scholarly journals Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [11C]PK11195- and [18F]FDG-PET Study

2009 ◽  
Vol 29 (6) ◽  
pp. 1216-1225 ◽  
Author(s):  
Michael Schroeter ◽  
Maria A Dennin ◽  
Maureen Walberer ◽  
Heiko Backes ◽  
Bernd Neumaier ◽  
...  
Keyword(s):  
At Risk ◽  
Cerebral Ischemia ◽  
Fdg Pet ◽  
Energy Demand ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Benzodiazepine Receptors ◽  
Transient Ischemia ◽  
Infarct Core ◽  
Infarct Zone

Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [11C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [11C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [11C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [11C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [11C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93 ± 0.49), colocalizing with a 60% increase in the [18F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct.

scholarly journals Osteopontin Augments M2 Microglia Response and Separates M1- and M2-Polarized Microglial Activation in Permanent Focal Cerebral Ischemia

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Anne Ladwig ◽  
Helene Luise Walter ◽  
Jörg Hucklenbroich ◽  
Antje Willuweit ◽  
Karl-Josef Langen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Infarct Core ◽  
M2 Microglia ◽  
Photothrombotic Stroke ◽  
M2 Phenotype

Background.Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microgliain vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after strokein vivo, with focus on infarct demarcation.Methods.Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation.Results.After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ M1 cells while increasing M2 microglia, shifting the M1/M2 balance towards an M2 phenotype. Moreover, OPN polarized astrocytes towards the infarct.Conclusion.Microglial activation and M1 and M2 polarization have distinct but overlapping spatial patterns in permanent focal ischemia. Data suggest that OPN is involved in separating M1 and M2 subpopulations, as well as in shifting microglia polarization towards the M2 phenotype modulating beneficially inflammatory responses after focal infarction.

scholarly journals Microtubular Proteolysis in Focal Cerebral Ischemia

1996 ◽  
Vol 16 (6) ◽  
pp. 1189-1202 ◽  
Author(s):  
L. Creed Pettigrew ◽  
Mary L. Holtz ◽  
Susan D. Craddock ◽  
Stephen L. Minger ◽  
Nathan Hall ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Significant Loss ◽  
Calpain Activity ◽  
Infarct Zone ◽  
Ischemic Brain ◽  
Τ Protein ◽  
Map2 Immunoreactivity ◽  
Apical Dendrites

Calpain, a neutral protease activated by calcium, may promote microtubular proteolysis in ischemic brain. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. The earliest sign of tissue injury was observed after no more than 15 min of ischemia, with coiling of apical dendrites immunolabeled to show microtubule-associated protein 2 (MAP2). After 6 h of ischemia, MAP2 immunoreactivity was markedly diminished in the infarct zone. Quantitative Western analysis demonstrated that MAP2 was almost unmeasurable after 24 h of ischemia. An increase in calpain activity, shown by an antibody recognizing calpain-cleaved spectrin fragments, paralleled the loss of MAP2 immunostaining. Double-labeled immunofluorescent studies showed that intraneuronal calpain activity preceded evidence of MAP2 proteolysis. Perikaryal immunolabeling of τ protein became increasingly prominent between 1 and 6 h in neurons located within the transition zone between ischemic and unaffected tissue. Western blot experiments confirmed that dephosphorylation of τ protein occurred during 24 h of ischemia, but was not associated with significant loss of τ antigen. We conclude that focal cerebral ischemia is associated with early microtubular proteolysis caused by calpain.

scholarly journals Cortical Neurogenesis in Adult Rats after Reversible Photothrombotic Stroke

2000 ◽  
Vol 20 (8) ◽  
pp. 1166-1173 ◽  
Author(s):  
WeiGang Gu ◽  
Thomas Brännström ◽  
Per Wester
Keyword(s):  
At Risk ◽  
Cell Proliferation ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Three Dimensional ◽  
Brain Regions ◽  
Specific Marker ◽  
Cortical Region ◽  
Adult Rats ◽  
Adult Rat

Neurogenesis occurs throughout life in the dentate gyrus of hippocampus and subventricular zone, but this phenomenon has rarely been observed in other brain regions of adult mammals. The aim of the current study was to investigate the cell proliferation process in the ischemically challenged region-at-risk after focal cerebral ischemia in the adult rat brain. A reversible photothrombotic ring stroke model was used, which features sustained hypoperfusion followed by late spontaneous reperfusion and a remarkable morphologic tissue recovery in the anatomically well defined somatosensory cortical region-at-risk. Twelve-week-old male Wistar rats received repeated intraperitoneal injections of the cell proliferation specific marker 5-bromodeoxyuridine (BrdU) after stroke induction. Immunocytochemistry of coronal brain sections revealed that the majority of BrdU-positive cells were of glial, macrophage, and endothelial origin, whereas 3% to 6% of the BrdU-positive cells were double-labeled by BrdU and the neuron-specific marker Map-2 at 7 and 100 days after stroke onset in the region-at-risk. They were distributed randomly in cortical layers II-VI. Three-dimensional confocal analyses of BrdU and the neuronal-specific marker Neu N by double immunofluorescence confirmed their colocalization within the same cells at 72 hours and 30 days after stroke induction. This study suggests that, as a potential pathway for brain repair, new neurons can be generated in the cerebral cortex of adult rats after sublethal focal cerebral ischemia.

scholarly journals Sustained Blockade of Brain AT1 Receptors before and after Focal Cerebral Ischemia Alleviates Neurologic Deficits and Reduces Neuronal Injury, Apoptosis, and Inflammatory Responses in the Rat

2004 ◽  
Vol 24 (5) ◽  
pp. 536-547 ◽  
Author(s):  
Min Lou ◽  
Annegret Blume ◽  
Yi Zhao ◽  
Peter Gohlke ◽  
Günther Deuschl ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
At1 Receptor ◽  
Neuroprotective Effects ◽  
Reactive Microglia ◽  
At1 Receptors ◽  
Before And After

In the present study, we investigate whether a long-term blockade of brain AT1 receptors in male Wistar rats before and after ischemic injury exerts neuroprotective effects and modulates apoptosis and inflammatory responses, which are associated with the post-ischemic progression of brain damage. The AT1 receptor antagonist irbesartan was continuously infused intracerebroventricularly using osmotic minipumps over a 5-day period before and for 3 or 7 days after middle cerebral artery occlusion (MCAO) for 90 minutes. Neurologic status was evaluated daily, starting 24 hours after MCAO. After MCAO (3 and 7 days), brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis and accumulation of reactive microglia and macrophages. Treatment with irbesartan before ischemia improved motor functions, whereas post-ischemic treatment improved sensory functions. Blockade of brain AT1 receptors reduced the infarct size on days 3 and 7 after MCAO. In the peri-infarct cortex, irbesartan treatment decreased the number of apoptotic cells on day 3 and attenuated the invasion of activated microglia and macrophages on days 3 and 7 after ischemia. Long-term blockade of brain AT1 receptors improves the recovery from cerebral ischemia. Antiapoptotic mechanisms and inhibition of post-ischemic inflammation are involved in the AT1 receptor blockade-induced neuroprotective effects in ischemic brain tissue.

scholarly journals Brain-to-cervical lymph node signaling after stroke

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Elga Esposito ◽  
Bum Ju Ahn ◽  
Jingfei Shi ◽  
Yoshihiko Nakamura ◽  
Ji Hyun Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Node ◽  
Cerebral Ischemia ◽  
Systemic Inflammation ◽  
Cervical Lymph Node ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Surgical Removal ◽  
Lymphatic Endothelial Cells

AbstractAfter stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

scholarly journals Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia

2004 ◽  
Vol 24 (11) ◽  
pp. 1272-1279 ◽  
Author(s):  
Alexandra Benchoua ◽  
Jérôme Braudeau ◽  
Aurélia Reis ◽  
Cécile Couriaud ◽  
Brigitte Onténiente
Keyword(s):  
Cell Death ◽  
Cathepsin B ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Critical Role ◽  
Early Event ◽  
Ischemic Damage ◽  
Activation Pattern ◽  
Infarct Core

Cathepsins and caspases are two families of proteases that play pivotal roles in ischemic cell death. This study investigated the existence of a cross-talk between cathepsin B and proinflammatory caspases in stroke-induced cell death, as recently suggested by in vitro data. Cortical ischemic damage was induced in mice by distal and permanent occlusion of the middle cerebral artery. Cytoplasmic activation of cathepsin B was observed from the early stages of infarction, and displayed an activation pattern parallel to the activation pattern of caspase-1 and −11. Immunohistochemistry revealed the colocalization of cathepsin B with each caspase in cells of the infarct core. The apical position of cathepsin B in both caspase-activation cascades was confirmed by pretreatment of the animals with the cathepsin B inhibitor CA-074, which also potently protected cortical structures from ischemic damage, indicating involvement of the proteases in the lesion process. The results show that cathepsin B release is an early event following occlusion of cerebral arteries, which eventually triggers the activation of proinflammatory caspases in the absence of reperfusion. This new pathway may play a critical role in brain infarction by promoting inflammatory responses, and/or by amplifying the apoptotic process.

Specific expression of galanin in the peri-infarct zone after permanent focal cerebral ischemia in the rat

2006 ◽  
Vol 134 (1) ◽  
pp. 38-45 ◽  
Author(s):  
Manuela De Michele ◽  
Giuseppe Sancesario ◽  
Danilo Toni ◽  
Alessandro Ciuffoli ◽  
Giorgio Bernardi ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Zone ◽  
Specific Expression
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