scholarly journals Enriched Environment Reduces Apolipoprotein E (ApoE) in Reactive Astrocytes and Attenuates Inflammation of the Peri-Infarct Tissue after Experimental Stroke

2009 ◽  
Vol 29 (11) ◽  
pp. 1796-1805 ◽  
Author(s):  
Karsten Ruscher ◽  
Emelie Johannesson ◽  
Elena Brugiere ◽  
Agnes Erickson ◽  
Mattias Rickhag ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Interleukin 1 ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Enriched Environment ◽  
Reactive Astrocytes ◽  
Experimental Stroke ◽  
Housing Conditions ◽  
Tissue Reorganization ◽  
Cerebral Artery Occlusion

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 S100 β+/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/S100 β+ reactive astrocytes. In addition, the levels of interleukin 1 β 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.

scholarly journals Power spectrum slope and motor function recovery after focal cerebral ischemia in the rat

2018 ◽  
Author(s):  
Susan Leemburg ◽  
Bo Gao ◽  
Ertugrul Cam ◽  
Johannes Sarnthein ◽  
Claudio L. Bassetti
Keyword(s):  
Power Spectrum ◽  
Motor Function ◽  
Focal Cerebral Ischemia ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Models ◽  
Eeg Changes ◽  
Cerebral Artery Occlusion ◽  
Spectrum Slope

AbstractEEG changes across vigilance states have been observed after ischemic stroke in patients and experimental stroke models, but their relation to functional recovery remains unclear. Here, we evaluate motor function, as measured by single pellet reaching (SPR), as well as local EEG changes in NREM, REM and wakefulness during a 30-day recovery period after middle cerebral artery occlusion (MCAO) or sham surgery in rats. Small cortical infarcts resulted in poor SPR performance and induced widespread changes in EEG spectra in the ipsilesional hemisphere in all vigilance states, without causing major changes in sleep-wake architecture. Ipsilesional 1–4 Hz power was increased after stroke, whereas power in higher frequencies was reduced, resulting in a steeper slope of the power spectrum. Multielectrode array analysis of ipsilesional M1 showed that these spectral changes were present on the microelectrode level throughout M1 and were not related to increased synchronization between electrodes. Spectrum slope was significantly correlated with post-stroke motor function.

scholarly journals The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

2021 ◽  
Author(s):  
Yong-Ming Zhu ◽  
Liang Lin ◽  
Chao Wei ◽  
Yi Guo ◽  
Yuan Qin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Glial Scar ◽  
Scar Formation ◽  
Reactive Astrocytes ◽  
Interacting Protein ◽  
Protein Levels ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

AbstractNecroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar. Graphical Abstract

Abstract 91: Remodeling After Stroke: The Recovering Brain Is Vulnerable To Lipoxygenase-dependent Semaphorin Signaling

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Anton Pekcec ◽  
Kazim Yigitkanli ◽  
Joo Eun Jung ◽  
Hulya Karatas ◽  
Eng H Lo ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cortical Neurons ◽  
Second Messengers ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Axon Extension ◽  
Cultured Cortical Neurons ◽  
Cerebral Artery Occlusion

Background and Purpose— Recovery from stroke is limited in part by an inhibitory environment in the post-ischemic brain, but factors preventing successful remodeling are not well known. We sought to investigate if signaling from the axon guidance molecule semaphorin 3A (Sema3A) via eicosanoid second messengers can contribute to this inhibitory environment, and if blocking the Sema3A pathway can provide a benefit following experimental stroke. Methods— Cultured cortical neurons from mice were treated with recombinant Sema3A, or with the eicosanoids 12-HETE and 12-HPETE. Neurons from ALOX15 knockout mice, and a human brain endothelial cell line, were treated similarly. The filament model of MCAO was used to induce experimental stroke in mice, in some of which Sema3A was injected stereotactically into the striatum. The 12/15-LOX inhibitor LOXBlock-1 was injected intraperitoneally one week after MCAO. Results— Expression levels of 12/15-lipoxygenase (12/15-LOX) were increased within two hours after exposure of primary neurons to 90nM recombinant Sema3A. Either Sema3A, or the 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE and 12-HPETE at 300nM, blocked axon extension in neurons compared to solvent controls, and decreased tube formation in endothelial cells. The Sema3A effect was reversed by inhibiting 12/15-LOX, and neurons derived from 12/15-LOX knockout mice were insensitive to Sema3A. Following middle cerebral artery occlusion to induce stroke in mice, immunohistochemistry showed both Sema3A and 12/15-LOX are increased in the cortex up to two weeks. To determine if a Sema3A-dependent damage pathway is activated following ischemia, we injected recombinant Sema3A into the striatum. Sema3A alone did not cause injury in normal brains. But when injected into post-ischemic brains, Sema3A increased cortical damage by 79%, and again this effect was reversed by 12/15-LOX inhibition. Administration of the 12/15-LOX inhibitor LOXBlock-1 7 days after transient MCAO increased vascularization in the infarcted and peri-infarct area one week later. Conclusions— Our findings suggest that blocking the semaphorin pathway may provide a novel therapeutic strategy to improve stroke recovery.

Abstract WP118: The Flavanol (-)-Epicatechin Improves Functional Recovery In Mice Subjected To Experimental Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Christopher C Leonardo ◽  
Sean Robbins ◽  
Abdullah A Ahmad ◽  
Sylvain Dore
Keyword(s):  
Functional Recovery ◽  
Transcriptional Activation ◽  
Infarct Volume ◽  
Epidemiological Studies ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Adhesive Tape ◽  
Dietary Consumption ◽  
Therapeutic Doses ◽  
Cerebral Artery Occlusion

Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to develop cerebrovascular disease. Available data suggest actions on multiple pro-inflammatory pathways, yet it remains unclear which pathways mediate functional recovery after stroke. Our goal is to begin identifying the mechanisms by which the flavanol (-)-epicatechin (EC) improves anatomical and functional outcomes. Based upon data from initial dose-response experiments, ongoing studies are investigating hypothesized protective pathways involving matrix metalloproteinase-mediated blood brain barrier protection and Nrf2 transcriptional activation. Methods: Male, 8-10wk old C57BL/6 mice were pretreated with EC 90m prior to permanent distal middle cerebral artery occlusion. Vehicle or EC was administered by oral gavage to mimic dietary consumption. Mice were evaluated 1, 4 and 7d post-stroke for performance on various sensorimotor tasks prior to histological assessments. Results: Initial experiments demonstrated that mice treated with 15mg/kg EC showed reduced latency to remove adhesive tape at 1d compared to vehicle controls (n=12, p<0.01). Similarly, immunoreactivity for the microglia/macrophage marker Iba1 was increased in the ipsilateral hemispheres of mice 7d after treatment with vehicle (p<0.01), whereas pretreatment with 15mg/kg blocked this effect (n=4). Mice treated with 15mg/kg also showed a trend toward reduced infarct volume relative to vehicle controls (n=5-9 per group). In subsequent reduced dosing studies, vehicle-treated mice again showed deficiencies in removing adhesive tape at 1d (n=8, p<0.01). Remarkably, mice treated with 15, 10 or 5mg/kg EC showed no deficits. Similarly, vehicle control mice showed grip strength impairments up to 7d (n=8, p<0.05) that were absent in all groups of EC-treated mice. Conclusions: Preventative administration of EC promotes functional recovery in mice subjected to experimental stroke. Investigations are underway to determine the pathways mediated by EC following administration at these therapeutic doses. Together, these data will provide insights into the potential for (-)-epicatechin as a clinical therapeutic.

scholarly journals Impact of Key Nicotinic AChR Subunits on Post-Stroke Pneumococcal Pneumonia

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 253
Author(s):  
Sandra Jagdmann ◽  
Claudia Dames ◽  
Daniel Berchtold ◽  
Katarzyna Winek ◽  
Luis Weitbrecht ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Experimental Stroke ◽  
Medical Complication ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Post Stroke ◽  
Cholinergic Signaling ◽  
Cerebral Artery Occlusion ◽  
Pathogen Clearance ◽  
The Impact ◽  
Alveolar Capillary

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

scholarly journals Oxytocin Mediates Social Neuroprotection After Cerebral Ischemia

Stroke ◽  
2011 ◽  
Vol 42 (12) ◽  
pp. 3606-3611 ◽  
Author(s):  
Kate Karelina ◽  
Kathleen A. Stuller ◽  
Brant Jarrett ◽  
Ning Zhang ◽  
Jackie Wells ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Receptor Antagonist ◽  
Social Housing ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Outcome ◽  
Socially Isolated ◽  
Cerebral Artery Occlusion ◽  
And Oxidative Stress

Background and Purpose— The reduced incidence, morbidity, and mortality of stroke among humans with strong social support have been well-documented; however, the mechanisms underlying these socially mediated phenomena remain unknown, but may involve oxytocin (OT), a hormone that modulates some aspects of social behavior in humans and other animals. Methods— In the present study, adult male mice were socially isolated (housed individually) or socially paired (housed with an ovariectomized female); social pairing increased hypothalamic OT gene expression. To determine whether a causal relationship exists between increased OT and improved stroke outcome, mice were treated with exogenous OT or OT receptor antagonist beginning 1 week before induction of experimental stroke via middle cerebral artery occlusion. Results— Relative to social isolation, social housing attenuated infarct size, neuroinflammation, and oxidative stress following experimental stroke; the neuroprotective effect of social housing was eliminated by receptor antagonist treatment. In contrast, administration of OT to socially isolated mice reproduced the neuroprotection conferred by social housing. We further report evidence for a direct suppressive action of OT on cultured microglia, which is a key instigator in the development of neuroinflammation after cerebral ischemia. Conclusions— These findings support the hypothesis that OT mediates the neuroprotective effect of social interaction on stroke outcome.

Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1

2003 ◽  
Vol 45 (3) ◽  
pp. 313-324 ◽  
Author(s):  
Hirokazu Ohtaki ◽  
Hisayuki Funahashi ◽  
Kenji Dohi ◽  
Takiko Oguro ◽  
Reiko Horai ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neuronal Damage ◽  
Interleukin 1 ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion

scholarly journals Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

2021 ◽  
Author(s):  
Danielle A Becktel ◽  
Jacob C Zbesko ◽  
Jennifer B Frye ◽  
Amanda G Chung ◽  
Megan Hayes ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Plasma Cells ◽  
Spatial Working Memory ◽  
Repeated Administration ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Innate And Adaptive Immunity ◽  
Chronic Inflammatory Response ◽  
Cerebral Artery Occlusion ◽  
Distal Middle Cerebral Artery

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that contributes to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide developed to solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion + hypoxia (DH) mouse model of stroke. We subcutaneously injected young adult and aged mice with vehicle or HPβCD three times per week for up to 7 weeks following stroke and evaluated them using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPβCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPβCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD also improved recovery through the preservation of neurons in the striatum and thalamus, induction of c-Fos in hippocampal regions, protection of hippocampal-dependent spatial working memory, and reduction in impulsivity at 7 weeks after stroke. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline.

Sign in / Sign up

Export Citation Format

Share Document