induced by an air-drying endothelial denudation method after high cholesterol diet for 2weeks. Plasma cholesterol, carotid pathomorphology, oxidative stress and inflammation in cerebral microvessels and brain parenchyma were measured at 7, 14 and 28days after carotid surgery. The results showed that plasma concentrations of total cholesterol and low density lipoprotein-cholesterol were significantly increased, and severe carotid atherosclerosis and stenosis was observed in the complex rat model at 14 and 28days after carotid surgery. The activity of superoxide dismutase was decreased, while the content of malondialdehyde was increased in cerebral microvessels and brain parenchyma. The levels of tumor necrosis factor-α and interleukin-1β were elevated in brain tissues of this model. Almost all above changes were more severe than those in either hypercholesterolemia alone group or carotid injury alone group. These results suggest that this complex rat model may more resemble human disease than the classic acute ischemic insult model for assessing the impact of carotid atherosclerosis as a preexisting disease on cerebral microcirculation and brain tissue.

Cardiac Troponin I A164H and pH-Dependent Inotropy

Ischemic heart disease is the most common cause of mortality in the world. To develop novel therapeutic strategies and gain mechanistic insight we are using time-resolved fluorescence measurements to detect structural changes within the cardiac troponin complex that occur during acute ischemic insult. During myocardial ischemia, penultimate to cell death, there is a shift from oxidative to glycolytic metabolism resulting in an acidification that severely impairs sarcomere function. In cardiac myocytes, this decrease in pH uncouples calcium homeostasis from force-generation. We and others have shown that the neonatal cardiac isoform of TnI, ssTnI, confers pH-insensitivity in this regard compared to the adult cTnI isoform. However ssTnI confers deleterious effects of impaired relaxation in the adult myocyte. Alignment and functional studies have demonstrated that this pH-insensitivity is derived from ssTnI residue H132. Introduction of a histidine at the cognate position in cTnI (A164H) mitigates the pH-sensitivity of the calcium-force relationship in cardiac myocytes while retaining relaxation enhancement via the N-term domain relative to ssTnI. We are establishing a time-resolved fluorescence methodology for detecting alterations in the calcium sensitivity of the thin filament during ischemia. We have engineered a single cysteine mutation for labeling with environmentally sensitive fluorophores designed to detect Ca2+ and pH-sensitive structural changes in cTnI and cTnC. We will discuss progress using this approach to interrogate troponin function in ischemia mimetic conditions.

Assessment of collateral flow in patients with cerebrovascular disorders

The ability to maintain cerebral parenchymal perfusion during states of acute or chronic ischemic insult depends largely on the capacity of the cerebral collateral circulation. Perfusion techniques, including perfusion-CT and arterial spin labeling, may not only describe the overall status of the collateral network, but can also quantify the pathophysiologic collateral reserve, which is occult to conventional imaging techniques. The following review details advanced imaging modalities capable of resolving pathophysiologic collateral circulation in a functional and dynamic manner, with regards to the evaluation of both acute ischemic penumbra and chronic cerebral vascular reserve. Specifically, the applications of perfusion-CT, arterial spin labeling MRI techniques, and transcranial Doppler are reviewed in the context of collateral circulation with emphasis on perfusion techniques and proposed clinical utility.

Fine-tuning Metabolic Switches

Fine-tuning Metabolic Switches

Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway

PurposeCarbon monoxide (CO) is an accepted cytoprotective molecule. The extent and mechanisms of protection in neuronal systems have not been well studied. We hypothesized that delivery of CO via a novel releasing molecule (CORM) would impart neuroprotection in vivo against ischemia-reperfusion injury (IRI)-induced apoptosis of retinal ganglion cells (RGC) and in vitro of neuronal SH-SY5Y-cells via activation of soluble guanylate-cyclase (sGC).MethodsTo mimic ischemic respiratory arrest, SH-SY5Y-cells were incubated with rotenone (100 nmol/L, 4 h) ± CORM ALF186 (10–100 µmol/L) or inactivated ALF186 lacking the potential of releasing CO. Apoptosis and reactive oxygen species (ROS) production were analyzed using flow-cytometry (Annexin V, mitochondrial membrane potential, CM-H2DCFDA) and Western blot (Caspase-3). The impact of ALF186± respiratory arrest on cell signaling was assessed by measuring expression of nitric oxide synthase (NOS) and soluble guanylate-cyclase (sGC) and by analyzing cellular cGMP levels. The effect of ALF186 (10 mg/kg iv) on retinal IRI in Sprague-Dawley rats was assessed by measuring densities of fluorogold-labeled RGC after IRI and by analysis of apoptosis-related genes in retinal tissue.ResultsALF186 but not inactivated ALF186 inhibited rotenone-induced apoptosis (Annexin V positive cells: 25±2% rotenone vs. 14±1% ALF186+rotenone, p<0.001; relative mitochondrial membrane potential: 17±4% rotenone vs. 55±3% ALF186+rotenone, p<0.05). ALF186 increased cellular cGMP levels (33±5 nmol/L vs. 23±3 nmol/L; p<0.05) and sGC expression. sGC-inhibition attenuated ALF186-mediated protection (relative mitochondrial membrane potential: 55±3% ALF186+rotenone vs. 20±1% ODQ+ALF186+rotenone, p<0.05). ALF186 protected RGC in vivo (IRI 1255±327 RGC/mm2 vs. ALF186+IRI 2036±83; p<0.05) while sGC inhibition abolished the protective effects of ALF186 (ALF186+IRI 2036±83 RGC/mm2 vs. NS-2028+ALF186+IRI 1263±170, p<0.05).ConclusionsThe CORM ALF186 inhibits IRI-induced neuronal cell death via activation of sGC and may be a useful treatment option for acute ischemic insults to the retina and the brain.

Symptomatic palatal tremor of cortical origin due to stroke

Palatal tremor (PT) is usually considered a movement disorder that presents with recurring rhythmic contractions of the soft palate. The inferior olive shows a characteristic pseudohypertrophy secondary to brainstem lesions in the triangle of Mollaret and Guillain that interrupt dentato-olivary and tegmental pathways. We report a 35-year-old man with a history of uncontrolled hypertension who presented to the emergency department with PT after a left middle cerebral artery ischemic stroke. The diagnostic work-up consisted of brain MRI, which revealed restricted diffusion over the left frontoparietal lobes without involvement of the brainstem. During hospitalization, the patient reported two brief episodes of soft palate and base-of-the-tongue high-frequency, low-amplitude and rhythmic tremor that resolved after intravenous administration of lorazepam. A 2-hour video electroencephalogram showed no abnormalities. After initiation of levetiracetam therapy, no further spells were reported by the patient. At the 2-month follow-up, the patient had had no episodes of stereotypical PT or upper limb tremors since discharge. This report provides further evidence of the central role of the cortex in the generation of PT. The cortical origin of symptomatic palatal tremor (SPT) should be considered in patients presenting after an acute ischemic insult, particularly if there is no evidence of a brainstem lesion. Potential causes of SPT of cortical origin include focal epilepsy and diaschisis.