Unusual and Rare Causes of Monocular Elevation Deficit.

INTRODUCTION: To study the rare and unusual causes of monocular elevation deficit. METHODS: Five patients presenting to us with diplopia and elevation deficit were thoroughly examined and were found to have monocular elevation deficit due to rare causes. OBSERVATIONS: All five were found to have different underlying etiologies - iatrogenic, sphenoid wing meningioma, cysticercosis, sarcoidosis and mid brain infarct, and were managed appropriately. DISCUSSION: Monocular Elevation Deficit can occur due to a variety of causes. Having a high index of suspicion for the more serious etiologies is of utmost importance. Thorough clinical examination and imaging help clinch the diagnosis.

Continuous Quantitative Electroencephalogram (EEG) Monitoring for Early Detection of Brain Herniation in Large Hemispheric Infarction (LHI): A Case Report.

BACKGROUND: Computer-assisted electroencephalography (EEG) systems may improve the likelihood of detecting abnormal EEGs in adult patients with severe disease. CASE PRESENTATION: We implemented long-range EEG monitoring in a patient with large hemispheric infarction (LHI) and explored its real-time changes in reflecting the patient's brain function. The bands of Alpha, Beta, Delta, Theta, DAR (Delta/Alpha), DTABR (Delta+Theta/Alpha+Beta), and brain symmetry index (BSI) were calculated as a ratio of total power. The test results showed that this patient presents a progressive worsening trend and developed brain herniation. The sigh at the electrophysiological level of brain herniation could be seen 6 h in advance based on the quantitative EEG (QEEG) parameters test. We calculated QEEG at both C3 and C4, electrode locations simultaneously, and the results showed that the trend of QEEG at both electrodes was consistent with the global, affected, and unaffected side. CONCLUSIONS: QEEG parameters can reflect the trend of LHI patients in real-time and may predict the occurrence of LHI brain herniation. For LHI patients, monitoring with fewer EEG electrodes can be tried to predict the changes in conditions.

Selective therapeutic cooling: To maximize benefits and minimize side effects related to hypothermia.

Selective therapeutic cooling is a promising technique for reducing final infarct volume and improving outcomes in ischemic stroke, especially as research regarding brain reperfusion continues to be explored. A recent study provided promising results on the safety and feasibility of selective therapeutic hypothermia via a closed-loop cooling catheter system for intra-carotid blood cooling in an ovine stroke model, but they failed to find efficacy of this method in this model. It is a major step forward from bench to bed side, but enhancing benefits of selective therapeutic cooling may need to take into account a more targeted induction of brain hypothermia and should mitigate potential side effects related to inducing hypothermia.

The assessment of cognitive functions in patients with isolated cerebellar infarctions: A follow-up study.

The role of the cerebellum on cognitive functions have been well-defined; however, the information related to the progress in time process is limited. In this study, we aimed to evaluate the cognitive function of patients with isolated cerebellar infarction in both the acute stage and the follow-up period. Twenty-three patients with isolated cerebellar infarction and 22 healthy control were examined through an extensive neuropsychological assessment battery. The patients were evaluated in the acute stage and at least six months after the stroke in the follow-up period. There were no significant differences between the patients and the controls regarding age (52.2 ± 7.0 and 54.9 ± 6.6, p = 0.184) and gender (Female/Male: 6/17 and 7/15, p = 0.672). There was no statistically significant difference between patients with right cerebellar infarction and left cerebellar infarction in terms of cognitive functions. Verbal fluency, attention, and verbal and non-verbal episodic memory scores were significantly lower in patient group in the acute stage when compared to the control group. When the follow-up evaluation was compared to acute stage, it was revealed that patients had recovered in all areas; however, less improvement was seen in word reading time. Our results support that lesions of the cerebellum affect cognitive functions in the acute stage. However, the improvement was demonstrated in all cognitive functions in the follow-up period.

Astrocytes constitute the major TNF-α-producing cell population in the infarct cortex in dMCAO rats receiving intravenous MSC infusion.

Recent studies report that inhibiting TNF-α might be a novel therapeutic strategy for managing brain ischemia. Our previous study reported that mesenchymal stem cell (MSC) transplantation could suppress TNF-α level in both serum and brain. However, the cell type(s) that contribute to the production of TNF-α during ischemia following MSC transplantation has not been well studied. In the present study, we found by fluorescent immunohistochemistry, that 7.95 ± 6.17% of TNF-α+ cells co-expressed Iba-1 in the infarct area of dMCAO rats, a majority of which were found to be CD68+ (activated microglia), suggesting that resident microglial population were not the major source of TNF-α expression. 68.49 ± 5.12% of the TNF-α+ cells in the infarct area could be labeled by GFAP, a specific marker for astrocytes, indicating that resident GFAP+ astrocytes might be the major source of TNF-α expression in the infarct area. In addition to the infarct area, the GFAP+/TNF-α+ double-positive astrocytes accounted for 73.68 ± 7.48% of the TNF-α+ cells in striatum and corpus callosum. The infiltrating cells, including monocytes and lymphocytes, were not the main source of TNF-α either. In response to MSC transplantation, the total TNF-α+ cells as well as the percentage of TNF-α-expressing astrocytes were significantly reduced in the infarct area, suggesting that MSC transplantation could suppress the expression of TNF-α by astrocytes. Taken together, the results demonstrated that resident astrocytes, but not microglia, were the major source of TNF-α expression and could be suppressed by MSC infusion.

Prognostic Factors for Long-Term Recovery of Homonymous Visual Field Defects After Posterior Circulation Ischemic Stroke.

OBJECTIVES: Ischemic stroke (IS) is the main cause of homonymous visual field defects (HVFDs) in adults. Some reports suggest recovery even in late-phase strokes, but data is sparse. This study examines the frequency of long-term recovery from HVFDs in patients with posterior circulation infarction (POCI) and evaluates whether demographic or clinical characteristics are prognostic factors of perimetric recovery. MATERIALS AND METHODS: Our study included patients with HVFDS due to POCI who had undergone 2 or more kinetic perimetric evaluations at least 6 months after the index IS. Clinical and imaging data were systematically reviewed and we performed univariate and multivariate logistic regression analyses to determine whether demographic, stroke etiology (TOAST classification), and initial perimetric patterns were prognostic factors of visual recovery occurring 6 months and beyond from POCI. RESULTS: One hundred one patients with POCI were included. Median subject age was 60 years and 54.4% were female. After a median perimetric follow-up time of 13.5 months, spontaneous visual improvement was observed in 15.8% of patients. Prognostic factors for visual improvement were age < 50 years (OR 4.6; P = 0.093), POCI associated with hypercoagulable states (OR 12.3; P = 0.048), and vertebral artery dissection (OR 12.6; P = 0.048), while the presence of complete homonymous hemianopia was a negative predictor of recovery (OR 0.2; P = 0.048). CONCLUSION: Partial visual recovery in HVFDs is observed even 6 months and beyond POCI. Age < 50 years and stroke etiology were predictors of recovery.

Mapping Cerebrovascular Reactivity Impairment in Patients With Symptomatic Unilateral Carotid Artery Disease.

Background Comprehensive hemodynamic impairment mapping using blood oxygenation-level dependent (BOLD) cerebrovascular reactivity (CVR) can be used to identify hemodynamically relevant symptomatic unilateral carotid artery disease. Methods and Results This prospective cohort study was conducted between February 2015 and July 2020 at the Clinical Neuroscience Center of the University Hospital Zurich, Zurich, Switzerland. One hundred two patients with newly diagnosed symptomatic unilateral internal carotid artery (ICA) occlusion or with 70% to 99% ICA stenosis were included. An age-matched healthy cohort of 12 subjects underwent an identical BOLD functional magnetic resonance imaging examination. Using BOLD functional magnetic resonance imaging with a standardized CO2 stimulus, CVR impairment was evaluated. Moreover, embolic versus hemodynamic ischemic patterns were evaluated on diffusion-weighted imaging. Sixty-seven patients had unilateral ICA occlusion and 35 patients unilateral 70% to 99% ICA stenosis. Patients with ICA occlusion exhibited lower whole-brain and ipsilateral hemisphere mean BOLD-CVR values as compared with healthy subjects (0.12±0.08 versus 0.19±0.04, P=0.004 and 0.09±0.09 versus 0.18±0.04, P<0.001) and ICA stenosis cohort (0.12±0.08 versus 0.16±0.05, P=0.01 and 0.09±0.09 versus 0.15±0.05, P=0.01); however, only 40 (58%) patients of the cohort showed significant BOLD-CVR impairment. Conversely, there was no difference in mean BOLD-CVR values between healthy patients and patients with ICA stenosis, although 5 (14%) patients with ICA stenosis showed a significant BOLD-CVR impairment. No significant BOLD-CVR difference was discernible between patients with hemodynamic ischemic infarcts versus those with embolic infarct distribution (0.11±0.08 versus 0.13±0.06, P=0.12). Conclusions Comprehensive BOLD-CVR mapping allows for identification of hemodynamically relevant symptomatic unilateral carotid artery stenosis or occlusion.

Prediction of ambulatory outcome in patients with corona radiata infarction using deep learning.

Deep learning (DL) is an advanced machine learning approach used in diverse areas such as bioinformatics, image analysis, and natural language processing. Here, using brain magnetic resonance imaging (MRI) data obtained at early stages of infarcts, we attempted to develop a convolutional neural network (CNN) to predict the ambulatory outcome of corona radiata infarction at six months after onset. We retrospectively recruited 221 patients with corona radiata infarcts. A favorable outcome of ambulatory function was defined as a functional ambulation category (FAC) score of ≥ 4 (able to walk without a guardian's assistance), and a poor outcome of ambulatory function was defined as an FAC score of < 4. We used a CNN algorithm. Of the included subjects, 69.7% (n = 154) were assigned randomly to the training set and the remaining 30.3% (n = 67) were assigned to the validation set to measure the model performance. The area under the curve was 0.751 (95% CI 0.649-0.852) for the prediction of ambulatory function with the validation dataset using the CNN model. We demonstrated that a CNN model trained using brain MRIs captured at an early stage after corona radiata infarction could be helpful in predicting long-term ambulatory outcomes.

Recovery of Hypoxic Regions in a Rat Model of Microembolism.

OBJECTIVES: Endovascular treatment (EVT) has become the standard of care for acute ischemic stroke. Despite successful recanalization, a limited subset of patients benefits from the new treatment. Human MRI studies have shown that during removal of the thrombus, a shower of microclots is released from the initial thrombus, possibly causing new ischemic lesions. The aim of the current study is to quantify tissue damage following microembolism. MATERIALS AND METHODS: In a rat model, microembolism was generated by injection of a mixture of polystyrene fluorescent microspheres (15, 25 and 50 µm in diameter). The animals were killed at three time-points: day 1, 3 or 7. AMIRA and IMARIS software was used for 3D reconstruction of brain structure and damage, respectively. CONCLUSIONS: Microembolism induces ischemia, hypoxia and infarction. Infarcted areas persist, but hypoxic regions recover over time suggesting that repair processes in the brain rescue the regions at risk.

Utility of Magnetic Resonance Spectroscopy for the Progression of Neurological Symptoms in Lenticulostriate Artery Territory Infarction.

OBJECTIVES: The present study aimed to examine the effectiveness of proton magnetic resonance spectroscopy (1HMRS) in determining the progression of neurological symptoms resulting in acute ischemic stroke in patients with lenticulostriate artery (LSA) infarction. MATERIALS AND METHODS: 1HMRS was performed within 72 h after neurological symptom onset. Voxel of interest was placed in tissue that included the pyramidal tract and identified diffusion weighted echo planar spin-echo sequence (DWI) coronal images. Infarct volume in DWI was calculated using the ABC/2 method. 1HMRS data (tNAA, tCr, Glx, tCho, and Ins) were analyzed using LCModel. Progressive neurological symptoms were defined as an increase of 1 or more in the NIHSS score. Patients who underwent 1HMRS after progressive neurological symptoms were excluded. RESULTS: In total, 77 patients were enrolled. Of these, 19 patients had progressive neurological symptoms. The patients with progressive neurological symptoms were significantly more likely to be female and had higher tCho/tCr values, higher rates of axial slices ≥ 3 slices on DWI, higher infarct volume on DWI, higher maximum diameter of infarction of axial slice on DWI, and higher SBP on admission compared to those without. Multivariable logistic analysis revealed that higher tCho/tCr values were independently associated with progressive neurological symptoms after adjusting for age, sex, and initial DWI infarct volume (tCho/tCr per 0.01 increase, OR 1.26, 95% CI 1.03-1.52, P = 0.022). CONCLUSIONS: Increased tCho/tCr score were associated with progressive neurological symptoms in patients with LSA ischemic stroke. Quantitative evaluation of 1HMRS parameters may be useful for predicting the progression of neurological symptoms.

Effects of autophagy inhibitor 3-Methyladenine on ischemic stroke: A protocol for systematic review and meta-analysis.

BACKGROUND: Ischemic stroke is a huge threat to human health globally. Rescuing neurons in the ischemic penumbra (IP) is pivotal after the onset of ischemic stroke, and autophagy is essential to the survival of IP neurons and the development of related pathological processes. As the most common autophagy inhibitor, 3-Methyladenine (3-MA) is widely used in studies related to the mechanism of neuronal autophagy in ischemic stroke; however, there is no consensus has been reached on its effects of neuroprotection or neurodamage, which hinders the development and clinical application of autophagy-targeted therapy strategies for the treatment of ischemic stroke. METHODS: We will search the following electronic bibliographic databases: PubMed, EMBASE, Scopus, Science Direct, and Web of Science. Participant intervention comparator outcomes of this study are as flowing: P, animal models of ischemic stroke; I, received 3-MA treatment merely; C, received only vehicle or sham treatment, or no treatment; O, Primary outcomes are infarct volume; neuro-behavioral scores. Secondary outcomes are cerebral blood flow, blood-brain barrier permeability, cerebral hemorrhage, brain water content. Review Manager 5.3 and Stata 15.1 will be used in data analysis. The characteristics of the studies, the experimental model, and the main results will be described, the quality assessment and the risk of bias assessment will be conducted. A narrative synthesis will be made for the included studies. Besides, if sufficient qualitative data is available, a meta-analysis will be conducted. I2 statistics will be used to assess heterogeneity. DISCUSSION: This systematic review and meta-analysis of the autophagy inhibitor 3-MAs effects on animal models of ischemic stroke can help us to understand whether inhibiting autophagy brings protection or damage to IP neurons; in addition, it also helps to clarify the specific role of autophagy in cerebral infarction. Therefore, this study can provide evidence for the future development of therapy strategies targeting autophagy and bring more hope to patients with ischemic stroke. PROSPERO REGISTRATION NUMBER: CRD42020194262.

Aß (Amyloid Beta) and Tau Tangle Pathology Modifies the Association Between Small Vessel Disease and Cortical Microinfarcts.

BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aß (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aß or tau tangle burden. METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aß and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aß or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts. RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aß and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aß (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aß (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005). CONCLUSIONS: These findings suggest that in the presence of elevated Aß or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.

Validation of a Polish version of the Israeli Vertebrobasilar Stroke Scale - An attempt to more accurately assess posterior Stroke.

OBJECTIVE: Posterior circulation stroke, in contrast to anterior circulation stroke, has a greater complexity and variability of clinical symptoms. This could be responsible for delayed diagnosis and treatment time and, as a consequence, worse prognosis. Certain blame in this respect can also be attributed to the clinimetric scales used to assess stroke severity, which are characterized by significantly lower accuracy than with anterior strokes. The Israeli Vertebrobasilar Stroke Scale (IVBSS) was the first attempt dedicated to posterior strokes and was devised for better measurement of clinical condition. We aimed to develop a Polish version of the IVBSS (PL-IVBSS) to assess the reliability, validity and psychometric properties of the tool to confirm its clinical utility. METHODS: We enrolled 126 posterior circulation ischemic stroke subjects. Four researchers estimated stroke severity using appropriate and widely accepted devices (the modified Rankin Scale - mRS, the National Institutes of Health Stroke Scale - NIHSS, the Barthel Index, and the Glasgow Coma Scale - GCS) and compared with the PL-IVBSS. We analyzed inter- and intrarater agreements, repeatability, concurrent and predictive validity, internal consistency, scalability and homogeneity, reflecting the psychometric features of a validated instrument. RESULTS: Cronbach's alpha coefficient was 0.67, and the median inter-item correlation coefficient was 0.22, indicating moderate internal consistency and insufficient homogeneity. A total of 63.6% of the individual items obtained required discriminatory power (r > 0.3), showing moderate scalability. The PL-IVBSS achieved a good coefficient of repeatability (CR = 1.21 95%CI 1.08-1.38) and narrow limits of agreement in Bland-Altman analysis, emphasizing the accuracy and high reproducibility. Excellent intraclass correlation coefficients and weighted kappa values (all >0.90) underlined the high reliability of the PL-IVBSS. Highly significant correlations with other relevant devices (all r > 0.5, p < 0.0001) highlighted the satisfactory concurrent and predictive validity of a validated clinimetric tool. CONCLUSION: We devised a validated version of the IVBSS, indicating the high reproducibility, repeatability and accuracy of the PL-IVBSS and confirming its clinical utility. Despite moderate psychometric properties, our findings support the need for its clinical application and widespread use in stroke units for a reliable assessment of posterior stroke severity.

Effects of mechanical thrombectomy for post-stroke patients with upper limb hemiparesis: Use of Propensity Score Matching.

BACKGROUND: Mechanical Thrombectomy (MT) is a recommended approach for post-cerebral ischemia in acute settings. Although a large amount of evidence suggests the use of MT, existing evidence has primarily focused on assessing lower limb performance or gait performance as an outcome measure. METHODS: This study was to investigate whether MT would be an effective approach for improving upper limb performance in post-stroke patients.This case control was divided into two groups: 154 patients as a control group only given conventional rehabilitation; and 25 patients as an intervention group given MT and conventional rehabilitation. Outcome variables were measured by calculating the change of Fugl-Meyer Assessment score at the last intervention compared with the beginning of the intervention. RESULT: By comparing the FMA scores after, the propensity matching compared between before receiving therapy intervention and after, the intervention group showed as follows: 30.4 ± 26.4-44.3 ± 25.4, p = 0.0019, r = 0.59. The control group showed as follows: 39.9 ± 24.1-49.1 ± 21.3, p = 0.002, r = 0.69. Lastly, a comparison of the intervention group with the control group about their FMA score change indicates as follows: intervention group: 13.9 ± 19.4, control group 9.2 ± 10.0, p = 0.2967, r = 0.15. CONCLUSION: This study indicated that there was no significant difference between MT and a conventional approach for improving UE function. However, this is the first study to investigate the course of recovery of UE function in the acute phase after MT, and this finding supports the need for further research.

Diverse manifestations of a sickle cell crisis.

We describe the case of a 21-year-old man with a background of sickle cell disease (SCD) who was on acute presentation in a sickle cell crisis required immediate intensive care admission with red blood cell exchange and ventilatory support. He had right frontal lobe infarcts and extensive bilateral deep white matter lesions most likely secondary to fat embolism. Inpatient investigations demonstrated a patent foramen ovale, explaining the route of spread of the fat embolus. He then had a transcatheter closure of the atrial defect. The patient needed prolonged inpatient rehabilitation. He was discharged from hospital in a wheelchair secondary to severe lower limb neurology and bilateral knee heterotopic ossification. He lives with the possibility of early onset dementia and cognitive decline, requiring constant care. The case highlights the multiple manifestations of SCD and their diverse and debilitating consequences.

Evaluation of hemodynamic characteristics in posterior circulation infarction patients with vertebral artery dominance by color doppler flow imaging and transcranial doppler sonography.

PURPOSE: The aim of this study was to investigate the hemodynamic characteristics of posterior circulation infarction (PCI) patients with the vertebral artery dominance (VAD) using Color Doppler flow imaging (CDFI) and Transcranial Doppler sonography (TCD) and to explore the pathogenesis of PCI caused by VAD. MATERIALS AND METHODS: A total of 186 consecutive PCI patients were enrolled. All the patients underwent magnetic resonance (MR) examination and the clinical data were collected. According to the brain magnetic resonance angiography (MRA), the patients were divided into VAD and non-VAD groups. CDFI and TCD were performed to identify the hemodynamic parameters of the vertebral artery (VA) and basilar artery (BA). RESULTS: The male population was significantly more frequent in the VAD group (71.3%) as compared to the non-VAD group (53.1%). The significant difference in hemodynamic parameters was observed between VAD and non-VAD groups. Resistance index (RI) of extracranial and intracranial VA was different as well. There were also differences in the VA side-to-side diameter difference-value, peak velocity (Vp), mean velocity (Vm) and pulsatility index (PI) with varying degrees of BA curvature. CONCLUSIONS: VA and BA hemodynamic changes caused by VAD may be an important risk factor in the process of occurrence of PCI. The combination of CDFI and TCD can help to detect the hemodynamic changes in the intracranial and extracranial segments of VA and BA. This can have important clinical value in understanding the pathogenesis of PCI.

Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation.

The association of blood pressure (BP) and hypertension with the presence of different types of brain lesions in patients with atrial fibrillation is unclear. BP values were obtained in a multicenter cohort of patients with atrial fibrillation. Systolic and diastolic BP was categorized in predefined groups. All patients underwent brain magnetic resonance imaging and neurocognitive testing. Brain lesions were classified as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, or white matter lesions. White matter lesions were graded according to the Fazekas scale. Overall, 1738 patients with atrial fibrillation were enrolled in this cross-sectional analysis (mean age, 73 years, 73% males). Mean BP was 135/79 mm Hg, and 67% of participants were taking BP-lowering treatment. White matter lesions Fazekas ≥2 were found in 54%, large noncortical or cortical infarcts in 22%, small noncortical infarcts in 21%, and microbleeds in 22% of patients, respectively. Compared with patients with systolic BP <120 mm Hg, the adjusted odds ratios (95% CI) for Fazekas≥2 was 1.25 (0.94-1.66), 1.41 (1.03-1.93), and 2.54 (1.65-3.95) among patients with systolic BP of 120 to 140, 140 to 160, and ≥160 mm Hg (P for linear trend<0.001). Per 5 mm Hg increase in systolic and diastolic BP, the adjusted ß-coefficient (95% CI) for log-transformed white matter lesions was 0.04 (0.02-0.05), P<0.001 and 0.04 (0.01-0.06), P=0.004. Systolic BP was associated with small noncortical infarcts (odds ratios [95% CI] per 5 mm Hg 1.05 [1.01-1.08], P=0.006), microbleeds were associated with hypertension, but large noncortical or cortical infarcts were not associated with BP or hypertension. After multivariable adjustment, BP and hypertension were not associated with neurocognitive function. Among patients with atrial fibrillation, BP is strongly associated with the presence and extent of white matter lesions, but there is no association with large noncortical or cortical infarcts. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke.

Despite the promising neuroprotective effects of uric acid (UA) in acute ischemic stroke, the seemingly pleiotropic underlying mechanisms are not completely understood. Recent evidence points to transcription factors as UA targets. To gain insight into the UA mechanism of action, we investigated its effects on pertinent biomarkers for the most relevant features of ischemic stroke pathophysiology: (1) oxidative stress (antioxidant enzyme mRNAs and MDA), (2) neuroinflammation (cytokine and Socs3 mRNAs, STAT3, NF-κB p65, and reactive microglia), (3) brain swelling (Vegfa, Mmp9, and Timp1 mRNAs), and (4) apoptotic cell death (Bcl-2, Bax, caspase-3, and TUNEL-positive cells). Adult male Wistar rats underwent intraluminal filament transient middle cerebral artery occlusion (tMCAO) and received UA (16 mg/kg) or vehicle (Locke's buffer) i.v. at 20 min reperfusion. The outcome measures were neurofunctional deficit, infarct, and edema. UA treatment reduced cortical infarct and brain edema, as well as neurofunctional impairment. In brain cortex, increased UA: (1) reduced tMCAO-induced increases in Vegfa and Mmp9/Timp1 ratio expressions; (2) induced Sod2 and Cat expressions and reduced MDA levels; (3) induced Il6 expression, upregulated STAT3 and NF-κB p65 phosphorylation, induced Socs3 expression, and inhibited microglia activation; and (4) ameliorated the Bax/Bcl-2 ratio and induced a reduction in caspase-3 cleavage as well as in TUNEL-positive cell counts. In conclusion, the mechanism for morphological and functional neuroprotection by UA in ischemic stroke is multifaceted, since it is associated to activation of the IL-6/STAT3 pathway, attenuation of edematogenic VEGF-A/MMP-9 signaling, and modulation of relevant mediators of oxidative stress, neuroinflammation, and apoptotic cell death.

Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression.

A striking result from epidemiological studies show a correlation between low alcohol intake and lower incidence for ischemic stroke and severity of derived brain injury. Although reduced apoptosis and inflammation has been suggested to be involved, little is known about the mechanism mediating this effect in vivo. Increase in intracellular chloride concentration and derived depolarizing GABAAR-mediated transmission are common consequences following various brain injuries and are caused by the abnormal expression levels of the chloride cotransporters NKCC1 and KCC2. Downstream pro-apoptotic signaling through p75NTR may link GABAA depolarization with post-injury neuronal apoptosis. Here, we show that changes in GABAergic signaling, Cl- homeostasis, and expression of chloride cotransporters in the post-traumatic mouse brain can be significantly reduced by administration of 3% ethanol to the drinking water. Ethanol-induced upregulation of KCC2 has a positive impact on neuronal survival, preserving a large part of the cortical peri-infarct zone, as well as preventing the massive post-ischemic upregulation of the pro-apoptotic protein p75NTR. Importantly, intracortical multisite in vivo recordings showed that ethanol treatment could significantly ameliorate stroke-induced reduction in cortical activity. This surprising finding discloses a pathway triggered by low concentration of ethanol as a novel therapeutically relevant target.