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Patricia D Hurn - One of the best experts on this subject based on the ideXlab platform.
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recombinant t cell receptor ligand treats Experimental Stroke
Stroke, 2009Co-Authors: Sandhya Subramanian, Arthur A Vandenbark, Patricia D Hurn, Bing Zhang, Yasuharu Kosaka, Gregory G Burrows, Marjorie R Grafe, Halina OffnerAbstract:Background and Purpose— Experimental Stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of Stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function. Methods— Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus. Results— Treatment with RTL551 (I-Ab molecule linked to MOG-35-55 peptide) reduced cortic...
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Experimental Stroke induces massive rapid activation of the peripheral immune system
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Halina Offner, Sandhya Subramanian, Susan M Parker, Michael Afentoulis, Arthur A Vandenbark, Patricia D HurnAbstract:Clinical Experimental Stroke induces injurious local brain inflammation. However, effects on the peripheral immune system have not been well characterized. We quantified mRNA and protein levels for cytokines, chemokines, and chemokine receptors (CCR) in brain, spinal cord, peripheral lymphoid organs (spleen, lymph node, blood, and cultured mononuclear cells from these sources), and blood plasma after reversible middle cerebral artery occlusion (MCAO) or sham treatment in male C57BL/6 mice. Middle cerebral artery occlusion induced a complex, but organ specific, pattern of inflammatory factors in the periphery. At both 6 and 22 h after MCAO, activated spleen cells from Stroke-injured mice secreted significantly enhanced levels of TNF-alpha, IFN-gamma, IL-6, MCP-1, and IL-2. Unstimulated splenocytes expressed increased chemokines and CCR, including MIP-2 and CCR2, CCR7 and CCR8 at 6 h; and MIP-2, IP-10, and CCR1 and CCR2 at 22 h. Also at 22 h, T cells from blood and lymph nodes secreted increased levels of inflammatory cytokines after activation. As expected, there were striking proinflammatory changes in postischemic brain. In contrast, spinal cord displayed suppression of all mediators, suggesting a compensatory response to intracranial events. These data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.
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estradiol regulates angiopoietin 1 mrna expression through estrogen receptor α in a rodent Experimental Stroke model
Stroke, 2005Co-Authors: Agnieszka A Ardelt, Patricia D Hurn, Louise D Mccullough, Kenneth S Korach, Michael M Wang, Diane H MunzenmaierAbstract:Background and Purpose— Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17β-estradiol (E2) reduce damage in Experimental Stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in Stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO). Methods— Female animals were ovariectomized, treated with 25 μg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted. Results— E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor-α knocko...
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postischemic estrogen reduces hypoperfusion and secondary ischemia after Experimental Stroke
Stroke, 2001Co-Authors: Louise D Mccullough, Nabil J Alkayed, Richard J Traystman, Megan J Williams, Patricia D HurnAbstract:Background and Purpose—Estrogen is a known neuroprotective and vasoprotective agent in Experimental cerebral ischemia. Preischemic steroid treatment protects animals of both sexes from focal cerebral ischemia. This study determined whether intravenous estrogen acts as a vasodilator when administered on reperfusion and whether the resulting increase in cerebral blood flow (CBF) provides tissue protection from middle cerebral artery occlusion. Methods—Adult male Wistar rats were treated with reversible middle cerebral artery occlusion (2 hours), then infused with intravenous estrogen (Premarin; 1 mg/kg) or vehicle during the first minutes of reperfusion (n=15 per group). Cortical laser-Doppler flowmetry was used to assess adequacy of occlusion. Ischemic lesion volume was determined at 22 hours after occlusion by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Cortical and striatal CBF was measured by 14[C]iodoantipyrine autoradiography at 10 (n=10) or 90 (n=11) minutes of reperfusion. Resul...
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Experimental Stroke in the female diabetic db db mouse
Journal of Cerebral Blood Flow and Metabolism, 2001Co-Authors: Susan J Vannucci, Patricia D Hurn, Nabil J Alkayed, Lisa B Willing, Shozo Goto, Robert M Brucklacher, Teresa L Wood, Javad Towfighi, Ian A SimpsonAbstract:Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic-ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics - male controls > female controls. Endischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia-ischemia in the female diabetic brain.
Halina Offner - One of the best experts on this subject based on the ideXlab platform.
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splenectomy reduces infarct volume and neuroinflammation in male but not female mice in Experimental Stroke
Journal of Neuroimmunology, 2015Co-Authors: Halina Offner, Abby L Dotson, Jianming Wang, Julie A Saugstad, Stephanie J MurphyAbstract:The peripheral immune response contributes to neurodegeneration after Stroke yet little is known about how this process differs between males and females. The current study demonstrates that splenectomy prior to Experimental Stroke eliminates sex differences in infarct volume and activated brain monocytes/microglia. In the periphery of both sexes, activated T cells correlate directly with Stroke outcome while monocytes are reduced by splenectomy only in males. This study provides new information about the sex specific mechanisms of the peripheral immune response in neurodegeneration after Stroke and demonstrates the need for representation of both sexes in basic and clinical Stroke research.
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different immunological mechanisms govern protection from Experimental Stroke in young and older mice with recombinant tcr ligand therapy
Frontiers in Cellular Neuroscience, 2014Co-Authors: Abby L Dotson, Nabil J Alkayed, Nicole L Libal, Halina OffnerAbstract:Stroke is a leading cause of death and disability in the United States. The lack of clinical success in Stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from Experimental Stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to Stroke that allow unique targeting of Stroke immunotherapies.
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pd l1 enhances cns inflammation and infarct volume following Experimental Stroke in mice in opposition to pd 1
Journal of Neuroinflammation, 2013Co-Authors: Halina Offner, Arthur A Vandenbark, Stephanie J Murphy, Sheetal Bodhankar, Yingxin ChenAbstract:Stroke severity is worsened by recruitment of inflammatory immune cells into the brain. This process depends in part on T cell activation, in which the B7 family of co-stimulatory molecules plays a pivotal role. Previous studies demonstrated more severe infarcts in mice lacking programmed death-1 (PD-1), a member of the B7 family, thus implicating PD-1 as a key factor in limiting Stroke severity. The purpose of this study was to determine if this protective effect of PD-1 involves either of its ligands, PD-L1 or PD-L2. Central nervous system (CNS) inflammation and infarct volume were evaluated in male PD-L1 and PD-L2 knockout (-/-) mice undergoing 60 minutes of middle cerebral artery occlusion (MCAO) followed by 96 hours of reperfusion and compared to wild-type (WT) C57BL/6J mice. PD-L1-/- and PD-L2-/- mice had smaller total infarct volumes compared to WT mice. The PD-L1-/- and to a lesser extent PD-L2-/- mice had reduced levels of proinflammatory activated microglia and/or infiltrating monocytes and CD4+ T cells in the ischemic hemispheres. There was a reduction in ischemia-related splenic atrophy accompanied by lower activation status of splenic T cells and monocytes in the absence of PD-L1, suggesting a pathogenic rather than a regulatory role for both PD-1 ligands (PD-Ls). Suppressor T cells (IL-10-producing CD8+CD122+ T cells) trafficked to the brain in PD-L1-/- mice and there was decreased expression of CD80 on splenic antigen-presenting cells (APCs) as compared to the WT and PD-L2-/- mice. Our novel observations are the first to implicate PD-L1 involvement in worsening outcome of Experimental Stroke. The presence of suppressor T cells in the right MCAO-inflicted hemisphere in mice lacking PD-L1 implicates these cells as possible key contributors for controlling adverse effects of ischemia. Increased expression of CD80 on APCs in WT and PD-L2-/- mice suggests an overriding interaction leading to T cell activation. Conversely, low CD80 expression by APCs, along with increased PD-1 and PD-L2 expression in PD-L1-/- mice suggests alternative T cell signaling pathways, leading to a suppressor phenotype. These results suggest that agents (for example antibodies) that can target and neutralize PD-L1/2 may have therapeutic potential for treatment of human Stroke.
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recombinant t cell receptor ligand treats Experimental Stroke
Stroke, 2009Co-Authors: Sandhya Subramanian, Arthur A Vandenbark, Patricia D Hurn, Bing Zhang, Yasuharu Kosaka, Gregory G Burrows, Marjorie R Grafe, Halina OffnerAbstract:Background and Purpose— Experimental Stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of Stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function. Methods— Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus. Results— Treatment with RTL551 (I-Ab molecule linked to MOG-35-55 peptide) reduced cortic...
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Experimental Stroke induces massive rapid activation of the peripheral immune system
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Halina Offner, Sandhya Subramanian, Susan M Parker, Michael Afentoulis, Arthur A Vandenbark, Patricia D HurnAbstract:Clinical Experimental Stroke induces injurious local brain inflammation. However, effects on the peripheral immune system have not been well characterized. We quantified mRNA and protein levels for cytokines, chemokines, and chemokine receptors (CCR) in brain, spinal cord, peripheral lymphoid organs (spleen, lymph node, blood, and cultured mononuclear cells from these sources), and blood plasma after reversible middle cerebral artery occlusion (MCAO) or sham treatment in male C57BL/6 mice. Middle cerebral artery occlusion induced a complex, but organ specific, pattern of inflammatory factors in the periphery. At both 6 and 22 h after MCAO, activated spleen cells from Stroke-injured mice secreted significantly enhanced levels of TNF-alpha, IFN-gamma, IL-6, MCP-1, and IL-2. Unstimulated splenocytes expressed increased chemokines and CCR, including MIP-2 and CCR2, CCR7 and CCR8 at 6 h; and MIP-2, IP-10, and CCR1 and CCR2 at 22 h. Also at 22 h, T cells from blood and lymph nodes secreted increased levels of inflammatory cytokines after activation. As expected, there were striking proinflammatory changes in postischemic brain. In contrast, spinal cord displayed suppression of all mediators, suggesting a compensatory response to intracranial events. These data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.
Nabil J Alkayed - One of the best experts on this subject based on the ideXlab platform.
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different immunological mechanisms govern protection from Experimental Stroke in young and older mice with recombinant tcr ligand therapy
Frontiers in Cellular Neuroscience, 2014Co-Authors: Abby L Dotson, Nabil J Alkayed, Nicole L Libal, Halina OffnerAbstract:Stroke is a leading cause of death and disability in the United States. The lack of clinical success in Stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from Experimental Stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to Stroke that allow unique targeting of Stroke immunotherapies.
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delayed administration of a pten inhibitor bpv improves functional recovery after Experimental Stroke
Neuroscience, 2013Co-Authors: Lunlin Mao, Xiaomei Zhou, Xuechu Zhen, Jia Jia, Yunqi Xiao, Yali Wang, Xiaowei Mao, Yangtai Guan, Nabil J Alkayed, Jian ChengAbstract:Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitors administered prior to or immediately after Experimental Stroke confer acute neuroprotection. However, it remains unclear if delayed treatment with a PTEN inhibitor improves long-term functional recovery after Stroke. We addressed the issue in this study. Adult male mice were subjected to 1h of middle cerebral artery occlusion (MCAO) followed by treatment with a well-established PTEN inhibitor BPV or saline daily for 14 days, starting at 24h after MCAO. Functional recovery was assessed with behavioral tests and acute infarct volumes were analyzed histologically. Delayed BPV treatment did not reduce infarction during the acute phase, but significantly improved long-term functional recovery after MCAO. Since PTEN is a critical intrinsic inhibitory factor in axonal regeneration, we further examined BPV effects on axonal densities following MCAO using bielschowsky silver staining and immunohistochemistry with antibodies against myelin basic protein. Delayed BPV treatment significantly increased axon densities in the ischemic brain at 14 days after MCAO. Moreover, PTEN expression persistently remained high in the ischemic brain over 14 days after MCAO, and BPV treatment increased post-ischemic activation of Akt and mTOR in the ischemic brain. Akt and mTOR activation are the well-established cascades downstream to PTEN inhibition and have been shown to contribute to post-injury axonal regrowth in response to PTEN inhibition. Consistently, in an in vitro neuronal ischemia model, BPV enhanced axonal outgrowth of primary cortical neurons after oxygen-glucose deprivation and the enhancing effects were abolished by Akt/mTOR inhibition. In conclusion, delayed BPV treatment improved functional recovery from Experimental Stroke possibly via enhancing axonal growth and Akt/mTOR activation contributed to BPV-enhanced post-Stroke axon growth.
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postischemic estrogen reduces hypoperfusion and secondary ischemia after Experimental Stroke
Stroke, 2001Co-Authors: Louise D Mccullough, Nabil J Alkayed, Richard J Traystman, Megan J Williams, Patricia D HurnAbstract:Background and Purpose—Estrogen is a known neuroprotective and vasoprotective agent in Experimental cerebral ischemia. Preischemic steroid treatment protects animals of both sexes from focal cerebral ischemia. This study determined whether intravenous estrogen acts as a vasodilator when administered on reperfusion and whether the resulting increase in cerebral blood flow (CBF) provides tissue protection from middle cerebral artery occlusion. Methods—Adult male Wistar rats were treated with reversible middle cerebral artery occlusion (2 hours), then infused with intravenous estrogen (Premarin; 1 mg/kg) or vehicle during the first minutes of reperfusion (n=15 per group). Cortical laser-Doppler flowmetry was used to assess adequacy of occlusion. Ischemic lesion volume was determined at 22 hours after occlusion by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Cortical and striatal CBF was measured by 14[C]iodoantipyrine autoradiography at 10 (n=10) or 90 (n=11) minutes of reperfusion. Resul...
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Experimental Stroke in the female diabetic db db mouse
Journal of Cerebral Blood Flow and Metabolism, 2001Co-Authors: Susan J Vannucci, Patricia D Hurn, Nabil J Alkayed, Lisa B Willing, Shozo Goto, Robert M Brucklacher, Teresa L Wood, Javad Towfighi, Ian A SimpsonAbstract:Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic-ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics - male controls > female controls. Endischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia-ischemia in the female diabetic brain.
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Experimental Stroke in the female diabetic db db mouse
Journal of Cerebral Blood Flow and Metabolism, 2001Co-Authors: Susan J Vannucci, Patricia D Hurn, Nabil J Alkayed, Lisa B Willing, Shozo Goto, Robert M Brucklacher, Teresa L Wood, Javad Towfighi, Ian A SimpsonAbstract:Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have ...
Tadeusz Wieloch - One of the best experts on this subject based on the ideXlab platform.
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Enriched housing enhances recovery of limb placement ability and reduces aggrecan-containing perineuronal nets in the rat somatosensory cortex after Experimental Stroke. PLoS One. 2014; 9: e93121. doi: 10.1371/journal.pone.0093121 PMID: 24664200
2016Co-Authors: Re Madinier, Karsten Ruscher, Miriana Jlenia Quattromani, Tadeusz WielochAbstract:Stroke causes life long disabilities where few therapeutic options are available. Using electrical and magnetic stimulation of the brain and physical rehabilitation, recovery of brain function can be enhanced even late after Stroke. Animal models support this notion, and housing rodents in an enriched environment (EE) several days after Experimental Stroke stimulates lost brain function by multisensory mechanisms. We studied the dynamics of functional recovery of rats with a lesion to the fore and hind limb motor areas induced by photothrombosis (PT), and with subsequent housing in either standard (STD) or EE. In this model, skilled motor function is not significantly enhanced by enriched housing, while the speed of recovery of sensori-motor function substantially improves over the 9-week study period. In particular, this Stroke lesion completely obliterates the fore and hind limb placing ability when visual and whisker guidance is prevented, a deficit that persists for up to 9 weeks of recovery, but that is markedly restored within 2 weeks by enriched housing. Enriched housing after Stroke also leads to a significant loss of perineuronal net (PNN) immunoreactivity; detection of aggrecan protein backbone with AB1031 antibody was decreased by 13–22%, and labelling of a glycan moiety of aggrecan with Cat-315 antibody was reduced by 25–30 % in the peri-infarct area and in the somatosensory cortex, respectively. The majority of these cells are parvalbumin/GABA inhibitory interneurons that are important in sensori-information processing. We conclude that damage to the fore and hind limb motor areas provides a model of loss of limb placing response without visual guidance, a defici
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can diffusion kurtosis imaging improve the sensitivity and specificity of detecting microstructural alterations in brain tissue chronically after Experimental Stroke comparisons with diffusion tensor imaging and histology
NeuroImage, 2014Co-Authors: Umesh S Rudrapatna, Tadeusz Wieloch, Karsten Ruscher, Kerstin Beirup, Wouter B Mol, Pavel Yanev, Alexander Leemans, Annette Van Der Toorn, Rick M DijkhuizenAbstract:Imaging techniques that provide detailed insights into structural tissue changes after Stroke can vitalize development of treatment strategies and diagnosis of disease. Diffusion-weighted MRI has been playing an important role in this regard. Diffusion kurtosis imaging (DKI), a recent addition to this repertoire, has opened up further possibilities in extending our knowledge about structural tissue changes related to injury as well as plasticity. In this study we sought to discern the microstructural alterations characterized by changes in diffusion tensor imaging (DTI) and DKI parameters at a chronic time point after Experimental Stroke. Of particular interest was the question of whether DKI parameters provide additional information in comparison to DTI parameters in understanding structural tissue changes, and if so, what their histological origins could be. Region-of-interest analysis and a data-driven approach to identify tissue abnormality were adopted to compare DTI- and DKI-based parameters in post mortem rat brain tissue, which were compared against immunohistochemistry of various cellular characteristics. The unilateral infarcted area encompassed the ventrolateral cortex and the lateral striatum. Results from region-of-interest analysis in the lesion borderzone and contralateral tissue revealed significant differences in DTI and DKI parameters between ipsi- and contralateral sensorimotor cortex, corpus callosum, internal capsule and striatum. This was reflected by a significant reduction in ipsilateral mean diffusivity (MD) and fractional anisotropy (FA) values, accompanied by significant increases in kurtosis parameters in these regions. Data-driven analysis to identify tissue abnormality revealed that the use of kurtosis-based parameters improved the detection of tissue changes in comparison with FA and MD, both in terms of dynamic range and in being able to detect changes to which DTI parameters were insensitive. This was observed in gray as well as white matter. Comparison against immunohistochemical stainings divulged no straightforward correlation between diffusion-based parameters and individual neuronal, glial or inflammatory tissue features. Our study demonstrates that DKI allows sensitive detection of structural tissue changes that reflect post-Stroke tissue remodeling. However, our data also highlights the generic difficulty in unambiguously asserting specific causal relationships between tissue status and MR diffusion parameters.
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effects of chronic clozapine administration on apolipoprotein d levels and on functional recovery following Experimental Stroke
Brain Research, 2010Co-Authors: Karsten Ruscher, Enida Kuric, Agnes Erickson, Ana R. Inácio, Tadeusz WielochAbstract:Elevated brain levels of apolipoprotein D (ApoD) correlate with improved neurological recovery after Experimental Stroke. Hence, a pharmacological induction of ApoD in the postischemic brain could be beneficial for recovery after Stroke. Here we investigated the effect of Clozapine, a compound that increases the expression of ApoD, in two rat models of Experimental Stroke. Rats were subjected to permanent occlusion of the middle cerebral artery (pMCAO) and treated with Clozapine (i.p. 10 mg/kg body weight) or saline for 8 or 28 days starting on the second day after MCAO. ApoD levels increased by 35% in the peri-infarct area after 10 and 30 days after pMCAO, mainly in neuron-specific nuclear protein (NeuN) positive neurons and glial fibrillary acidic protein (GFAP) positive astrocytes. Clozapine did not affect the neurological deficit assessed by the rotating pole test and a grip strength test at 7 days, 14 days, 21 days, and 28 days after pMCAO. Functional outcome and the infarct size were similar in rats subjected to transient MCAO and injected with Clozapine (i.p. 10 mg/kg body weight) or saline for 26 days starting on the second day after tMCAO. We conclude that Clozapine affects cellular processes involved in peri-infarct tissue reorganization, but does not affect functional recovery after MCAO.
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The asparaginyl endopeptidase legumain after Experimental Stroke.
Journal of Cerebral Blood Flow & Metabolism, 2010Co-Authors: Taku Ishizaki, Tadeusz Wieloch, Agnes Erickson, Enida Kuric, Mehrdad Shamloo, Ikuko Hara-nishimura, Ana R. Inácio, Karsten RuscherAbstract: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.
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enriched environment reduces apolipoprotein e apoe in reactive astrocytes and attenuates inflammation of the peri infarct tissue after Experimental Stroke
Journal of Cerebral Blood Flow and Metabolism, 2009Co-Authors: Karsten Ruscher, Agnes Erickson, Emelie Johannesson, Elena Brugiere, Mattias Rickhag, Tadeusz WielochAbstract:Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after Experimental Stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after Experimental Stroke, by using animal housing conditions that differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100beta(+)/glial fibrillary acidic protein (GFAP) negative reactive astrocytes at 4 to 7 days of recovery. Enriched housing after MCAO caused a marked decrease in ApoE levels compared with standard housing conditions, particularly in the ApoE/S100beta(+) reactive astrocytes. In addition, the levels of interleukin 1beta were lower in animals housed in an enriched environment. We propose that during the subacute phase after Experimental Stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates the inflammatory response after Stroke decreasing the level of ApoE that may contribute to the observed improvement of functional recovery.
Louise D Mccullough - One of the best experts on this subject based on the ideXlab platform.
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critical role of sphingosine 1 phosphate receptor 2 in the disruption of cerebrovascular integrity in Experimental Stroke
Nature Communications, 2015Co-Authors: Gab Seok Kim, Louise D Mccullough, Li Yang, Guoqi Zhang, Honggang Zhao, Magdy Selim, Michael J Kluk, Teresa SanchezAbstract:The use and effectiveness of current Stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in Experimental Stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to Stroke patients.
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ultrasonic vocalization changes and foxp2 expression after Experimental Stroke
Behavioural Brain Research, 2015Co-Authors: Sarah J Doran, Cassandra Trammel, Venugopal Reddy Venna, Sharon E Benashaski, Louise D McculloughAbstract:Speech impairments affect one in four Stroke survivors. However, animal models of post-ischemic vocalization deficits are limited. Male mice vocalize at ultrasonic frequencies when exposed to an estrous female mouse. In this study we assessed vocalization patterns and quantity in male mice after cerebral ischemia. FOXP2, a gene associated with verbal dyspraxia in humans, with known roles in neurogenesis and synaptic plasticity, was also examined after injury. Using a transient middle cerebral artery occlusion (MCAO) model, we assessed correlates of vocal impairment at several time-points after Stroke. Further, to identify possible lateralization of vocalization deficits induced by left and right hemispheric Strokes were compared. Significant differences in vocalization quantity were observed between Stroke and sham animals that persisted for a month after injury. Injury to the left hemisphere reduced early vocalizations more profoundly than those to the right hemisphere. Nuclear expression of Foxp2 was elevated early after Stroke (at 6h), but significantly decreased 24h after injury in both the nucleus and the cytoplasm. Neuronal Foxp2 expression increased in Stroke mice compared to sham animals 4 weeks after injury. This study demonstrates that quantifiable deficits in ultrasonic vocalizations (USVs) are seen after Stroke. USV may be a useful tool to assess chronic behavioral recovery in murine models of Stroke.
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effects of metformin in Experimental Stroke
Stroke, 2010Co-Authors: Sharon E Benashski, Venugopal Reddy Venna, Louise D McculloughAbstract:Background and Purpose— Adenosine 5′-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces Stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in Experimental Stroke. Methods— Male mice were subjected to middle cerebral artery occlusion after acute (3 days) or chronic (3 weeks) administration of metformin. Infarct volumes, AMPK activation, lactate accumulation, and behavioral outcomes were assessed. The roles of neuronal nitric oxide synthase and AMPK were examined using mice with targeted deletion of AMPK or neuronal nitric oxide synthase. Results— Acute metformin exacerbated Stroke damage, enhanced AMPK activation, and led to metabolic dysfunction. This effect was lost in AMPK and neuronal nitric oxide synthase knockout mice. In contrast, chronic metformin given preStroke was neuroprotective, improved Stroke-induced lactate generation, and ameliorated Stroke-induced activation of AMPK. Similarly, the neuroprotective effect of chronic preStroke metformin was lost in neuronal nitric oxide synthase knockout mice. Conclusions— AMPK is an important potential target for Stroke treatment and prevention. These studies show that the timing, duration, and amount of AMPK activation are key factors in determining the ultimate downstream effects of AMPK on the ischemic brain.
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changes in Experimental Stroke outcome across the life span
Journal of Cerebral Blood Flow and Metabolism, 2009Co-Authors: Fudong Liu, Sharon E Benashski, Rongwen Yuan, Louise D McculloughAbstract:Acute ischemic Stroke is a leading cause of mortality and disability in the elderly. Age is the most important nonmodifiable risk factor for Stroke, yet many preclinical models continue to examine only young male animals. It remains unclear how Experimental Stroke outcomes change with aging and with biologic sex. If sex differences are present, it is not known whether these reflect an intrinsic differing sensitivity to Stroke or are secondary to the loss of estrogen with aging. We subjected both young and aging mice of both sexes to middle cerebral artery occlusion (MCAO). Young female mice had smaller Strokes compared with age-matched males, an effect that was reversed by ovariectomy. Stroke damage increased with aging in female mice, whereas male mice had decreased damage after MCAO. Blood-brain barrier (BBB) permeability changes are correlated with infarct size. However, aging mice had significantly less edema formation, an effect that was independent of sex and histologic damage. Differences in the cellular response to Stroke occur across the life span in both male and female mice. These differences need to be considered when developing relevant therapies for Stroke patients, the majority of whom are elderly.
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estradiol regulates angiopoietin 1 mrna expression through estrogen receptor α in a rodent Experimental Stroke model
Stroke, 2005Co-Authors: Agnieszka A Ardelt, Patricia D Hurn, Louise D Mccullough, Kenneth S Korach, Michael M Wang, Diane H MunzenmaierAbstract:Background and Purpose— Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17β-estradiol (E2) reduce damage in Experimental Stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in Stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO). Methods— Female animals were ovariectomized, treated with 25 μg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted. Results— E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor-α knocko...
