Brain Ischemic Insult Research Articles

Impact of site, size and severity of ischemic cerebrovascular stroke on sleep in a sample of Egyptian patients a polysomnographic study

BackgroundSleep difficulties following a cerebrovascular stroke are an interesting topic in the scientific community. Following a brain ischemic insult, a variety of sleep problems can occur.Aim of workTo study the sleep architecture following stroke and to identify the impact of site, size and severity of ischemic cerebrovascular troke on sleep microstructure.Subjects and methodsthis was a case control study; polysomnogram was done for 93 patients admitted to the stroke unit at El- Hadara university hospital with the first ever ischemic stroke. NIHSS was calculated immediately and 1 month after stroke onset. 50 age matched control subjects with no evidence of central nervous system or major psychiatric disorder by history or clinical examination.ResultsTotal sleep time, sleep efficiency were lower in ischemic cerebrovascular stroke patients than in control group and this was statistically significant (p = .001* p = .0001* respectively). Arousal index limb movement index and snoring index were all higher among the ischemic cerebrovascular stroke group in comparison to the control group and this was statistically significant (p = .0001*p = .05*p = .0001). Both the REM(rapid eye movement) and REM latency were highest among brain stem stroke, and this was statistically significant p = .043*, p = .0.001*.cortical infarcts showed higher AHI (apnea hypopnea index)and this was statistically significant p = 0.002* Limb movement index was higher among sizable size stroke and this was statistically significant (p = 0.038). NIHSS National Institutes of Health Stroke Scale after 1 month follow up showed a significant indirect correlation with the lowest oxygen saturation during sleep (p = 0.047). Lowest oxygen saturation was lowest among sizable stokes and desaturation index was highest among sizable size strokes both were statistically significant p = 0.006. NIHSS2 had a significant negative correlation with the lowest oxygen saturation during sleep p = 0.047.ConclusionThe microstructure of sleep is significantly impacted by cerebrovascular stroke. Brain stem strokes had the highest REM and REM latency, while cortical strokes had the highest moderate-to-severe AHI. Sizable strokes displayed increased indices of limb movement, desaturation, and oxygen saturation.

302 Super Mitochondria, the Next Super Therapy to Reverse Ischemic Damage in Stroke?

INTRODUCTION: Stroke represents a massive healthcare emergency, ranking in the top 5 causes of death and disability and impacting nearly 800,000 Americans annually. Current therapies are limited. A deeper analysis of the mechanisms of cell death after ischemic brain insult may usher novel safe and effective treatments. Mitochondrial damage serves as a key modulator of ischemic cell death, which may be reversible with transfer of healthy mitochondria from mesenchymal stem cells (MSCs) to ischemic neurons. METHODS: MSCs were grown under ambient condition (normal MSCs) (nMSCs) or metabolic switching paradigm involving exchanging galactose for glucose in the cell culture medium (switched MSCs) (sMSCs) then assayed for oxygen consumption rates using the Seahorse technology. Subsequently, primary neurons were subjected to OGD then co-cultured with either nMSCs or sMSCs, and assessed for cell viability, cell metabolism, mitochondrial reactive oxidative species mRNA, and mitochondrial ATP mRNA. RESULTS: Compared to nMSCs, sMSCs displayed robust mitochondrial respiration as evidenced by higher basal energy production, larger spare respiratory capacity, greater ATP production, and decreased proton (H+) leak. Co-culture of OGD-exposed neurons with sMSCs conferred increased cell viability and enhanced cell metabolism, coupled with reduced mitochondrial reactive oxidative species mRNA and elevated mitochondrial ATP mRNA, which were significantly better than those afforded by nMSCs. CONCLUSIONS: These findings suggest sMSCs generated “super” mitochondria. Metabolic switching produces healthy mitochondria that may enhance the mitochondrial transfer between MSCs and ischemic cells warranting consideration as a stroke therapeutic.

Propofol ameliorates ischemic brain injury by blocking TLR4 pathway in mice.

Ischemic brain injury is one of the most serious perioperative complications. However, effective preventative methods have not yet been established. This study aimed to investigate whether propofol has neuroprotective effects against ischemic brain injury, with a specific focus on Toll-like receptor 4 (TLR4). Focal brain ischemia was induced via a combination of left common carotid artery occlusion and distal left middle cerebral artery coagulation in mice. Either propofol (10 mg/kg) or vehicle was intravenously injected 10 min prior to the induction of brain ischemia in wild-type and TLR4 knockout mice. Infarct volume, pro-inflammatory cytokine expression, inflammatory cell infiltration, and neurobehavioral function were assessed. Propofol administration significantly reduced infarct volume in wild-type mice (26.9 ± 2.7 vs 15.7 ± 2.0 mm3 at day 7), but not in TLR4 knockout mice. Compared with the control mice, the propofol-treated wild-type mice exhibited lower levels of IL-6 (0.57 ± 0.23 vs 1.00 ± 0.39 at 24 h), and smaller numbers of TLR4-expressing microglia in the penumbra (11.7 ± 3.1 vs 25.1 ± 4.7 cells/0.1 mm2). In conclusion, propofol administration prior to ischemic brain insult attenuated brain injury by blocking the TLR4-dependent pathway and suppressing pro-inflammatory cytokine production.

Decreased Expression of CIRP Induced by Therapeutic Hypothermia Correlates with Reduced Early Brain Injury after Subarachnoid Hemorrhage.

Early brain injury is considered to be a primary reason for the poor prognosis of patients suffering from subarachnoid hemorrhage (SAH). Due to its pro-inflammatory activity, cold-inducible RNA-binding protein (CIRP) has been implicated in the ischemic brain insult, but its possible interplay with hypothermia in SAH treatment remains to be evaluated. One-hundred and thirty-eight Sprague-Dawley rats (300–350 g males) were randomly allocated into the following groups: sham-operated (Sham); SAH; and SAH + hypothermia (SAH + H), each comprised of 46 animals. After treatments, the brain tissues of the three groups were randomly collected after 12 h, 1 d, 3 d, and 7 d, and the expression levels of the CIRP and mitochondrial apoptosis pathway-related proteins Bax, Bcl-2, caspase-9, caspase-3, and cytochrome c measured using Western blotting and real-time PCR. Brain damage was assessed by TUNEL and Nissl staining, the electron microscopy of brain tissue slices as well as functional rotarod tests. Expression of CIRP, Bax, caspase-9, caspase-3, and cytochrome c as well as reduced motor function incidence were higher in the SAH group, particularly during the first 3 d after SAH induction. Hypothermia blunted these SAH responses and apoptosis, thereby indicating reduced inflammatory signaling and less brain cell injury in the early period after SAH. Hypothermia treatment was found to effectively protect the brain tissue from early SAH injury in a rat model and its further evaluation as a therapeutic modality in SAH patients requires further study.

Osteopontin mediates the formation of corpora amylacea-like structures from degenerating neurons in the CA1 region of the rat hippocampus after ischemia.

We previously demonstrated that osteopontin (OPN) is closely associated with calcium precipitation in response to ischemic brain insults. The present study was designed to elucidate the possible association between deposition of OPN and progressive neurodegeneration in the ischemic hippocampus. To address this, we analyzed the OPN deposits in the rat hippocampus after global cerebral ischemia in the chronic phase (4 to 12weeks) after reperfusion using immunoelectron microscopy and correlative light and electron microscopy. We identified three different types of OPN deposits based on their morphological characteristics, numbered according to the order in which they evolved. Dark degenerative cells that retained cellular morphology were frequently observed in the pyramidal cell layer, and type I OPN deposits were degenerative mitochondria that accumulated among these cells. Type II deposits evolved into more complex amorphous structures with prominent OPN deposits within their periphery and within degenerative mitochondria-like structures. Finally, type III had large concentric laminated structures with irregularly shaped bodies in the center of the deposits. In all types, OPN expression was closely correlated with calcification, as confirmed by calcium fixation and Alizarin Red staining. Notably, type II and III deposits were highly reminiscent of corpora amylacea, glycoprotein-rich aggregates found in aged brains, or neurodegenerative disease, which was further confirmed by ubiquitin expression and periodic acid-Schiff staining. Overall, our data provide a novel link between ongoing neurodegeneration and the formation of corpora amylacea-like structures and calcium deposits in the ischemic hippocampus, suggesting that OPN may play an important role in such processes.

Proteasome and Neuroprotective Effect of Hyperbaric Oxygen Preconditioning in Experimental Global Cerebral Ischemia in Rats

ObjectivesWe investigated the involvement of the proteasome in the mechanism of preconditioning with hyperbaric oxygen (HBO-PC).MethodsThe experiments were performed on male Wistar rats subjected to a transient global cerebral ischemia of 5 min duration (2-vessel occlusion model) and preconditioned or not with HBO for 5 preceding days (1 h HBO at 2.5 atmosphere absolute [ATA] daily). In subgroups of preconditioned rats, the proteasome inhibitor MG132 was administered 30 min prior to each preconditioning session. Twenty-four hours and 7 days post-ischemia, after neurobehavioral assessment, the brains were collected and evaluated for morphological changes and quantitative immunohistochemistry of cell markers and apoptosis-related proteins.ResultsWe observed reduced damage of CA1 pyramidal cells in the HBO preconditioned group only at 7 days post-ischemia. However, both at early (24 h) and later (7 days) time points, HBO-PC enhanced the tissue expression of 20S core particle of the proteasome and of the nestin, diminished astroglial reactivity, and reduced p53, rabbit anti-p53 upregulated modulator of apoptosis (PUMA), and rabbit anti-B cell lymphoma-2 interacting mediator of cell death (Bim) expressions in the hippocampus and cerebral cortex. HBO-PC also improved T-maze performance at 7 days. Proteasome inhibitor abolished the beneficial effects of HBO-PC on post-ischemic neuronal injury and functional impairment and reduced the ischemic alterations in the expression of investigated proteins.SignificancePreconditioning with hyperbaric oxygen-induced brain protection against severe ischemic brain insult appears to involve the proteasome, which can be linked to a depletion of apoptotic proteins and improved regenerative potential.

Mood disorders in children following neonatal hypoxic-ischemic encephalopathy

Few studies on the consequences following newborn hypoxic-ischemic encephalopathy (NHIE) assess the risk of mood disorders (MD), although these are prevalent after ischemic brain injury in adults. To study the presence of MD in children survivors of NHIE. 14 children survivors of NHIE treated with hypothermia and without cerebral palsy and 15 healthy children without perinatal complications were studied aged three to six years for developmental status (Ages and Stages Questionnaire 3 [ASQ-3]) and for socio-emotional status (Preschool Symptom Self-Report [PRESS] and Child Behavior Checklist [CBCL] 1.5-5 tests). Maternal depression was assessed using Montgomery-Asberg Depression Rating Scale (MADRS). Socio-economic factors such as parental educational level or monthly income were also studied. NHIE children did not present delay but scored worse than healthy children for all ASQ3 items. NHIE children showed higher scores than healthy children for PRESS as well as for anxious/depressive symptoms and aggressive behavior items of CBCL. In addition, in three NHIE children the CBCL anxious/depressive symptoms item score exceeded the cutoff value for frank pathology (P = 0.04 vs healthy children). There were no differences in the other CBCL items as well as in maternal MADRS or parental educational level or monthly income. Neither ASQ3 scores nor MADRS score or socio-economic factors correlated with PRESS or CBCL scores. In this exploratory study children survivors of NHIE showed increased risk of developing mood disturbances, in accordance with that reported for adults after brain ischemic insults. Considering the potential consequences, such a possibility warrants further research.

Detection of opioid effect with pupillometry.

Opioids produce pupillary constriction but their impact on pupillary unrest and the dynamic parameters of the pupillary light reflex have not been characterized. Given the increasing use of portable pupillometers for care of critically ill patients, it is important to distinguish between opioid effects on the pupil versus those that have been reported to arise from traumatic and ischemic brain insults. We undertook this study to determine which pupillary responses are most profoundly and consistently affected by a progressive infusion of remifentanil. We studied the effect of remifentanil on the pupil using two portable infrared pupillometers in 18 volunteers. One pupillometer measured pupillary unrest in ambient light (PUAL) and the other pupillometer measured neurological pupillary index (NPi), constriction velocity (CV), pupil diameter (PD), latency, and % reflex (% reflex) following a transient light flash. Remifentanil was administered at predetermined weight-adjusted rates to raise opioid effect site concentration up to a range known to produce respiratory depression and oxyhemoglobin desaturation, based on a previously published pharmacokinetic model. PUAL was ablated by remifentanil, declining 94±6% from baseline at the time of maximum drug effect. Other pupillary measurements decreased 50-65% from baseline. NPi was unchanged. At the time of oxyhemoglobin desaturation, deviations in PD, CV, and % reflex were widely scattered, whereas PUAL consistently approached zero. PUAL is a highly specific indicator of central opioid effect. As a non-invasive measure, it may provide useful data to clinicians who prescribe opioids.

Potential role of susceptibility-weighted imaging in the diagnosis of non-neoplastic pediatric neurological diseases

BackgroundThis study aimed to assess the added value and current applications of SWI in the diagnosis of pediatric non-neoplastic neurological diseases, including its ability to characterize hemorrhage in various brain lesions and its important role in the evaluation of both arterial as well as venous ischemic brain lesions.ResultsForty pediatric patients with a median age of 9 years were included in our prospective study; 23 were males and 17 females. SWI had a significantly higher detection rate than conventional MRI for traumatic brain injury (TBI) lesions, hemorrhagic lesions in acute necrotizing encephalopathy (ANEC), and cavernoma lesions (p = 0.005, p = 0.038, and p = 0.046, respectively). The sensitivity, specificity and accuracy of SWI for the detection of venous ischemic insult was 88.9%, 50%, and 76.9% respectively. SWI was significantly better than the conventional MRI (p = 0.046) for the detection of chronic ischemic brain insults and ischemic lesions with added hemorrhagic components.ConclusionSWI is a technique with reasonable acquisition time that could improve the diagnostic performance of MRI for the evaluation of various pediatric non-neoplastic neurological diseases.

Changes in Cyclin D1, cdk4, and Their Associated Molecules in Ischemic Pyramidal Neurons in Gerbil Hippocampus after Transient Ischemia and Neuroprotective Effects of Ischemic Preconditioning by Keeping the Molecules in the Ischemic Neurons.

Simple SummaryCyclin D1 and cyclin-dependent kinase 4 (cdk4) is implicated in neuronal death induced by various pathological conditions. Ischemic preconditioning (IPC) confers neuroprotective effect, but underlying mechanisms have been poorly addressed. In this study, IPC protected pyramidal neurons (cells) in gerbil hippocampus after transient ischemia. Additionally, IPC controlled expressions of cyclin D1, cdk4, phosphorylated retinoblastoma (p-Rb), and E2 promoter binding factor 1 (E2F1). In particular, the expression of p16INK4a was not different by IPC. These findings indicate that cyclin D1/cdk4-related signals may play important roles in events in neurons related to damage/death following ischemic insults. Especially, the preservation of p16INK4a by IPC may be crucial in attenuating neuronal death/damage or protecting neurons after brain ischemic insults.Inadequate activation of cell cycle proteins including cyclin D1 and cdk4 is involved in neuronal cell death induced by diverse pathological stresses, including transient global brain ischemia. The neuroprotective effect of ischemic preconditioning is well-established, but the underlying mechanism is still unknown. In this study, we examined changes in cyclin D1, cdk4, and related molecules in cells or neurons located in Cornu Ammonis 1 (CA1) of gerbil hippocampus after transient ischemia for 5 min (ischemia and reperfusion) and investigated the effects of IPC on these molecules after ischemia. Four groups were used in this study as follows: sham group, ischemia group, IPC plus (+) sham group, and IPC+ischemia group. IPC was developed by inducing 2-min ischemia at 24 h before 5-min ischemia (real ischemia). Most pyramidal cells located in CA1 of the ischemia group died five days after ischemia. CA1 pyramidal cells in the IPC+ischemia group were protected. In the ischemia group, the expressions of cyclin D1, cdk4, phosphorylated retinoblastoma (p-Rb), and E2F1 (a transcription factor regulated by p-Rb) were significantly altered in the pyramidal cells with time after ischemia; in the IPC+ischemia group, they were controlled at the level shown in the sham group. In particular, the expression of p16INK4a (an endogenous cdk inhibitor) in the ischemia group was reversely altered in the pyramidal cells; in the IPC+TI group, the expression of p16INK4a was not different from that shown in the sham group. Our current results indicate that cyclin D1/cdk4-related signals may have important roles in events in neurons related to damage/death following ischemia and reperfusion. In particular, the preservation of p16INK4a by IPC may be crucial in attenuating neuronal death/damage or protecting neurons after brain ischemic insults.

Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult.

Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca2+ ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmed in vitro, on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, and in vivo, in ischemic mice. Early lead 3b, showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice.

Ischemia-Reperfusion under Hyperthermia Increases Heme Oxygenase-1 in Pyramidal Neurons and Astrocytes with Accelerating Neuronal Loss in Gerbil Hippocampus.

It has been studied that the damage or death of neurons in the hippocampus is different according to hippocampal subregions, cornu ammonis 1–3 (CA1–3), after transient ischemia in the forebrain, showing that pyramidal neurons located in the subfield CA1 (CA1) are most vulnerable to this ischemia. Hyperthermia is a proven risk factor for brain ischemia and can develop more severe and extensive brain damage related with mortality rate. It is well known that heme oxygenase-1 (HO-1) activity and expression is increased by various stimuli in the brain, including hyperthermia. HO-1 can be either protective or deleterious in the central nervous system, and its roles depend on the expression levels of enzymes. In this study, we investigated the effects of hyperthermia during ischemia on HO-1 expression and neuronal damage/death in the hippocampus to examine the relationship between HO-1 and neuronal damage/death following 5-min transient ischemia in the forebrain using gerbils. Gerbils were assigned to four groups: (1) sham-operated gerbils with normothermia (Normo + sham group); (2) ischemia-operated gerbils with normothermia (Normo + ischemia group); (3) sham-operated gerbils with hyperthermia (39.5 ± 0.2 °C) during ischemia (Hyper + sham group); and (4) ischemia-operated gerbils with hyperthermia during ischemia (Hyper + ischemia group). HO-1 expression levels in CA1–3 of the Hyper + ischemia group were significantly higher than those in the Normo + ischemia group. HO-1 immunoreactivity in the Hyper + ischemia group was significantly increased in pyramidal neurons and astrocytes with time after ischemia, and the immunoreactivity was significantly higher than that in the Normo + ischemia group. In the Normo + Ischemia group, neuronal death was shown in pyramidal neurons located only in CA1 at 5 days after ischemia. However, in the Hyper + ischemia group, pyramidal neuronal death occurred in CA1–3 at 2 days after ischemia. Taken together, our findings showed that brain ischemic insult during hyperthermic condition brings up earlier and severer neuronal damage/death in the hippocampus, showing that HO-1 expression in neurons and astrocytes is different according to brain subregions and temperature condition. Based on these findings, we suggest that hyperthermia in patients with ischemic stroke must be taken into the consideration in the therapy.

Physiological and Biochemical Changes in NRF2 Pathway in Aged Animals Subjected to Brain Injury.

Oxidative stress plays a key role in aging, which in turn represents a substantial risk factor for brain injuries. The aim of the present study was to investigate the differences in physiological and biochemical changes in the brain during injury-related inflammation and oxidative stress, comparing young and old mice. Young and old mice were subjected to focal cerebral ischemia induced by transient middle cerebral artery occlusion or to traumatic brain injury performed by a controlled cortical impactor. At the end of both experiments, mice were sacrificed 24h after injuries and brains were collected to perform biochemical analysis. In both ischemic stroke and traumatic brain injury, aging has not only led to damage-induced worsening of motor function and behavioural changes but also increased of infarct area compared to young animals. Moreover, aged mice show increased evidence of oxidative stress and reduced antioxidant capacity when compared to younger animals, as demonstrated by Nrf2-Keap1 signalling pathway and lower expression of antioxidant enzymes, such as HO-1, SOD-1 and GSH-Px. Additionally, brain tissues collected from elderly mice showed an increased IκB-α degradation into the cytoplasm and consequently NF-κB translocation into the nucleus, compared to young mice subjected to same injuries. The elderly mice showed significantly higher levels of iNOS and CoX-2 expression than the young mice, as well as higher levels of inflammatory cytokines such as TNFα, IL-1β, and IL-6 after MCAO and TBI. Preserving and keeping the NRF-2 pathway active counteracts the onset of oxidative stress and consequent inflammation after ischemic and traumatic brain insult, particularly in the elderly. Not only that, NRF-2 pathway could represent a possible therapeutic target in the management of brain injuries.

Machine learning analysis of factors influencing ischemic stroke after coronary artery bypass grafting

Abstract Aims Ischemic Stroke (IS) is a devastating complication of coronary bypass (CABG) surgery, significantly increasing mortality, morbidity, cost, and the need for long-term care, and reducing the quality of life. With the aim of a learning-machine method, we investigated factors influencing the occurrence of IS after CABG. Methods and results We employed a statistical learning method – random forests – to examine which of various variables had the greatest impact on postoperative IS. A dataset including 16,255 consecutive patients undergoing isolated CABG between 1997 and 2017 In one Institution was examined. Along with demographic and clinical variables technical-related factors were included, encompassing surgical technique, number of touches on the aorta, cardiopulmonary bypass, total aortic clamping, use of the side-biting clamp, or number of proximal anastomoses. A ranking score based on the average percent increase in mean squared error and obtained for all variables was employed to quantify the importance of any variable in predicting IS. A total of 641 strokes occurred (3.9%). Total aortic clamp showed the highest incidence of stroke (n=570, 88.95% of total). Total aortic clamp had the highest score among all variables followed by previous stroke and carotid artery disease >50%. In contrast, other variables related to surgical technique showed low ranking scores in predicting IS. In patients undergoing CABG with the use of total aortic, a previous brain ischemic insult as well as age >75 years increase the risk of IS (fIGURE) Conclusions The use of total aortic clamp is the strongest predictor of stroke. A clamp-less technique is recommended whenever possible especially in older patients and those who experienced preoperative stroke or who had significant carotid stenosis. Importance of variables in predicting IS Funding Acknowledgement Type of funding source: None

Arterial Oxygenation in Traumatic Brain Injury-Relation to Cerebral Energy Metabolism, Autoregulation, and Clinical Outcome.

Background:Ischemic and hypoxic secondary brain insults are common and detrimental in traumatic brain injury (TBI). Treatment aims to maintain an adequate cerebral blood flow with sufficient arterial oxygen content. It has been suggested that arterial hyperoxia may be beneficial to the injured brain to compensate for cerebral ischemia, overcome diffusion barriers, and improve mitochondrial function. In this study, we investigated the relation between arterial oxygen levels and cerebral energy metabolism, pressure autoregulation, and clinical outcome.Methods:This retrospective study was based on 115 patients with severe TBI treated in the neurointensive care unit, Uppsala university hospital, Sweden, 2008 to 2018. Data from cerebral microdialysis (MD), arterial blood gases, hemodynamics, and intracranial pressure were analyzed the first 10 days post-injury. The first day post-injury was studied in particular.Results:Arterial oxygen levels were higher and with greater variability on the first day post-injury, whereas it was more stable the following 9 days. Normal-to-high mean pO2 was significantly associated with better pressure autoregulation/lower pressure reactivity index (P = .02) and lower cerebral MD-lactate (P = .04) on day 1. Patients with limited cerebral energy metabolic substrate supply (MD-pyruvate below 120 µM) and metabolic disturbances with MD-lactate-/pyruvate ratio (LPR) above 25 had significantly lower arterial oxygen levels than those with limited MD-pyruvate supply and normal MD-LPR (P = .001) this day. Arterial oxygenation was not associated with clinical outcome.Conclusions:Maintaining a pO2 above 12 kPa and higher may improve oxidative cerebral energy metabolism and pressure autoregulation, particularly in cases of limited energy substrate supply in the early phase of TBI. Evaluating the cerebral energy metabolic profile could yield a better patient selection for hyperoxic treatment in future trials.

Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke.

Stroke research has traditionally focused on the cerebral processes following ischemic brain injury, where oxygen and glucose deprivation incite prolonged activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, reactive oxygen species proliferation, and ultimately neuronal death. A recent growing body of evidence, however, points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, peripheral immunodepression in conjunction with hyperstimulation of autonomic and neuroendocrine pathways and motor pathway impairment result in dysfunction of the respiratory, urinary, cardiovascular, gastrointestinal, musculoskeletal, and endocrine systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke. Using a pathophysiology-based approach, this current review discusses the pathophysiological mechanisms following ischemic brain insult that result in end organ dysfunction. By characterizing stroke as a systemic disease, future research must consider bidirectional interactions between the brain and peripheral organs to inform treatment paradigms and develop effective, comprehensive therapeutics for acute ischemic stroke.

Low doses of Perampanel protect striatal and hippocampal neurons against in vitro ischemia by reversing the ischemia-induced alteration of AMPA receptor subunit composition

Energy depletion caused by ischemic brain insults may result in persistent neuronal depolarization accompanied by hyper-stimulation of ionotropic glutamate receptors and excitotoxic phenomena, possibly leading to cell death. The use of glutamate receptor antagonists, such as the AMPARs antagonist Perampanel (PER), might be a pharmacological approach to counteract the excessive over-activation of glutamate receptors providing neuroprotective effects. Using electrophysiological and molecular analyses, we investigated the effect of PER against in vitro ischemia obtained by oxygen and glucose deprivation (OGD) in rat slices of two brain structures particularly sensitive to ischemic insults, the nucleus striatum and the hippocampus. We found that in these regions PER was able to avoid the OGD-induced neuronal suffering, at low doses not reducing basal excitatory synaptic transmission and not altering long-term potentiation (LTP) induction. Furthermore, in both the analysed regions, PER blocked a pathological form of LTP, namely ischemic LTP (iLTP). Finally, we hypothesized that the protective effect of PER against OGD was due to its capability to normalize the altered synaptic localization and function of AMPAR subunits, occuring after an ischemic insult. Taken together these findings support the idea that PER is a drug potentially effective to counteract ischemic damage.

Clinical Value of the Carotid Ultrasound in Evaluation of Plaque Composition as Compared to the Carotid MRI

Abstract Background: The main aim of carotid imaging studies is the assessment of the carotid plaque morphology with the detection of vulnerable plaques which is associated with increased risk of cerebrovascular insult, hence proper deline-ation of plaque composition is a crucial step for further management of brain ischemic insult. Aim of Study: To define the inter method agreement between the carotid ultrasound and carotid MRI for charac-terization of vulnerable plaques with further assessment of carotid ultrasound sensitivity and specificity. Material and Methods: The study was conducted over 60 patients. The modified G-W classification was used to assess the sonographic features of the carotid plaques, and compared with the plaque composition using carotid MRI. Results: Our study included 60 patients, their ages ranged between 53 and 78 years with a mean age of 60.3±9.8 years. 56.7% of patients was male. The agreement between carotid ultrasound and carotid MRI was good with k=0.734, sensitivity of the carotid ultrasound to detect the vulnerable plaque was 88.1% with an overall accuracy of 88.3%. Conclusion: The carotid ultrasound examination is con-sidered the first-line modality for assessment of the carotid plaque composition, with good agreement with carotid MRI and acceptable sensitivity and accuracy for characterization of vulnerable plaques.

Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke

Apoptosis and necroptosis are two regulated cell death mechanisms; however, the interaction between these cell death pathways in vivo is unclear. Here we used cerebral ischemia/reperfusion as a model to investigate the interaction between apoptosis and necroptosis. We show that the activation of RIPK1 sequentially promotes necroptosis followed by apoptosis in a temporally specific manner. Cerebral ischemia/reperfusion insult rapidly activates necroptosis to promote cerebral hemorrhage and neuroinflammation. Ripk3 deficiency reduces cerebral hemorrhage and delays the onset of neural damage mediated by inflammation. Reduced cerebral perfusion resulting from arterial occlusion promotes the degradation of TAK1, a suppressor of RIPK1, and the transition from necroptosis to apoptosis. Conditional knockout of TAK1 in microglial/infiltrated macrophages and neuronal lineages sensitizes to ischemic infarction by promoting apoptosis. Taken together, our results demonstrate the critical role of necroptosis in mediating neurovascular damage and hypoperfusion-induced TAK1 loss, which subsequently promotes apoptosis and cerebral pathology in stroke and neurodegeneration.

YES-10, A Combination of Extracts from Clematis mandshurica RUPR. and Erigeron annuus (L.) PERS., Prevents Ischemic Brain Injury in A Gerbil Model of Transient Forebrain Ischemia.

Clematis mandshurica RUPR. (CMR) and Erigeron annuus (L.) PERS. (EALP) have pharmacological effects including anti-inflammatory activity and been used in traditional medicines in Asia. However, neuroprotective effects of CMR and/or EALP extracts against brain ischemic insults have never been addressed. Thus, the aim of this study was to examine neuroprotective effects of YES-10, a combination of extracts from CMR and EALP (combination ratio, 1:1), in the hippocampus following ischemia/reperfusion in gerbils. Protection of neurons was investigated by cresyl violet staining, fluoro-jade B histofluorescence staining and immunohistochemistry for neuronal nuclei. In addition, attenuation of gliosis was studied by immunohistochemistry for astrocytic and microglial markers. Treatments with 50 or 100 mg/kg YES-10 failed to protect neurons in the hippocampus after ischemia/reperfusion injury. However, administration of 200 mg/kg YES-10 protected neurons from ischemia/reperfusion injury and attenuated reactive gliosis. These findings strongly suggest that a combination of extracts from CMR and EALP can be used as a prevention approach/drug against brain ischemic damage.