scholarly journals The Asparaginyl Endopeptidase Legumain after Experimental Stroke

2010 ◽  
Vol 30 (10) ◽  
pp. 1756-1766 ◽  
Author(s):  
Taku Ishizaki ◽  
Agnes Erickson ◽  
Enida Kuric ◽  
Mehrdad Shamloo ◽  
Ikuko Hara-Nishimura ◽  
...  
Keyword(s):  
Immune Cell ◽  
Infarct Volume ◽  
Recovery Period ◽  
Gene Array ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Asparaginyl Endopeptidase ◽  
Infarct Area ◽  
Deficient Mice

Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1+ microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74+ cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.

scholarly journals Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

2018 ◽  
Vol 39 (10) ◽  
pp. 1906-1918 ◽  
Author(s):  
Kota Kurisu ◽  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Jian Shi ◽  
Atsushi Kanoke ◽  
...  
Keyword(s):  
Cell Activation ◽  
Infarct Volume ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Neurological Outcomes ◽  
Intact Brain ◽  
The Brain

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

scholarly journals Infarct Volume is a Major Determiner of Post-Stroke Immune Cell Function and Susceptibility to Infection

Stroke ◽  
2009 ◽  
Vol 40 (10) ◽  
pp. 3226-3232 ◽  
Author(s):  
Andreas Hug ◽  
Alexander Dalpke ◽  
Nina Wieczorek ◽  
Thomas Giese ◽  
Alexander Lorenz ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Infarct Volume ◽  
Immune Cell Function ◽  
Post Stroke ◽  
Susceptibility To Infection

scholarly journals Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis

2020 ◽  
Author(s):  
Stefano Raffaele ◽  
Paolo Gelosa ◽  
Elisabetta Bonfanti ◽  
Marta Lombardi ◽  
Laura Castiglioni ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Senescence ◽  
Stroke Recovery ◽  
Post Stroke

scholarly journals Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

2021 ◽  
Vol 22 (13) ◽  
pp. 6693
Author(s):  
Katarzyna Zalewska ◽  
Rebecca J. Hood ◽  
Giovanni Pietrogrande ◽  
Sonia Sanchez-Bezanilla ◽  
Lin Kooi Ong ◽  
...  
Keyword(s):  
White Matter ◽  
Biochemical Analysis ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Experimental Stroke ◽  
White Matter Tract ◽  
Ipsilateral Hemisphere ◽  
Post Stroke ◽  
Sham Surgery ◽  
Prolonged Stress

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.

scholarly journals Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice

2021 ◽  
Author(s):  
Ri Yu ◽  
Nam-Suk Kim ◽  
Yan Li ◽  
Jin-Young Jeong ◽  
Sang-Joon Park ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Knockout Mice ◽  
Vascular Remodeling ◽  
Infarct Volume ◽  
Brain Infarction ◽  
Adult Brain ◽  
Stroke Recovery ◽  
Neurological Deficits ◽  
Post Stroke ◽  
Vegf Signaling

AbstractPost-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Recently, axon guidance molecules were revealed as key players in injured vessel remodeling. One such molecule, Semaphorin 3E (Sema3E), and its receptor, Plexin-D1, control vascular development by regulating vascular endothelial growth factor (VEGF) signaling. In this study, using a mouse model of transient brain infarction, we aimed to investigate whether Sema3E-Plexin-D1 signaling was involved in cerebrovascular remodeling after ischemic injury. We found that ischemic damage rapidly induced Sema3e expression in the neurons of peri-infarct regions, followed by Plexin-D1 upregulation in remodeling vessels. Interestingly, Plexin-D1 reemergence was concurrent with brain vessels entering an active angiogenic process. In line with this, Plxnd1 ablation worsened neurological deficits, infarct volume, neuronal survival rate, and blood flow recovery. Furthermore, reduced and abnormal vascular morphogenesis was caused by aberrantly increased VEGF signaling. In Plxnd1 knockout mice, we observed significant extravasation of intravenously administered tracers in the brain parenchyma, junctional protein downregulation, and mislocalization in regenerating vessels. This suggested that the absence of Sema3E-Plexin-D1 signaling is associated with blood–brain barrier (BBB) impairment. Finally, the abnormal behavioral performance, aberrant vascular phenotype, and BBB breakdown defects in Plxnd1 knockout mice were restored following the inhibition of VEGF signaling during vascular remodeling. These findings demonstrate that Sema3E-Plexin-D1 signaling can promote functional recovery by downregulating VEGF signaling in the injured adult brain.

scholarly journals Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

2021 ◽  
Author(s):  
Thuy-Vi V. Nguyen ◽  
Rachael H. Crumpacker ◽  
Kylie E. Calderon ◽  
Frankie G. Garcia ◽  
Jacob C. Zbesko ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cognitive Abilities ◽  
Immune Cell ◽  
Principal Component ◽  
Stroke Recovery ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Ipsilateral Hemisphere ◽  
Chronic Inflammatory Response ◽  
Post Stroke

ABSTRACTThe aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis, and had higher levels of glutamate, serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nesting test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery.SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer’s disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

scholarly journals Lempel-Ziv complexity of the EEG predicts long-term functional recovery after stroke in rats

2018 ◽  
Author(s):  
Susan Leemburg ◽  
Claudio L. Bassetti
Keyword(s):  
Motor Function ◽  
Functional Recovery ◽  
Brain Function ◽  
Complexity Analysis ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Multiscale Entropy ◽  
Experimental Stroke ◽  
Reaching Task ◽  
Post Stroke

AbstractNon-linear complexity of the EEG signal can be used to detect abnormal brain function relating to behavioral deficits. Here, we compare the effects of experimental stroke on EEG complexity using Lempel-Ziv complexity analysis (LZC) and multiscale entropy analysis (SampEn).EEG was recorded in bilateral motor cortex at baseline and during a 30-day recovery period after distal middle cerebral artery occlusion in rats. Motor function was assessed using a single pellet reaching task. Stroke caused an acute drop in both LZC and SampEn in the ipsilesional hemisphere in wakefulness, NREM and REM sleep, as well as reduced pellet reaching success. SampEn reductions persisted for at least 10 days post-stroke, whereas LZC had returned to baseline levels by day 4. EEG complexity in the contralesional hemisphere and in sham-operated animals were unaffected.If EEG complexity reflects post-stroke brain function, post-stroke asymmetry could be used to predict behavioral recovery. In rats, acute LZC asymmetry was significantly correlated with the amount of motor function recovery by post-stroke day 31, but SampEn asymmetry was not. EEG LZC may thus be a useful tool for predicting functional recovery after stroke. MSE could be effective in identifying cortical dysfunction, but does not reflect behavioral outcomes.

scholarly journals Growth Hormone Promotes Motor Function after Experimental Stroke and Enhances Recovery-Promoting Mechanisms within the Peri-Infarct Area

2020 ◽  
Vol 21 (2) ◽  
pp. 606 ◽  
Author(s):  
Sonia Sanchez-Bezanilla ◽  
N. David Åberg ◽  
Patricia Crock ◽  
Frederick R. Walker ◽  
Michael Nilsson ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Proliferation ◽  
Motor Function ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Post Stroke ◽  
Positive Effects ◽  
Infarct Area

Motor impairment is the most common and widely recognised clinical outcome after stroke. Current clinical practice in stroke rehabilitation focuses mainly on physical therapy, with no pharmacological intervention approved to facilitate functional recovery. Several studies have documented positive effects of growth hormone (GH) on cognitive function after stroke, but surprisingly, the effects on motor function remain unclear. In this study, photothrombotic occlusion targeting the motor and sensory cortex was induced in adult male mice. Two days post-stroke, mice were administered with recombinant human GH or saline, continuing for 28 days, followed by evaluation of motor function. Three days after initiation of the treatment, bromodeoxyuridine was administered for subsequent assessment of cell proliferation. Known neurorestorative processes within the peri-infarct area were evaluated by histological and biochemical analyses at 30 days post-stroke. This study demonstrated that GH treatment improves motor function after stroke by 50%–60%, as assessed using the cylinder and grid walk tests. Furthermore, the observed functional improvements occurred in parallel with a reduction in brain tissue loss, as well as increased cell proliferation, neurogenesis, increased synaptic plasticity and angiogenesis within the peri-infarct area. These findings provide new evidence about the potential therapeutic effects of GH in stroke recovery.

scholarly journals Influence of metabolic syndrome on post-stroke outcome, angiogenesis and vascular function in old rats determined by dynamic contrast enhanced MRI

2020 ◽  
pp. 0271678X2097641
Author(s):  
Jesús M Pradillo ◽  
Macarena Hernández-Jiménez ◽  
María E Fernández-Valle ◽  
Violeta Medina ◽  
Juan E Ortuño ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Vascular Function ◽  
Infarct Volume ◽  
Stroke Recovery ◽  
Contrast Imaging ◽  
Dce Mri ◽  
Post Stroke ◽  
Non Invasive ◽  
Contrast Enhanced ◽  
Old Rats

Stroke affects primarily aged and co-morbid people, aspects not properly considered to date. Since angiogenesis/vasculogenesis are key processes for stroke recovery, we purposed to determine how different co-morbidities affect the outcome and angiogenesis/vasculogenesis, using a rodent model of metabolic syndrome, and by dynamic enhanced-contrast imaging (DCE-MRI) to assess its non-invasive potential to determine these processes. Twenty/twenty-two month-old corpulent (JCR:LA-Cp/Cp), a model of metabolic syndrome and lean rats were used. After inducing the experimental ischemia by transient MCAO, angiogenesis was analyzed by histology, vasculogenesis by determination of endothelial progenitor cells in peripheral blood by flow cytometry and evaluating their pro-angiogenic properties in culture and the vascular function by DCE-MRI at 3, 7 and 28 days after tMCAO. Our results show an increased infarct volume, BBB damage and an impaired outcome in corpulent rats compared with their lean counterparts. Corpulent rats also displayed worse post-stroke angiogenesis/vasculogenesis, outcome that translated in an impaired vascular function determined by DCE-MRI. These data confirm that outcome and angiogenesis/vasculogenesis induced by stroke in old rats are negatively affected by the co-morbidities present in the corpulent genotype and also that DCE-MRI might be a technique useful for the non-invasive evaluation of vascular function and angiogenesis processes.

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