Intraoperative neuromonitoring as real-time diagnostic for cerebral ischemia in endovascular treatment of ruptured brain aneurysms.

OBJECTIVE: To evaluate the diagnostic accuracy of intraoperative neurophysiological monitoring (IONM) during endovascular treatment (EVT) of ruptured intracranial aneurysms (rIA). METHODS: IONM and clinical data from 323 patients who underwent EVT for rIA from 2014-2019 were retrospectively reviewed. Significant IONM changes and outcomes were evaluated based on visual review of data and clinical documentation. RESULTS: Of the 323 patients undergoing EVT, significant IONM changes were noted in 30 patients (9.29%) and 46 (14.24%) experienced postprocedural neurological deficits (PPND). 22 out of 30 (73.33%) patients who had significant IONM changes experienced PPND. Univariable analysis showed changes in somatosensory evoked potential (SSEP) and electroencephalogram (EEG) were associated with PPND (p-values: <0.001 and <0.001, retrospectively). Multivariable analysis showed that IONM changes were significantly associated with PPND (Odd ratio (OR) 20.18 (95%CI:7.40-55.03, p-value: <0.001)). Simultaneous changes in both IONM modalities had specificity of 98.9% (95% CI: 97.1%-99.7%). While sensitivity when either modality had a change was 47.8% (95% CI: 33.9%-62.0%) to predict PPND. CONCLUSIONS: Significant IONM changes during EVT for rIA are associated with an increased risk of PPND. SIGNIFICANCE: IONM can be used confidently as a real time neurophysiological diagnostic guide for impending neurological deficits during EVT treatment of rIA.

Cerebral microcirculation mapped by echo particle tracking velocimetry quantifies the intracranial pressure and detects ischemia.

Affecting 1.1‰ of infants, hydrocephalus involves abnormal accumulation of cerebrospinal fluid, resulting in elevated intracranial pressure (ICP). It is the leading cause for brain surgery in newborns, often causing long-term neurologic disabilities or even death. Since conventional invasive ICP monitoring is risky, early neurosurgical interventions could benefit from noninvasive techniques. Here we use clinical contrast-enhanced ultrasound (CEUS) imaging and intravascular microbubble tracking algorithms to map the cerebral blood flow in hydrocephalic pediatric porcine models. Regional microvascular perfusions are quantified by the cerebral microcirculation (CMC) parameter, which accounts for the concentration of micro-vessels and flow velocity in them. Combining CMC with hemodynamic parameters yields functional relationships between cortical micro-perfusion and ICP, with correlation coefficients exceeding 0.85. For cerebral ischemia cases, the nondimensionalized cortical micro-perfusion decreases by an order of magnitude when ICP exceeds 50% of the MAP. These findings suggest that CEUS-based CMC measurement is a plausible noninvasive method for assessing the ICP and detecting ischemia.

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors.

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4ß2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1ß, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1ß, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.

Influence of Melatonin on Behavioral and Neurological Function of Rats with Focal Cerebral Ischemia-Reperfusion Injury via the JNK/FoxO3a/Bim Pathway.

OBJECTIVE: To investigate the influence of melatonin on behavioral and neurological function of rats with focal cerebral ischemia-reperfusion injury via the JNK/FoxO3a/Bim pathway. METHODS: One hundred and twenty healthy male SD rats were randomized into the model group (Model: the middle cerebral artery occlusion (MCAO) model was constructed and received an equal volume of normal saline containing 5% DMSO), sham operation group (Sham: received no treatment except normal feeding), and low, medium, and high dose of melatonin group (L-MT, M-MT, and H-MT intraperitoneally injected 10, 20, and 40 mg/kg melatonin 30 min after IR, respectively), with 24 rats in each group. Following 24 h of reperfusion, the rats in each of the above groups were tested for neurological deficit symptoms and behavioral changes to screen the rats included in the study. HE and TUNEL stainings were performed to observe pathological changes. Levels of oxidative stress-related indexes, inflammatory factor-related indexes, nuclear factor-κB p65 (NF-κB p65), and interferon-γ (IFN-γ) in the rat brain were measured by ELISA. The JNK/FoxO3a/Bim pathway-related proteins as well as Bcl-2, Caspase-3, and Bax were examined using Western blot. RESULTS: Detection of behavioral indicators showed that the MACO model was successfully constructed in rats. L-MT, M-MT, and L-MT groups presented reduced malondialdehyde (MDA), reactive oxygen species (ROS), tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-1ß, IFN-γ, NF-κB p65, and apoptosis compared with the Model group (P < 0.05), and the improvement degree was better in the M-MT group versus the L-HT group. Bcl-2 protein expression in the brain tissue of L-MT, M-MT, and H-MT groups increased significantly, while Bax, Caspase-3, p-JNK, p-FoxO3a, and Bim protein expression declined markedly, versus the Model group (P < 0.05). The changes of indexes were greater in the M-MT group compared with that in the L-MT group. No significant difference was observed in all the above indexes between the M-MT group and the H-MT group (P > 0.05). CONCLUSIONS: In the MACO rat model, melatonin can effectively reduce Bax and Caspase-3 levels by modulating the JNK/FoxO3a/Bim pathway, inhibit neuronal apoptosis, and alleviate neurological deficits by reducing the release of proinflammatory mediators, with anti-inflammatory and antioxidant effects. In addition, 20 mg/kg is the optimal melatonin concentration.

High fructose diet-induced obesity worsens post-ischemic brain injury in the hippocampus of female rats.

Objectives: Cerebral ischemia is caused by a reduction of the blood flow in a specific area in the brain, triggering cellular cascades in the tissue that result in neuronal death. This phenomenon leads to neurological decline in patients with stroke. The extent of the injury after stroke could be related to the condition of obesity. Thus, we aim to analyze the effect of obesity induced by a high fructose diet (HFD) on the brain after cerebral ischemia in rats.Methods: We induced the obesity model in female Wistar rats with 20% fructose in water for 11 weeks. We then performed cerebral ischemia surgery (2-vessel occlusion), carried out the neurological test 6, 24 and 48 h post-ischemia and analyzed the histological markers.Results: The HFD induced an obese phenotype without insulin resistance. The obese rats exhibited worse neurological performance at 6 h post-ischemia and showed neuronal loss and astroglial and microglial immunoreactivity changes in the caudate putamen, motor cortex, amygdala and hippocampus at 48 h post-ischemia. However, the most commonly affected area was the hippocampus, where we found an increase in interleukin 1ß in the blood vessels of the dentate gyrus, a remarkable disruption of MAP-2+ dendrites, a loss of brain-derived neurotrophic factor and the presence of PHF-tau. In conclusion, a HFD induces an obese phenotype and worsens the neuronal loss, inflammation and plasticity impairment in the hippocampus after cerebral ischemia.

HIF­1α in cerebral ischemia (Review).

Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia­inducible factor­1α (HIF­1α) is an oxygen­sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF­1α is the main molecule that responds to hypoxia. HIF­1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF­1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF­1α target, including biological factors, non­coding RNA, hypoxic­ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF­1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.

High-Intensity Interval Training Improves Physical Function, Prevents Muscle Loss, and Modulates Macrophage-Mediated Inflammation in Skeletal Muscle of Cerebral Ischemic Mice.

Although skeletal muscle is the main effector organ largely accounting for disability after stroke, considerably less attention is paid to the secondary abnormalities of stroke-related skeletal muscle loss. It is necessary to explore the mechanism of muscle atrophy after stroke and further develop effective rehabilitation strategy. Here, we evaluated the effects of high-intensity interval (HIIT) versus moderate-intensity aerobic training (MOD) on physical function, muscle mass, and stroke-related gene expression profile of skeletal muscle. After the model of middle cerebral artery occlusion (MCAO) was successfully made, the blood lactate threshold corresponding speed (S LT) and maximum speed (S max) were measured. Different intensity training protocols (MOD < S LT; S LT < HIIT < S max) were carried out for 3 weeks beginning at 7 days after MCAO in the MOD and HIIT groups, respectively. We found that both HIIT and MOD prevented stroke-related gastrocnemius muscle mass loss in MCAO mice. HIIT was more beneficial than MOD for improvements in muscle strength, motor coordination, walking competency, and cardiorespiratory fitness. Furthermore, HIIT was superior to MOD in terms of reducing lipid accumulation, levels of IL-1ß and IL-6 in paretic gastrocnemius, and improving peripheral blood CD4+/CD8+ T cell ratio, level of IL-10. Additionally, RNA-seq analysis revealed that the differentially expressed genes among HIIT, MOD, and MCAO groups were highly associated with signaling pathways involved in inflammatory response, more specifically the I-kappaB kinase/NF-kappaB signaling. Following the outcome, we further investigated the infiltrating immune cells abundant in paretic muscles. The results showed that HIIT modulated macrophage activation by downregulating CD86+ (M1 type) macrophages and upregulating CD163+ (M2 type) macrophages via inhibiting the TLR4/MyD88/NFκB signaling pathway and exerting an anti-inflammatory effect in paretic skeletal muscle. It is expected that these data will provide novel insights into the mechanisms and potential targets underlying muscle wasting in stroke.

Neuroprotective Effect of Quercetin during Cerebral Ischemic Injury Involves Regulation of Essential Elements, Transition Metals, Cu/Zn Ratio, and Antioxidant Activity.

Cerebral ischemia results in increased oxidative stress in the affected brain. Accumulating evidence suggests that quercetin possesses anti-oxidant and anti-inflammatory properties. The essential elements magnesium (Mg), zinc (Zn), selenium (Se), and transition metal iron (Fe), copper (Cu), and antioxidants superoxide dismutase (SOD) and catalase (CAT) are required for brain functions. This study investigates whether the neuroprotective effects of quercetin on the ipsilateral brain cortex involve altered levels of essential trace metals, the Cu/Zn ratio, and antioxidant activity. Rats were intraperitoneally administered quercetin (20 mg/kg) once daily for 10 days before ischemic surgery. Cerebral ischemia was induced by ligation of the right middle cerebral artery and the right common carotid artery for 1 h. The ipsilateral brain cortex was homogenized and the supernatant was collected for biochemical analysis. Results show that rats pretreated with quercetin before ischemia significantly increased Mg, Zn, Se, SOD, and CAT levels, while the malondialdehyde, Fe, Cu, and the Cu/Zn ratio clearly decreased as compared to the untreated ligation subject. Taken together, our findings suggest that the mechanisms underlying the neuroprotective effects of quercetin during cerebral ischemic injury involve the modulation of essential elements, transition metals, Cu/Zn ratio, and antioxidant activity.

Buyang Huanwu Decoction promotes neurogenesis via sirtuin 1/autophagy pathway in a cerebral ischemia model.

Stroke is one of the main causes of disease­related mortality worldwide. Buyang Huanwu Decoction (BHD) has been used to protect against stroke and stroke­induced disability for several years in China. Studies have shown that BHD can relieve neuronal damage in rats with cerebral ischemia/reperfusion (I/R) injury. However, the mechanism remains unclear. A middle cerebral artery occlusion and reperfusion (MCAO­R) model was used in the present study. The animals were treated with BHD (5, 10 and 20 g/kg) or rapamycin. Infarct size and modified neurological severity score were calculated on day 5 following MCAO­R surgery. Cellular changes around the ischemic penumbra were revealed by hematoxylin and eosin and Nissl staining. The protein expression levels of nestin, brain­derived neurotrophic factor (BDNF), doublecortin on the X chromosome (DCX) and autophagy­related proteins (beclin 1, LC3­II and p62) in the peri­ischemic area of the brain were detected. The results demonstrated that post­surgical treatment with BHD reduced the brain infarct size and improved neurological deficits in MCAO­R rats. BHD protected against MCAO­R­induced neuronal impairment and promoted neurogenesis, increased the protein expression of nestin, BDNF and DCX and markedly enhanced autophagy by increasing beclin 1 and LC3­II and decreasing p62. Meanwhile, BHD promoted the expression of sirtuin 1 (SIRT1), an important regulator of autophagy. In conclusion, the present study suggested that post­surgical treatment with BHD could protect rat brains from I/R injury, potentially through the SIRT1/autophagy pathway.

Local Application of Magnesium Sulfate Solution Suppressed Cortical Spreading Ischemia and Reduced Brain Damage in a Rat Subarachnoid Hemorrhage-Mimicking Model.

OBJECTIVE: Cortical spreading depolarization (CSD), cortical spreading ischemia (CSI), and early brain injury are involved in the occurrence of delayed brain ischemia after subarachnoid hemorrhage (SAH). We tested whether local application of magnesium (Mg) sulfate solution suppressed CSD and CSI, and decreased brain damage in a rat SAH-mimicking model. METHODS: Nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and high concentration potassium solution were topically applied to simulate the environment after SAH. We irrigated the parietal cortex with artificial cerebrospinal fluid (ACSF), containing L-NAME (1 mM), K+ (35 mM), and Mg2+ (5 mM). Forty-five rats were divided into 3 groups: sham surgery (sham group), L-NAME + [K+]ACSF (control group), and L-NAME + [K+]ACSF + [Mg2+] (Mg group). CSD was induced by topical application with 1 M KCl solution in 3 groups. The effects of Mg administration on CSD and cerebral blood flow were evaluated. Histological brain tissue damage, body weight, and neurological score were assessed at 2 days after insult. RESULTS: Mg solution significantly shortened the total depolarization time, and reduced CSI, histological brain damage, and brain edema compared with those of the control group (P < 0.05). Body weight loss was significantly suppressed in the Mg group (P < 0.05), but neurological score did not improve. CONCLUSIONS: Local application of Mg suppressed CSI and reduced brain damage in a rat SAH-mimicking model. Mg irrigation therapy may be beneficial to suppress brain damage due to CSI after SAH.

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.

The Diagnostic Accuracy of Intra-Operative Near Infrared Spectroscopy in Carotid Artery Endarterectomy Under Regional Anaesthesia: Systematic Review and Meta-Analysis.

OBJECTIVE: Intra-operative near infrared spectroscopy (NIRS) is a non-invasive tool used to monitor regional cerebral oxygen saturation during carotid endarterectomy (CEA), for which accuracy remains unclear. Therefore, this systematic review and meta-analysis aimed to determine the diagnostic accuracy of NIRS in patients undergoing CEA under regional anaesthesia (RA). DATA SOURCES: MEDLINE, Scopus, and Web of Science were searched for studies that compared NIRS with the "awake test" in patients undergoing CEA under RA. REVIEW METHODS: Bivariable random effects meta-analysis was performed to determine the diagnostic accuracy of NIRS to detect cerebral ischaemia. Meta-regression was performed to explore causes of heterogeneity. Meta-analysis of proportions was also performed to determine the accuracy of NIRS in predicting 30 day stroke. Study quality was evaluated using the QUADAS-2 criteria. RESULTS: Eleven primary studies were included, assessing 1 237 participants. The meta-analysis obtained a partial area under the summary receiver operating characteristic curve for diagnosing brain ischaemia of 0.646, with a summary sensitivity of 72.0% (95% confidence interval [CI] 58.1 - 82.7; I2 = 48.6%) and a specificity of 84.1% (95% CI 78.5-88.4; I2 = 48.6%). In meta-regression analysis, the frequency of hypertension (p = .011) and patients with symptomatic carotid stenosis (p = .031) were significant effect modifiers. Higher frequency of arterial hypertension (z score = -2.15; p = .032) and diabetes (z score = -2.12; p = .034) were associated with lower summary sensitivity, while a higher frequency of symptomatic carotid stenosis (z score = 2.11; p = .035) was associated with higher summary sensitivity. Point estimate sensitivity and specificity for predicting 30 day stroke occurrence were 41% (95% CI 19.5 - 66.6; I2 = 0%) and 81.4% (95% CI 74.4 - 86.9, I2 = 65.6%), respectively. CONCLUSION: The results of this study suggest that NIRS as a cerebral monitoring technique does not have sufficiently high sensitivity or specificity to be used alone in the neurological monitoring of patients undergoing CEA under RA.

Polyphenols and Ischemic Stroke: Insight into One of the Best Strategies for Prevention and Treatment.

Ischemic stroke (IS) is still among the leading causes of death and disability worldwide. The pathogenic mechanisms beyond its development are several and are complex and this is the main reason why a functional therapy is still missed. The beneficial effects of natural compounds against cardiovascular diseases and IS have been investigated for a long time. In this article, we reviewed the association between the most studied polyphenols and stroke protection in terms of prevention, effect on acute phase, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbens on ischemic mechanisms leading to stroke. We analyzed the principal animal models used to evaluate the impact of these micronutrients to cerebral blood flow and to molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We reported the most significant clinical trials demonstrated as the persistent use of polyphenols is clinically relevant in terms of the reduction of vascular risk factors for IS, such as Atrial Fibrillation. Interestingly, different kinds of polyphenols provide brain protection by activating different pathways and mechanisms, like inducing antithrombotic effect, such as Honokiol. For this reason, we discussed an appropriate integrative use of them as a possible therapeutic alternative against stroke.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1ß production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. METHODS: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. RESULTS: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. CONCLUSIONS: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Risk factors associated with recurrence of ischemic stroke after intracranial stenting in china: a case-control study.

Objectives: To investigate the factors affecting the risk of recurrent stroke after intracranial artery stenting.Methods: This is a subgroup analysis of a prospective single-arm registry study with 20 participating sites. Patients aged 18-85 years old with symptomatic intracranial atherosclerotic stenosis caused by 70-99% stenosis combined with poor collaterals were included in this study. The median follow-up in this study was 26.4 months.Results: A total of 260 patients were recruited in this study. Ischemic stroke related to target vessel occurred in 11 patients (4.2%) from 30 days to the last follow-up. The multivariate analysis revealed age ≥60 years old (OR: 11.991, 95% CI: 1.400-102.716; p = 0.023), no smoking (OR: 0.087, 95% CI: 0.010-0.787; p = 0.030), and Mori C type (OR: 5.129, 95% CI: 1.242-21.178; p = 0.024) retained significance in the model. There was no significant difference in the ischemic stroke based on medical history of hypertension, diabetes, dyslipidemia, baseline percent stenosis, length of stenosis, residual stenosis, and different stent types.Conclusions: Recurrence of ischemic stroke after intracranial stenting may be associated with elderly age, non-smoking, and Mori C type lesion. These factors will need to be monitored in future trials of intracranial stenting.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01968122.

Trillium tschonoskii rhizomes' saponins induces oligodendrogenesis and axonal reorganization for ischemic stroke recovery in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Trillium tschonoskii Maxim. is one of traditional Chinese medical herbs that has been utilized to treat brain damages and cephalalgia. The neuroprotective effect of total saponins from Trillium tschonoskii rhizome (TSTT) has been demonstrated efficacy in rats following ischemia. However, the axonal remodeling effect of TSTT and the detailed mechanisms after ischemic stroke have not been investigated. AIM OF THE STUDY: We aimed to estimate therapeutic role of TSTT in axonal remodeling using magnetic resonance imaging (MRI) technique, and explored possible mechanisms underlying this process followed by histological assays in ischemic rats. METHODS: Male Sprague-Dawley (SD) rats underwent permanently focal cerebral ischemia induced by occluding right permanent middle cerebral artery. TSTT was intragastrically administrated 6 h after surgery and once daily for consecutive 15 days. Neurological function was assessed by the motor deficit score and beam walking test. T2 relaxation mapping and diffusion tensor imaging (DTI) were applied for detecting cerebral tissues damages and microstructural integrity of axons. Luxol fast blue (LFB) and transmission electron microscope (TEM) were performed to evaluate histopathology in myelinated axons. Double immunofluorescent staining was conducted to assess oligodendrogenesis. Furthermore, the protein expressions regarding to axonal remodeling related signaling pathways were detected by Western blot assays. RESULTS: TSTT treatment (65, 33 mg/kg) markedly improved motor function after ischemic stroke. T2 mapping MRI demonstrated that TSTT decreased lesion volumes, and DTI further confirmed that TSTT preserved axonal microstructure of the sensorimotor cortex and internal capsule. Meanwhile, diffusion tensor tractography (DTT) showed that TSTT elevated correspondent density and length of fiber in the internal capsule. These MRI measurements were confirmed by histological examinations. Notably, TSTT significantly increased Ki67/NG2, Ki67/CNPase double-labeled cells along the boundary zone of ischemic cortex and striatum. Meanwhile, TSTT treatment up-regulated the phosphorylation level of Ser 9 in GSK-3ß, and down-regulated phosphorylated ß-catenin and CRMP-2 expression. CONCLUSION: Taken together, our findings indicated that TSTT (65, 33 mg/kg) enhanced post-stroke functional recovery, amplified endogenous oligodendrogenesis and promoted axonal regeneration. The beneficial role of TSTT might be correlated with GSK-3/ß-catenin/CRMP-2 modulating axonal reorganization after ischemic stroke.

Global cerebral ischemia in adolescent male Long Evans rats: Effects of vanillic acid supplementation on stress response, emotionality, and visuospatial memory.

The developmental period is critical in delineating plastic response to internal and external events. However, neurobehavioural effects of global cerebral ischemia (GCI) in the maturing brain remain largely unknown. This study characterised the effects of GCI experienced at puberty on adulthood (1) hippocampus CA1 neuronal damage, (2) cognitive and emotional impairments, and (3) glucocorticoid receptor (GR) expression. Effects of adolescent exposure to the phenol vanillic acid (VA) on post-ischemic outcomes were also determined. Male Long Evans rats (n = 35) were supplemented for 21 consecutive days (postnatal days 33-53) with VA (91 mg/kg) or nut paste vehicle (control) prior to a 10-min GCI or sham surgery. As adults, rats were tested in the Open Field Test (OFT), Elevated-Plus Maze (EPM), and Barnes Maze (BM). GR expression was determined in the basolateral amygdala (BLA), CA1, and paraventricular nucleus (PVN), and brain injury assessed via CA1 neuronal density. Adolescent GCI exposure induced extensive hippocampal CA1 injury, which was not prevented by VA supplementation. Behaviourally, GCI increased EPM exploration while having no impact on spatial memory. VA intake increased OFT peripheral exploration. Notably, while no delayed changes in CA1 and PVN GR immunoreactivity were noted, both treatments separately increased BLA GR expression when compared with sham-nut paste rats. Age at GCI occurrence plays a critical role on post-ischemic impairments. The observation of minimal functional impairments despite important CA1 neuronal damage supports use of compensatory mechanisms. Our findings also show daily VA supplementation during adolescence to have no protective effects on post-ischemic outcomes, contrasting adult intake.

MicroRNA-27b expression in rats submitted to physical exercise and experimental cerebral ischemia / Expresión de MicroRNA-27b en ratas sometidas a ejercicio físico e isquemia cerebral experimental

SUMMARY: Cerebral ischemia has not only a high mortality rate, which is the second leading cause of death worldwide, but is also responsible for severe disabilities in working age individuals, generating enormous public expending for treatment and rehabilitation of the affected individuals. The role of microRNAs in the pathophysiology of cerebral ischemia has been highlighted in current investigations. In addition, recent studies have also highlighted physical exercise as a possible protective factor both in the prevention and in the effects of cerebral ischemia, placing it as an important study resource. Thus, we investigated the role of physical exercise in experimental cerebral ischemia associated with the expression of microRNA-27b. 16 animals were used, divided into four experimental groups: Control, Physical Exercise, Cerebral Ischemia and Cerebral Ischemia associated with Physical Exercise. The real-time PCR methodology was used to analyze the expression of microRNA-27b. Although there were no statistically significant differences in the expression of microRNA-27b between the groups studied, the increased expression of microRNA-27b in the Physical Exercise group indicates its neuroprotective role in the pathophysiology of cerebral ischemia.

RESUMEN: La isquemia cerebral no solo tiene una alta tasa de mortalidad y es la segunda causa principal de muerte en todo el mundo, sino también es la causa de enfermedades invalidantes en personas en edad laboral, lo que genera un gasto público enorme para el tratamiento y la rehabilitación de las personas afectadas. El papel de los microARN en la fisiopatología de la isquemia cerebral se ha destacado en las investigaciones actuales. Además, estudios recientes también han destacado el ejercicio físico como un posible factor protector tanto en la prevención como en los efectos de la isquemia cerebral, situándolo como un importante recurso de estudio. Por lo tanto, investigamos el papel del ejercicio físico en la isquemia cerebral experimental asociada con la expresión del microARN-27b. Se utilizaron 16 animales, divididos en cuatro grupos experimentales: Control, Ejercicio Físico, Isquemia Cerebral e Isquemia Cerebral asociada al Ejercicio Físico. Se utili- zó la metodología de PCR en tiempo real para analizar la expresión de microARN-27b. Aunque no se observaron diferencias estadísticamente significativas en la expresión de microARN-27b entre los grupos estudiados, la mayor expresión de microARN-27b en el grupo de Ejercicio Físico indica su papel neuroprotector en la fisiopatología de la isquemia cerebral.

Extracellular DJ-1 induces sterile inflammation in the ischemic brain.

Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.

Consecutive and temporally distant perseverations after right brain damage: A prospective study.

Objective: Right brain-damaged patients may show omissions and/or additional marks in target cancellation. The latter is classified as perseverative behavior and has been attributed to defective response inhibition or attentional disengagement deficit. This study aimed at (a) verifying that consecutive (immediate) and return (temporally distant) motor perseverations could be due to different mechanisms; (b) investigating the relationships among different types of perseveration (e.g., consecutive, return, scribble), spatial neglect and the impairment in specific components of executive functioning. Method: Seventeen right brain-damaged patients underwent letter, star, bell, and apple cancellation tasks. A global index for each type of perseveration found and Mean Position of Hits, as a neglect index, were calculated. The following components of executive functioning were evaluated: motor programming (Frontal Assessment Battery [FAB] subtest), inhibitory control FAB, interference sensitivity (FAB and Stroop color-word interference test), set-shifting (Weigl sorting test, Phonemic/semantic alternate fluencies), and working memory (Backward Digit span). Results: Ten patients out of 17 showed some degree of perseveration. Regularized linear regression analyses demonstrated that interference sensitivity and Stroop test performances were related to return perseverations and backward digit to scribble ones. No significant relationships were found for consecutive perseverations and between neglect and any type of perseverations. Conclusions: The present study showed that return perseverations might have a distinct etiology from consecutive ones, being related to an inability to update and shift between action programs according to the visual stimuli. A finer classification of perseverations could help in unveiling the neuropsychological mechanisms underlying each type of behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).