Ischemic Penumbra Zone Research Articles

Exosomes from Hypoxia-treated Mesenchymal Stem Cells: Promoting Neuroprotection in Ischemic Stroke Through miR-214-3p/PTEN Mechanism.

Stroke stands as the second leading cause of death globally, surpassed only by ischemic heart disease. It accounts for 9% of total worldwide deaths. Given the swiftly evolving landscape, medical professionals and researchers are devoting increased attention to identifying more effective and safer treatments. Recent years have witnessed a focus on exosomes derived from mesenchymal stem cells cultivated under hypoxic conditions, referred to as Hypo-Exo. These specialized exosomes contain an abundance of components that facilitate the restoration of ischemic tissue, surpassing the content found in normal exosomes. Despite advancements, the precise role of Hypo-Exo in cases of cerebral ischemia remains enigmatic. Therefore, this study was designed to shed light on the potential efficacy of Hypo-Exo in stroke treatment. Our investigations unveiled promising outcomes, as the administration of Hypo-Exo led to improved behavioral deficits and reduced infarct areas in mice affected by ischemic conditions. Notably, these positive effects were hindered when Hypo-Exo loaded with anti-miR-214-3p were introduced, implying that the neuroprotective attributes of Hypo-Exo are reliant on miR-214-3p. This conclusion was substantiated by the high levels of miR-214-3p detected within Hypo-Exo. Furthermore, our examination of the ischemic penumbra zone revealed a gradual and sustained escalation in PTEN expression, a phenomenon effectively countered by Hypo-Exo treatment. Collectively, our findings suggest the existence of a regulatory pathway centered on miR-214-3p within Hypo-Exo. This pathway exerts a downregulating influence on the PTEN/Akt signaling pathway, thereby contributing to the amelioration of neurological function subsequent to ischemia-reperfusion events.

Effect of different combinations of neuroprotectors on neurological deficit, motor and orientation-research activity, cognitive functions during experimental ischemic stroke

Annotation. Today, the maximum efforts of scientists are aimed at preserving the functional capacity and restoring neurons in the ischemic penumbra zone by developing new methods of neuroprotection, one of such approaches could be the combination of different neuroprotectors according to the mechanism of action. The purpose of the study is to study the effect of different combinations of neuroprotectors on neurological deficits, motor and orientation-research activity, and cognitive functions during experimental ischemic stroke. The study was conducted in the modelling of acute stroke according to the ischemic type on non-linear male rats by bilateral ligation of the internal carotid arteries. The four most effective combinations of neuroprotective complexes were selected as neuroprotective complexes (NPC) under investigation: cerebrolysin + mexidol; cerebrolysin + citicoline; cerebrolysin + edaravone; cerebrolysin + choline alfoscerate, which were previously discovered after screening the therapeutic effectiveness of various neuroprotectors and their combinations. Evaluation of the therapeutic effect of NPC was carried out on the 4th and 7th day of therapy. Neurological deficits were assessed using the McGraw Stroke Index. Locomotor and orientation-research activity was determined in the “open field” test. Cognitive functions were investigated in the extrapolation release test. The study of the cerebroprotective properties of four different combinations of neuroprotectors on an experimental model of an ischemic impression of the brain based on indicators of neurological deficit, locomotor and orientation-research activity, and cognitive functions made it possible to identify the most effective combinations and arrange them in order of decreasing effectiveness: NPC № 2 ≥ NPC №1 > NPC №4 ≥ NPC №3.

A systematic observation of vasodynamics from different segments along the cerebral vasculature in the penumbra zone of awake mice following cerebral ischemia and recanalization

Different segments of the cerebral vascular network may react distinctly to brain ischemia and recanalization. However, there are limited systematic observations of these vascular responses in mice under a physiological state following ischemic stroke. Herein, we aimed to investigate the vasodynamics among several segments along the cerebral vessels in awake mice following cerebral ischemia/recanalization via two-photon imaging. Plasma in the blood vessels were labelled with fluorescein isothiocyanate dextran. Smooth muscle cells and pericytes were labelled via a genetic mouse line (PDGFRβ-tdTomato). We observed a no-reflow phenomenon in downstream microcirculation, and the vasodynamics of different segments of larger cerebral vessels varied in the penumbra area following cerebral ischemia-reperfusion. Despite obtaining reperfusion from the middle cerebral artery, there were significant constrictions of the downstream blood vessels in the ischemic penumbra zone. Interestingly, we observed an extensive constriction of the capillaries 3 hours following recanalization, both at the site covered by pericyte soma and by the pericyte process alone. In addition, we did not observe a significant positive correlation between the changed capillary diameter and pericyte coverage along the capillary. Taken together, abnormal constrictions and vasodynamics of cerebral large and small vessels may directly contribute to microcirculation failure following recanalization in ischemic stroke.

A Review of MRI Acute Ischemic Stroke Lesion Segmentation

Immediate treatment of a stroke can minimize long-term effects and even help reduce death risk. In the ischemic stroke cases, there are two zones of injury which are ischemic core and ischemic penumbra zone. The ischemic penumbra indicates the part that is located around the infarct core that is at risk of developing a brain infarction. Recently, various segmentation methods of infarct lesion from the MRI input images were developed and these methods gave a high accuracy in the extraction and detection of the infarct core. However, only some limited works have been reported to isolate the penumbra tissues and infarct core separately. The challenges exist in ischemic core identification are traditional approach prone to error, time-consuming and tedious for medical expert which could delay the treatment. In this paper, we study and analyse the segmentation algorithms for brain MRI ischemic of different categories. The focus of the review is mainly on the segmentation algorithms of infarct core with penumbra and infarct core only. We highlight the advantages and limitations alongside the discussion of the capabilities of these segmentation algorithms and its key challenges. The paper also devised a generic structure for automated stroke lesion segmentation. The performance of these algorithms was investigated by comparing different parameters of the surveyed algorithms. In addition, a new structure of the segmentation process for segmentation of penumbra is proposed by considering the challenges remains. The best accuracy for segmentation of infarct core and penumbra tissues is 82.1% whereas 99.1% for segmentation infarct core only. Meanwhile, the shortest average computational time recorded was 3.42 seconds for segmenting 10 slices of MR images. This paper presents an inclusive analysis of the discussed papers based on different categories of the segmentation algorithm. The proposed structure is important to enable a more robust and accurate assessment in clinical practice. This could be an opportunity for the medical and engineering sector to work together in designing a complete end-to-end automatic framework in detecting stroke lesion and penumbra.

Contrast enhanced ultrasound imaging for assessment of spinal cord blood flow in experimental spinal cord injury.

Reduced spinal cord blood flow (SCBF) (i.e., ischemia) plays a key role in traumatic spinal cord injury (SCI) pathophysiology and is accordingly an important target for neuroprotective therapies. Although several techniques have been described to assess SCBF, they all have significant limitations. To overcome the latter, we propose the use of real-time contrast enhanced ultrasound imaging (CEU). Here we describe the application of this technique in a rat contusion model of SCI. A jugular catheter is first implanted for the repeated injection of contrast agent, a sodium chloride solution of sulphur hexafluoride encapsulated microbubbles. The spine is then stabilized with a custom-made 3D-frame and the spinal cord dura mater is exposed by a laminectomy at ThIX-ThXII. The ultrasound probe is then positioned at the posterior aspect of the dura mater (coated with ultrasound gel). To assess baseline SCBF, a single intravenous injection (400 µl) of contrast agent is applied to record its passage through the intact spinal cord microvasculature. A weight-drop device is subsequently used to generate a reproducible experimental contusion model of SCI. Contrast agent is re-injected 15 min following the injury to assess post-SCI SCBF changes. CEU allows for real time and in-vivo assessment of SCBF changes following SCI. In the uninjured animal, ultrasound imaging showed uneven blood flow along the intact spinal cord. Furthermore, 15 min post-SCI, there was critical ischemia at the level of the epicenter while SCBF remained preserved in the more remote intact areas. In the regions adjacent to the epicenter (both rostral and caudal), SCBF was significantly reduced. This corresponds to the previously described "ischemic penumbra zone". This tool is of major interest for assessing the effects of therapies aimed at limiting ischemia and the resulting tissue necrosis subsequent to SCI.

Use of Succinates for Correction of Metabolic Impairments in the Ischemic Penumbra Zone in Stroke Patients

The aim of the present work was to use MR spectroscopy to assess the quantitative contents and ratios of different metabolites in the infarct nucleus, ischemic penumbra, and unaltered tissue in the opposite hemisphere in patients in the acute period of ischemic stroke. A total of 72 patients were studied, of whom 37 (the study group) received the antioxidant Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) in addition to basal treatment, while 35 patients received only standard treatment without use of antioxidants. Stroke severity was assessed on the NIHSS scale and functional outcomes on day 30 were evaluated using the Bartel index and modified Rankin scale. MR proton spectroscopy was performed twice: during the first 24 h of disease onset and on day 5. Use of the succinate-containing antioxidant Mexidol (500 mg i.v. for 14 days) during the acute period of ischemic stroke significantly decreased the intracellular lactate (p = 0.002) and inositol contents (p = 0.005) from the levels in the control group, which helped restore the balance between the aerobic and anaerobic mechanisms of oxidation and had favorable influences on the rehabilitation potentials of the patients. A positive correlation was found between the lactate content in the ischemic penumbra zone and values on the NIHSS (r = 0.5786, p = 0.049), along with a negative correlation between the lactate content in the ischemic penumbra zone and the level of functional recovery assessed on the Bartel index (r = –0.6305, p = 0.028), which supports the existence of an interaction between impaired glucose metabolism in hypoxic conditions and the level of injury to nervous tissue.

Effect of norepinephrine on spinal cord blood flow and parenchymal hemorrhage size in acute-phase experimental spinal cord injury

In the acute phase of spinal cord injury (SCI), ischemia and parenchymal hemorrhage are believed to worsen the primary lesions induced by mechanical trauma. To minimize ischemia, keeping the mean arterial blood pressure above 85 mmHg for at least 1 week is recommended, and norepinephrine is frequently administered to achieve this goal. However, no experimental study has assessed the effect of norepinephrine on spinal cord blood flow (SCBF) and parenchymal hemorrhage size. We have assessed the effect of norepinephrine on SCBF and parenchymal hemorrhage size within the first hour after experimental SCI. A total of 38 animals were included in four groups according to whether SCI was induced and norepinephrine injected. SCI was induced at level Th10 by dropping a 10-g weight from a height of 10 cm. Each experiment lasted 60 min. Norepinephrine was started 15 min after the trauma. SCBF was measured in the ischemic penumbra zone surrounding the trauma epicenter using contrast-enhanced ultrasonography. Hemorrhage size was measured repeatedly on parasagittal B-mode ultrasonography slices. SCI was associated with significant decreases in SCBF (P = 0.0002). Norepinephrine infusion did not significantly modify SCBF. Parenchymal hemorrhage size was significantly greater in the animals given norepinephrine (P = 0.0002). In the rat, after a severe SCI at the Th10 level, injection of norepinephrine 15 min after SCI does not modify SCBF and increases the size of the parenchymal hemorrhage.

Neurophysiological testing in neurocritical care

To summarize a consensus of European authorities about the applications of clinical neurophysiology in the ICU and, particularly, for a clinically useful management of individual patients. Clinical neurophysiology is useful for diagnosis (epilepsy, brain death, and neuromuscular disorders), prognosis (anoxic ischemic encephalopathy, head trauma, and neurological disturbances of metabolic and toxic origin), and follow-up. The prognostic significance of each test varies as a function of coma etiology. A distinction should be made between tests whose abnormalities are indicative of a poor prognosis (bilateral absence of N20 in anoxic coma, abnormalities suggesting pontine involvement in head trauma) and those whose relative normalcy constitutes an argument for a good prognosis (integrity of brainstem conductions in head trauma, presence of cognitive evoked potentials - mismatch negativity, P300 - irrespective of coma etiology).The highlights of the recent literature mainly concern continuous neuromonitoring for early detection of nonconvulsive seizures, both in adult and neonatal ICU, brain entry into the ischemic penumbra zone, and neuronal functional consequences of intracranial hypertension. The domain of clinical neurophysiology is similar to that of clinical examination and complementary to that of imaging techniques. It substantially improves the individual management of ICU patients.

Farmacología de la neuroprotección en el ictus isquémico agudo

Stroke leads the list of causes of disability in adults and represents the second leading cause of death worldwide. Knowledge about the pathophysiology of ischemic stroke has improved substantially over the past 25 years, and, as a result of this, new therapeutic strategies have been developed with two main aims: restoration of cerebral flow and the minimization of the deleterious effects of ischemia on neurons. Although so far there are no drugs approved for the neuroprotection therapy in stroke, there are some compounds with promising results. This paper makes a critical review of several studies on the preclinical stroke neuroprotection with drugs aimed to protect the brain tissue adjacent to the damaged central area or ischemic penumbra zone until either the physiological mechanisms or the treatment stop the ischemic insult. We expose the potential neuroprotective properties of these treatments mainly based on inhibiting excitotoxicity processes mediated by gamma-aminobutyric acid receptors, glutamate release and interacting with ion channels such as calcium and sodium. We focus on drugs which have shown to be capable of modulating intracellular degenerative pathways in mitochondria mediated apoptosis or the expression of apoptotic proteins in experimental models. It is very likely that the neuroprotective effects require a poly-drug therapy that combines different mechanisms of action.

Neuroprotective effect of tacrolimus (FK506) on ischemic brain damage following permanent focal cerebral ischemia in the rat

We investigated the neuroprotective effect of tacrolimus (FK506) on the ischemic cell death with respect to cytochrome c translocation and DNA fragmentation, which are pivotal events in the necrotic and apoptotic signaling pathway, using permanent focal cerebral ischemia in rats. Immunohistochemically, cytochrome c was observed in the cytoplasm as early as 1 h after middle cerebral artery (MCA) occlusion in the infarcted hemisphere. Cytosolic release of cytochrome c after MCA occlusion was also confirmed by Western blot analysis and enzyme immunoassay. Terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) showed DNA fragmentation evolving in the ipsilateral cortex and the caudate putamen after 3 and 6 h, respectively, following MCA occlusion. Tacrolimus (1 mg/kg, i.v.), administered immediately after MCA occlusion, significantly attenuated the release of cytochrome c in the ischemic region, the number of TUNEL-positive cells in the ischemic penumbra zone, and the size of cortical ischemic lesions. This study demonstrated that tacrolimus ameliorated the accumulation of cytochrome c in the cytosol and the increase of TUNEL-positive cells induced by cerebral ischemia, indicating that the neuroprotective action of tacrolimus on ischemic brain injury caused by permanent focal cerebral ischemia could partially be attributed to the attenuation of the activation of the apoptotic execution machinery.

The Effects of Dexamethasone and MK-801 on Edema Formation in Middle Cerebral Artery Occlusion Model of the Rat

Background: This study was conducted to determine the effects of dexamethasone and MK-801 on the formation of brain edema resulting from a focal ischemic injury by middle cerebral artery occlusion in rats. Methods : Fifteen Sprague-Dawley rats (220 280 g) were freely allowed to drink and eat until just before surgery. Anesthesia was induced with 4% isoflurane in oxygen and then maintained with 2% isoflurane in oxygen. Ischemic injury was induced by an intraluminal suture with a blunted tip inserted into the internal carotid artery and occlusion of the middle cerebral artery. All rats were divided randomly into three groups. In group I (n = 5), normal saline 1 ml was injected intravenously 10 minutes before MCA occlusion. In group II (n = 5), dexamethasone 3 mg/kg was administered 10 minutes before injury. In group III (n = 5), a N-methyl-D-aspartate receptor antagonist, MK-801 1 mg/kg was injected 30 minutes before injury. Rectal temperatures were monitored during the experiment. After 60 minutes of MCA occlusion, the intraluminal sutures were removed and all the rats were returned to their cages. Their brain were quickly removed and the cerebral hemispheres were sepaerated into ischemic cores and penumbra zones after 1 hour of reperfusion. The separated cerebral hemispheres were dried 7 days at 60oC dry oven. The cerebral water content was assessed by the dry-weight method. Results: In the dexamethasone group, there were no significant changes in cerebral edema formation in both ischemic core and the penumbra. In the MK-801 group, there were significant reductions in the brain edema formation in the penumbra (P＜ 0.05), but not in the core. Conclusions : Dexamethasone has no effect on ischemic brain edema; however, MK-801 is effective in the ischemic penumbra zone by reducing of edema formation. (Korean J Anesthesiol 1999; 37: 327∼333)

Clinical Monitoring of Early Pathophysiologic Events

Stroke is the most prevalent life-threatening neurologic disease. The opportunity to intervene in the acute setting with the use of thrombolytics or neuroprotective agents has led to an evolving interest in obtaining physiologic data points during the acute event. Several imaging techniques are available that can provide pertinent information during the acute phase of an ischemic episode. Some of these techniques, such as diffusion-weighted and perfusion-weighted MR imaging, show exciting promise for defining the ischemic penumbra zone, which is the target of acute intervention.