| 1. |
- Agyemang, Alex Adusei, et al.
(författare)
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Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?
- 2017
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 8:5, s. 461-473
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Tidskriftsartikel (refereegranskat)abstract
- Decreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.
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| 2. |
- Blomgren, Klas, 1963, et al.
(författare)
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Injury and repair in the immature brain.
- 2013
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Ingår i: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-601X .- 1868-4483. ; 4:2, s. 135-136
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Chumak, Tetyana, 1982, et al.
(författare)
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Maternal n-3 Polyunsaturated Fatty Acid Enriched Diet Commands Fatty Acid Composition in Postnatal Brain and Protects from Neonatal Arterial Focal Stroke
- 2022
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 13:3, s. 449-461
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Tidskriftsartikel (refereegranskat)abstract
- The fetus is strongly dependent on nutrients from the mother, including polyunsaturated fatty acids (PUFA). In adult animals, n-3 PUFA ameliorates stroke-mediated brain injury, but the modulatory effects of different PUFA content in maternal diet on focal arterial stroke in neonates are unknown. This study explored effects of maternal n-3 or n-6 enriched PUFA diets on neonatal stroke outcomes. Pregnant mice were assigned three isocaloric diets until offspring reached postnatal day (P) 10-13: standard, long-chain n-3 PUFA (n-3) or n-6 PUFA (n-6) enriched. Fatty acid profiles in plasma and brain of mothers and pups were determined by gas chromatography-mass spectrometry and cytokines/chemokines by multiplex protein analysis. Transient middle cerebral artery occlusion (tMCAO) was induced in P9-10 pups and cytokine and chemokine accumulation, caspase-3 and calpain-dependent spectrin cleavage and brain infarct volume were analyzed. The n-3 diet uniquely altered brain lipid profile in naive pups. In contrast, cytokine and chemokine levels did not differ between n-3 and n-6 diet in naive pups. tMCAO triggered accumulation of inflammatory cytokines and caspase-3-dependent and -independent cell death in ischemic-reperfused regions in pups regardless of diet, but magnitude of neuroinflammation and caspase-3 activation were attenuated in pups on n-3 diet, leading to protection against neonatal stroke. In conclusion, maternal/postnatal n-3 enriched diet markedly rearranges neonatal brain lipid composition and modulates the response to ischemia. While standard diet is sufficient to maintain low levels of inflammatory cytokines and chemokines under physiological conditions, n-3 PUFA enriched diet, but not standard diet, attenuates increases of inflammatory cytokines and chemokines in ischemic-reperfused regions and protects from neonatal stroke.
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| 4. |
- Delavaran, Hossein, et al.
(författare)
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Spontaneous Recovery of Upper Extremity Motor Impairment After Ischemic Stroke : Implications for Stem Cell-Based Therapeutic Approaches
- 2017
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 8:4, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical studies suggest that stem cell therapy (SCT) may improve sensorimotor recovery after stroke. Upper extremity motor impairment (UEMI) is common after stroke, often entailing substantial disability. To evaluate the feasibility of post-stroke UEMI as a target for SCT, we examined a selected sample of stroke patients potentially suitable for SCT, aiming to assess the frequency and recovery of UEMI, as well as its relation to activity limitations and participation restrictions. Patients aged 20–75 years with first-ever ischemic stroke, and National Institutes of Health Stroke Scale (NIHSS) scores 1–18, underwent brain diffusion-weighted MRI within 4 days of stroke onset (n = 108). Survivors were followed up after 3–5 years, including assessment with NIHSS, Fugl-Meyer assessment of upper extremity (FMA-UE), modified Rankin Scale (mRS), and Stroke Impact Scale (SIS). UEMI was defined as NIHSS arm/hand score ≥1. UEMI recovery was evaluated with change in NIHSS arm/hand scores between baseline and follow-up. Of 97 survivors, 84 were available to follow-up. Among 76 subjects (of 84) without recurrent stroke, 41 had UEMI at baseline of which 10 had residual UEMI at follow-up. The FMA-UE showed moderate-severe impairment in seven of 10 survivors with residual UEMI. UEMI was correlated to mRS (rs = 0.49, p < 0.001) and the SIS social participation domain (rs = −0.38, p = 0.001). Nearly 25% of the subjects with UEMI at baseline had residual impairment after 3–5 years, whereas about 75% showed complete recovery. Most of the subjects with residual UEMI had moderate-severe impairment, which correlated strongly to dependency in daily activities and social participation restrictions. Our findings suggest that SCT targeting post-stroke UEMI may be clinically valuable with significant meaningful benefits for patients but also emphasize the need of early prognostication to detect patients that will have residual impairment in order to optimize patient selection for SCT.
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| 5. |
- Dock, Hua, et al.
(författare)
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DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats
- 2015
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Ingår i: TRANSLATIONAL STROKE RESEARCH. - : Springer Verlag (Germany). - 1868-4483 .- 1868-601X. ; 6:4, s. 296-300
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Tidskriftsartikel (refereegranskat)abstract
- 5-Aza-deoxycytidine (5-aza-dC) confers neuroprotection in ischemic mice by inhibiting DNA methylation. Zebularine is another DNA methylation inhibitor, less toxic and more stable in aqueous solutions and, therefore more biologically suitable. We investigated Zebularines effects on brain ischemia in a rat middle cerebral artery occlusion (MCAo) model in order to elucidate its therapeutic potential. Male Wistar wild-type (WT) rats were randomly allocated to three treatment groups, vehicle, Zebularine 100 mu g, and Zebularine 500 mu g. Saline (10 mu L) or Zebularine (10 mu L) was administered intracerebroventricularly 20 min before 45-min occlusion of the middle cerebral artery. Reperfusion was allowed after 45-min occlusion, and the rats were sacrificed at 24-h reperfusion. The brains were removed, sliced, and stained with 2 % 2,3,5-triphenyltetrazolium chloride (TTC) before measuring infarct size. Zebularine (500 mu g) reduced infarct volumes significantly (p less than 0.05) by 61 % from 20.7 +/- 4.2 % in the vehicle treated to 8.1 +/- 1.6 % in the Zebularine treated. Zebularine (100 mu g) also reduced infarct volumes dramatically by 55 to 9.4 +/- 1.2 %. The mechanisms behind this neuroprotection is not yet known, but the results agree with previous studies and support the notion that Zebularine-induced inhibition of DNA methyltransferase ameliorates ischemic brain injury in rats.
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| 6. |
- Edvinsson, Lars, et al.
(författare)
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Plasticity of Cerebrovascular Smooth Muscle Cells After Subarachnoid Hemorrhage
- 2014
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 5:3, s. 365-376
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Tidskriftsartikel (refereegranskat)abstract
- Subarachnoid hemorrhage (SAH) is most often followed by a delayed phase of cerebral ischemia which is associated with high morbidity and mortality rates. The causes underlying this delayed phase are still unsettled, but are believed to include cerebral vasospasm, cortical spreading depression, inflammatory reactions, and microthrombosis. Additionally, a large body of evidence indicates that vascular plasticity plays an important role in SAH pathophysiology, and this review aims to summarize our current knowledge on the phenotypic changes of vascular smooth muscle cells of the cerebral vasculature following SAH. In light of the emerging view that the whole cerebral vasculature and the cells of the brain parenchyma should be viewed as one integrated neurovascular network, phenotypical changes are discussed both for the cerebral arteries and the microvasculature. Furthermore, the intracellular signaling involved in the vascular plasticity is discussed with a focus on the Raf-MEK1/2-ERK1/2 pathway which seems to play a crucial role in SAH pathology.
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| 7. |
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| 8. |
- Kokaia, Zaal, et al.
(författare)
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Neural Stem Cell-Based Therapy for Ischemic Stroke
- 2011
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 2:3, s. 272-278
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell-based approaches for the treatment of stroke have been the subject of intensive research over the past decade. Based on accumulated experimental evidence, stem cell-based therapy is a very promising prospect for the development of a novel treatment to restore stroke-damaged brain and impaired neurological function. Studies performed on experimental animal models of stroke employed a variety of stem cell types from diverse sources and have demonstrated their ability to replace lost neurons and functionally integrate into the brain, modulate inflammation, and stimulate angiogenesis and neurogenesis from an endogenous stem cell pool, most likely through trophic actions. A few clinical trials in stroke patients using stem cell transplantation have been completed or are on-going but the results have not yet proven the effectiveness of the stem cell-based approaches. A joint effort of stroke researchers and clinicians is needed to further optimize treatment protocols using safe and reproducible stem cell sources tested in relevant animal models of stroke and showing substantial neurological recovery of stroke-impaired function.
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| 9. |
- Kucharz, K., et al.
(författare)
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Fission and Fusion of the Neuronal Endoplasmic Reticulum
- 2013
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:6, s. 652-662
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Tidskriftsartikel (refereegranskat)abstract
- The endoplasmic reticulum (ER) is central for protein synthesis and is the largest intracellular Ca2+ store in neurons. The neuronal ER is classically described to have a continuous lumen spanning all cellular compartments. This allows neuronal ER to integrate spatially separate events in the cell. Recent in vitro as well as in vivo findings, however, demonstrate that the neuronal ER is a structurally dynamic entity, capable of rapid fragmentation, i.e., ER fission. The ER fragments can fuse back together and reinstate ER continuity. This reversible phenomenon can be induced repeatedly within the same cell, is temperature-dependent, and compatible with cell survival. The key trigger for dendritic ER fission is N-methyl D-aspartate (NMDA) receptor stimulation in the presence of extracellular Ca2+. However, the exact molecular machinery responsible for the fission and fusion of neuronal ER remains unknown. Reversible ER fission represents a new cell biological event downstream of NMDA receptor-gated Ca2+ influx and may thus influence many aspects of neuronal function in physiology and disease. Hence, it constitutes a new field for exploration in neuroscience that will benefit greatly from recent advances in light microscopy imaging techniques allowing dynamic characterization of cellular events in vitro and in vivo.
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| 10. |
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| 11. |
- Lundström, Annika, et al.
(författare)
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Prognostic Value of Circulating Microvesicle Subpopulations in Ischemic Stroke and TIA
- 2020
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 11:4, s. 708-719
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Tidskriftsartikel (refereegranskat)abstract
- Platelet microvesicles (PMV) have previously been found elevated in acute ischemic stroke (IS) and could be biomarkers for risk of recurrence. PMV surface antigens such as P-selectin and phosphatidylserine (PS) reflect platelet activation and procoagulance. Tissue factor-positive microvesicles (TF+MV) are considered procoagulant, in particular if co-expressing PS. We enumerated MV subpopulations with these surface antigens in a cohort of 211 patients with primarily non-cardioembolic IS or transient ischemic attack (TIA) and investigated their association with long-term outcome. MV concentrations were determined by flow cytometry in the acute and convalescent phase. Primary outcome was a composite of fatal and non-fatal recurrent IS or myocardial infarction. Secondary outcomes were recurrent IS and all-cause mortality. Outcome events were obtained from Swedish registers during a follow-up of 1100 patient years. Concentrations of PS-positive and PS-negative MV populations were elevated in patients compared with healthy controls in both the acute and convalescent phase. PS+TF+PMV displayed pronounced elevations, median fold change 77 in the acute phase (p < 0.0001) but were not associated with outcome, neither were PS+P-selectin(+)PMV. The only subpopulation positively associated with primary outcome was PS-TF+PMV, with adjusted hazard ratio of 1.86 (1.04-3.31,p = 0.036) by Cox regression. Unexpectedly, several MV subpopulations tended to be associated with reduced risk of poor long-term outcome. Our results suggest that PS+TF+PMV may be a promising marker for cerebral ischemia, and that the in vivo generation of PS-MV after IS/TIA warrants further study. Future MV studies should ideally enumerate PS(+)and PS-MV subpopulations separately.
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| 12. |
- Olson, Linus, et al.
(författare)
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Comparison of Three Hypothermic Target Temperatures for the Treatment of Hypoxic Ischemia : MRNA Level Responses of Eight Genes in the Piglet Brain
- 2013
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 248-257
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Tidskriftsartikel (refereegranskat)abstract
- Hypothermia can reduce neurodevelopmental disabilities in asphyxiated newborn infants. However, the optimal cooling temperature for neuroprotection is not well defined. We studied the effects of transient piglet brain hypoxic ischemia (HI) on transcriptional activity of eight genes and if mRNA level alterations could be counteracted by whole body cooling to 35, 33. 5 or 30 °C. BDNF mRNA was globally upregulated by the insult, and none of the cooling temperatures counteracted this change. In contrast, MANF mRNA was downregulated, and these changes were modestly counteracted in different brain regions by hypothermic treatment at 33. 5 °C, while 30 °C aggravated the MANF mRNA loss. MAP2 mRNA was markedly downregulated in all brain regions except striatum, and cooling to 33. 5 °C modestly counteract this downregulation in the cortex cerebri. There was a tendency for GFAP mRNA levels in core, but not mantle regions to be downregulated and for these changes to be modestly counteracted by cooling to 33. 5 or 35 °C. Cooling to 30 °C caused global GFAP mRNA decrease. HSP70 mRNA tended to become upregulated by HI and to be more pronounced in cortex and CA1 of hippocampus during cooling to 33. 5 °C. We conclude that HI causes alterations of mRNA levels of many genes in superficial and deep piglet brain areas. Some of these changes may be beneficial, others detrimental, and lowering body temperature partly counteracts some, but not all changes. There may be general differences between core and mantle regions, as well as between the different cooling temperatures for protection. Comparing the three studied temperatures, cooling to 33. 5 °C, appears to provide the best cooling temperature compromise.
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| 13. |
- Pujol-Calderón, Fani, et al.
(författare)
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Prediction of Outcome After Endovascular Embolectomy in Anterior Circulation Stroke Using Biomarkers.
- 2022
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Ingår i: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-601X .- 1868-4483. ; 13, s. 65-76
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Tidskriftsartikel (refereegranskat)abstract
- Stroke is a major public health problem that can cause a long-term disability or death due to brain damage. Serious stroke is frequently caused by a large vessel occlusion in the anterior circulation, which should be treated by endovascular embolectomy if possible. In this study, we investigated the use of the brain damage biomarkers tau, NFL, NSE, GFAp, and S100B to understand the progression of nervous tissue damage and their relationship to outcome in such stroke after endovascular treatment. Blood samples were taken from 90 patients pre-treatment and 2 h, 24 h, 48 h, 72 h and 3 months after endovascular treatment. Stroke-related neurological deficit was estimated using the National Institute of Health Stroke Scale (NIHSS) at admission and at 24 h. Neurological outcome was evaluated at 3 months. After stroke, tau, NFL, GFAp and S100B increased in a time dependent manner, while NSE remained constant over time. At 3 months, tau and GFAp levels were back to normal whereas NFL was still high. Tau, NFL and GFAp correlated well to outcome, as well as to infarct volume and NIHSS at 24 h. The best time for prediction of poor outcome was different for each biomarker. However, the combination of NIHSS at 24 h with either tau, NFL or GFAp at 48 h gave the best prediction. The use of biomarkers in the early setting after endovascular treatment of stroke will lead to a simplified and standardized way to estimate the nervous tissue damage and possibly complement the clinical judgement in foreseeing the need of rehabilitation measures.
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| 14. |
- Steliga, A, et al.
(författare)
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Neurovascular Unit as a Source of Ischemic Stroke Biomarkers-Limitations of Experimental Studies and Perspectives for Clinical Application
- 2020
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Ingår i: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-601X .- 1868-4483. ; 11:4, s. 553-579
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral stroke, which is one of the most frequent causes of mortality and leading cause of disability in developed countries, often leads to devastating and irreversible brain damage. Neurological and neuroradiological diagnosis of stroke, especially in its acute phase, is frequently uncertain or inconclusive. This results in difficulties in identification of patients with poor prognosis or being at high risk for complications. It also makes difficult identification of these stroke patients who could benefit from more aggressive therapies. In contrary to the cardiovascular disease, no single biomarker is available for the ischemic stroke, addressing the abovementioned issues. This justifies the need for identifying of effective diagnostic measures characterized by high specificity and sensitivity. One of the promising avenues in this area is studies on the panels of biomarkers characteristic for processes which occur in different types and phases of ischemic stroke and represent all morphological constituents of the brains’ neurovascular unit (NVU). In this review, we present the current state of knowledge concerning already-used or potentially applicable biomarkers of the ischemic stroke. We also discuss the perspectives for identification of biomarkers representative for different types and phases of the ischemic stroke, as well as for different constituents of NVU, which concentration levels correlate with extent of brain damage and patients’ neurological status. Finally, a critical analysis of perspectives on further improvement of the ischemic stroke diagnosis is presented.
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| 15. |
- Stridh, Linnea, 1983, et al.
(författare)
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Regulation of Toll-Like Receptors in the Choroid Plexus in the Immature Brain After Systemic Inflammatory Stimuli
- 2013
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 220-227
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Tidskriftsartikel (refereegranskat)abstract
- The choroid plexus is the site of the blood–cerebrospinal fluid (CSF) barrier (BCSFB) and has also been considered as a possible route for peripheral immune signals and cells to transfer to the central nervous system. Infection/inflammation stimulates innate and subsequent adaptive immune responses via Toll-like receptors (TLRs). In this study, we have investigated the mRNA expression of TLRs, cytokines, and tight junction proteins in the choroid plexus in the immature brain after systemic inflammation, as well as accumulation of immune cells into the CSF. Specific ligands for TLR-1/2, TLR-3, and TLR-4 were administered to postnatal day 8 mice and mRNA expression for the targeted genes was examined in the choroid plexus. We found that mRNA for all four TLRs was detected in the choroid plexus under control conditions. Following immune stimulation, expression of all the TLRs was upregulated by their respective ligands, except for TLR-4 mRNA, which was downregulated by Pam3CSK4 (PAM; a TLR-1/2 ligand). In addition, we investigated BCSFB regulation after TLR stimulation and found that TLR-1/2 and TLR-4 activation was associated with changes in mRNA expression of the tight junction protein occludin in the choroid plexus. PAM induced choroid plexus transcription of TNF-α and resulted in the most dramatic increase in numbers of white blood cells in the CSF. The data suggest a possible mechanism whereby systemic inflammation stimulates TLRs in the choroid plexus, which may lead to disturbances in choroid plexus barrier function, as well as infiltration of immune cells through the plexus.
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| 16. |
- Sävman, Karin, 1960, et al.
(författare)
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Microglia/Macrophage-Derived Inflammatory Mediators Galectin-3 and Quinolinic Acid are Elevated in Cerebrospinal Fluid from Newborn Infants After Birth Asphyxia.
- 2013
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Ingår i: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 228-235
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Tidskriftsartikel (refereegranskat)abstract
- Activation of microglia/macrophages is important in neonatal hypoxic-ischemic (HI) brain injury. Based on experimental studies, we identified macrophage/microglia-derived mediators with potential neurotoxic effects after neonatal HI and examined them in cerebrospinal fluid (CSF) from newborn infants after birth asphyxia. Galectin-3 is a novel inflammatory mediator produced by microglia/macrophages. Galectin-3 is chemotactic for inflammatory cells and activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase resulting in production and release of reactive oxygen species (ROS). Matrix metalloproteinase-9 (MMP-9) is a tissue-degrading protease expressed by activated microglia in the immature brain after HI. Both galectin-3 and MMP-9 contribute to brain injury in animal models for neonatal HI. Quinolinic acid (QUIN) is a neurotoxic N-methyl-d-aspartate (NMDA) receptor agonist also produced by activated microglia/macrophages. Galectin-3 and MMP-9 were measured by ELISA and QUIN by mass spectrometry. Asphyxiated infants (n=20) had higher levels of galectin-3 (mean (SEM) 2.64 (0.43) ng/mL) and QUIN (335.42 (58.9) nM) than controls (n=15) (1.36 (0.46) ng/mL and 116.56 (16.46) nM, respectively), p<0.05 and p<0.01. Infants with septic infections (n=10) did not differ from controls. Asphyxiated infants with abnormal outcome had higher levels of galectin-3 (3.96 (0.67) ng/mL) than those with normal outcome (1.76 (0.32) ng/mL), p=0.02, and the difference remained significant in the clinically relevant group of infants with moderate encephalopathy. MMP-9 was detected in few infants with no difference between groups. The potentially neurotoxic macrophage/microglia-derived mediators galectin-3 and QUIN are increased in CSF after birth asphyxia and could serve as markers and may contribute to injury.
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| 17. |
- Tack, Reinier W. P., et al.
(författare)
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Inflammation, Anti-inflammatory Interventions, and Post-stroke Cognitive Impairment: a Systematic Review and Meta-analysis of Human and Animal Studies
- 2023
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Ingår i: TRANSLATIONAL STROKE RESEARCH. - 1868-4483 .- 1868-601X.
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Forskningsöversikt (refereegranskat)abstract
- The pathophysiology and treatment of post-stroke cognitive impairment (PSCI) are not clear. Stroke triggers an inflammatory response, which might affect synapse function and cognitive status. We performed a systematic review and meta-analysis to assess whether patients with PSCI have increased levels of inflammatory markers and whether anti-inflammatory interventions in animals decrease PSCI. We systematically searched PubMed, EMBASE, and PsychInfo for studies on stroke. For human studies, we determined the standardized mean difference (SMD) on the association between PSCI and markers of inflammation. For animal studies, we determined the SMD of post-stroke cognitive outcome after an anti-inflammatory intervention. Interventions were grouped based on proposed mechanism of action. In patients, the SMD of inflammatory markers for those with versus those without PSCI was 0.46 (95% CI 0.18; 0.76; I2 = 92%), and the correlation coefficient between level of inflammation and cognitive scores was - 0.25 (95% CI - 0.34; - 0.16; I2 = 75%). In animals, the SMD of cognition for those treated with versus those without anti-inflammatory interventions was 1.43 (95% CI 1.12; 1.74; I2 = 83%). The largest effect sizes in treated animals were for complement inhibition (SMD = 1.94 (95% CI 1.50; 2.37), I2 = 51%) and fingolimod (SMD = 2.1 (95% CI 0.75; 3.47), I2 = 81%). Inflammation is increased in stroke survivors with cognitive impairment and is negatively correlated with cognitive functioning. Anti-inflammatory interventions seem to improve cognitive functioning in animals. Complement inhibition and fingolimod are promising therapies on reducing PSCI.
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| 18. |
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| 19. |
- van Dijk, B. J., et al.
(författare)
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Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage
- 2020
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 11, s. 678-688
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n=7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n =930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n =229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n =31) and CSF (n =10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n=15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was >1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3–10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.
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| 20. |
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| 21. |
- Zhu, Changlian, 1964, et al.
(författare)
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Inhaled nitric oxide protects males but not females from neonatal mouse hypoxia-ischemia brain injury
- 2013
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 201-207
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Tidskriftsartikel (refereegranskat)abstract
- It was recently discovered that while under normal conditions inhaled nitric oxide (iNO) does not affect cerebral blood flow, it selectively dilates arterioles in the ischemic penumbra during experimental cerebral ischemia, thereby increasing collateral blood flow and reducing ischemic brain damage. The mechanism was verified in multiple models, but only in male animals. Our aim was to evaluate the effects of iNO on brain injury in neonatal males and females. Nine-day-old mice were subjected to unilateral hypoxia–ischemia (HI), using 10 % oxygen balanced with nitrogen, with or without 50 ppm NO. Brain injury 72 h after HI was reduced by iNO as judged by percentage of injury (−21.7 %), atrophy (−23.7 %), and total pathological score (−29 %). The injury was significantly reduced in males (−32.4 %, p<0.05) but not in females (−7.1 %, n.s.). Neither the numbers nor the proliferation rates of neural stem cells in the dentate gyrus were affected by iNO. In summary, intraischemic iNO reduced neonatal HI brain injury in a gender-related manner.
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| 22. |
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| 23. |
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| 24. |
- Buizza, Carolina, et al.
(författare)
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The Transcriptional Landscape of Pericytes in Acute Ischemic Stroke
- 2023
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Ingår i: Translational Stroke Research. - 1868-4483.
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Tidskriftsartikel (refereegranskat)abstract
- The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3–4.5 h are still an unmet need to be addressed to improve stroke outcomes. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation, and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 h after stroke. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 h and characterized by the upregulation of genes mainly related to cytokine signaling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.
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| 25. |
- Edvinsson, Lars, et al.
(författare)
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Switching Off Vascular MAPK Signaling : A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage
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Ingår i: Translational Stroke Research. - 1868-4483.
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Forskningsöversikt (refereegranskat)abstract
- Patients who initially survive the rupture and repair of a brain aneurysm often take a devastating turn for the worse some days later and die or suffer permanent neurologic deficits. This catastrophic sequela is attributed to a delayed phase of global cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH), but we lack effective treatment. Here we present our view, based on 20 years of research, that the initial drop in blood flow at the time of rupture triggers genomic responses throughout the brain vasculature that manifest days later as increased vasoconstriction and decreased cerebral blood flow. We propose a novel treatment strategy to prevent DCI by early inhibition of the vascular mitogen-activated protein kinase (MAPK) pathway that triggers expression of vasoconstrictor and inflammatory mediators. We summarize evidence from experimental SAH models showing early treatment with MAPK inhibitors “switches off” these detrimental responses, maintains flow, and improves neurological outcome. This promising therapy is currently being evaluated in clinical trials.
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