scholarly journals Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

2016 ◽  
Vol 37 (7) ◽  
pp. 2383-2395 ◽  
Author(s):  
Minshu Li ◽  
Zhiguo Li ◽  
Honglei Ren ◽  
Wei-Na Jin ◽  
Kristofer Wood ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Lesion Size ◽  
Experimental Models ◽  
Colony Stimulating Factor ◽  
Receptor Inhibition ◽  
Experimental Mouse ◽  
The Brain ◽  
Stimulating Factor ◽  
Blood Brain Barrier Integrity

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

scholarly journals CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chritica Lodder ◽  
Isabelle Scheyltjens ◽  
Ilie Cosmin Stancu ◽  
Pablo Botella Lucena ◽  
Manuel Gutiérrez de Ravé ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Microglial Activation ◽  
Amyloid Plaques ◽  
Colony Stimulating Factor ◽  
Tau Pathology ◽  
Preclinical Models ◽  
Receptor Inhibition ◽  
Single Cell Rna Sequencing ◽  
The Brain ◽  
Stimulating Factor

AbstractAlzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

Abstract TP348: Quantitative Serial Neuroimaging of Iron in the Intracerebral Hemorrhage Pig Model

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Muhammad E Haque ◽  
Refaat E Gabr ◽  
Xiurong Zhao ◽  
Khader M Hasan ◽  
Ponnada A Narayana ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Iron Concentration ◽  
Susceptibility Mapping ◽  
Pig Model ◽  
Large Animal ◽  
Quantitative Susceptibility Mapping ◽  
Secondary Damage ◽  
Susceptibility Maps ◽  
The Brain

Objective: To serially quantify changes of iron concentration within hematomas in the intracerebral hemorrhage (ICH) pig model using non-invasive R2* and quantitative susceptibility mapping (QSM) MRI methods. Introduction: Hemolysis-related release of hemoglobin/heme/free iron after ICH causes cytotoxic injury. An accurate post hemorrhage assessment of iron would be valuable to develop strategies to prevent secondary damage. The T2* relaxation rate (R2* =1/T2*) on MRI depends on the regional oxy- versus deoxyhemoglobin. Post-ICH excess of deoxyhemoglobin has been applied as a quantitative marker to estimate iron in the brain. However, quantitative susceptibility mapping (QSM) is a new MRI technique that can quantify iron concentration within the hematoma by measuring induced magnetic susceptibility. Using R2* mapping and QSM in a large animal ICH model, we measured spatiotemporal changes in iron concentration in the brain. Methods: Lobar ICH was induced by infusion of 2.5 ml autologous blood in 8 Yorkshire pigs with average age/wt of 4-6wk/12.5±2.5kg. MRI was obtained at days 1 and 7. A 3D anatomical and multi-echo gradient echo images were obtained on a clinical 3.0 T Philips Ingenia MRI system. Parametric R2* and susceptibility maps were generated. Regions of interest were placed within hematoma and contralesional CSF. Results: R2* measurements in the hematoma at day 1 and day 7 were 41.3 ± 7.3 and 37.7 ± 7.7 s -1 , respectively, whereas the corresponding susceptibility measurements were 0.75± 0.3 and 0.70 ± 0.5 ppm. The CSF R2* were 5.53 ± 2.1 and 6.85 ± 2.4 s -1 , whereas susceptibility showed 0.06 ± 0.16 and 0.02 ± 0.03 ppm at the two time points. Both R2* and QSM showed no significant change in iron concentration within the hematoma ROI with p-value of 0.18 and 0.72 over a week. Absence of hyperintense regions remote from the hematoma in susceptibility maps suggested lack of diffuse iron deposition. Good correlation was observed between R2* and QSM (correlation coefficient 0.83 and 0.78 within hematoma, and -0.66 and -0.07 within CSF, at day 1 and 7, respectively). Conclusion: R2* and especially QSM, with their ability to provide quantitative iron content, are valuable tools to test new ICH treatments particularly targeting iron in this large animal model.

BLZ945 derivatives for PET imaging of colony stimulating factor-1 receptors in the brain

2021 ◽  
Author(s):  
Berend van der Wildt ◽  
Zheng Miao ◽  
Samantha T. Reyes ◽  
Jun H. Park ◽  
Jessica L. Klockow ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Colony Stimulating Factor ◽  
The Brain ◽  
Stimulating Factor

Granulocyte colony-stimulating factor potential use in the treatment of children with cerebral palsy

2017 ◽  
Vol 7 (1) ◽  
pp. 0-0
Author(s):  
G. Paszko-Patej ◽  
D. Sienkiewicz ◽  
B. Okurowska-Zawada ◽  
W. Kułak
Keyword(s):  
Cerebral Palsy ◽  
Tissue Repair ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Neuroprotective Actions ◽  
Apoptosis And Inflammation ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Stimulating Factor ◽  
Potential Use

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the blood. Recent studies demonstrated the presence of CSF-receptor (G-CSFR) system in the brain and spinal cord, and their roles in neuroprotection and neural tissue repair, as well as improvement in functional recovery. G-CSF exerts neuroprotective actions through the inhibition of apoptosis and inflammation, and the stimulation of neurogenesis. This review highlights recent studies on the potential use of G-CSF in cerebral palsy.

Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage

2005 ◽  
Vol 1041 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Hee-Kwon Park ◽  
Kon Chu ◽  
Soon-Tae Lee ◽  
Keun-Hwa Jung ◽  
Eun-Hee Kim ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Sensorimotor Recovery ◽  
Stimulating Factor

scholarly journals Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

2011 ◽  
Vol 31 (11) ◽  
pp. 2135-2151 ◽  
Author(s):  
Matthew A Kirkman ◽  
Stuart M Allan ◽  
Adrian R Parry-Jones
Keyword(s):  
Intracerebral Hemorrhage ◽  
Functional Outcomes ◽  
Oral Anticoagulant Therapy ◽  
Autologous Blood ◽  
Experimental Models ◽  
The Past ◽  
Collagenase Injection ◽  
Underlying Mechanisms ◽  
Supportive Management ◽  
Insight Into

Intracerebral hemorrhage (ICH) has the highest mortality of all stroke subtypes, yet treatments are mainly limited to supportive management, and surgery remains controversial. Despite significant advances in our understanding of ICH pathophysiology, we still lack preclinical models that accurately replicate the underlying mechanisms of injury. Current experimental ICH models (including autologous blood and collagenase injection) simulate different aspects of ICH-mediated injury but lack some features of the clinical condition. Newly developed models, notably hypertension- and oral anticoagulant therapy-associated ICH models, offer added benefits but further study is needed to fully validate them. Here, we describe and discuss current approaches to experimental ICH, with suggestions for changes in how this condition is studied in the laboratory. Although advances in imaging over the past few decades have allowed greater insight into clinical ICH, there remains an important role for experimental models in furthering our understanding of the basic pathophysiologic processes underlying ICH, provided limitations of animal models are borne in mind. Owing to differences in existing models and the failed translation of benefits in experimental ICH to clinical practice, putative neuroprotectants should be trialed in multiple models using both histological and functional outcomes until a more accurate model of ICH is developed.

Protective Effect of Granulocyte Colony-stimulating Factor on Intracerebral Hemorrhage in Rat

2009 ◽  
Vol 34 (7) ◽  
pp. 1317-1323 ◽  
Author(s):  
Lei Zhang ◽  
Xi-Ji Shu ◽  
Hong-Yan Zhou ◽  
Wei Liu ◽  
Ying Chen ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Protective Effect ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor
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