Control of cerebral ischemia with magnetic nanoparticles

The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

[1]  T. Ikeda,et al.  A novel reproducible model of neonatal stroke in mice: Comparison with a hypoxia–ischemia model , 2013, Experimental Neurology.

[2]  S. Ding,et al.  Reactive astrocytes and therapeutic potential in focal ischemic stroke , 2016, Neurobiology of Disease.

[3]  W. Gan,et al.  Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex , 2007, Nature Neuroscience.

[4]  R. Busto,et al.  Induction of reproducible brain infarction by photochemically initiated thrombosis , 1985, Annals of neurology.

[5]  S. Haneuse,et al.  Pathological correlates of dementia in a longitudinal, population‐based sample of aging , 2007, Annals of neurology.

[6]  C. Kleinschnitz,et al.  Animal models of ischemic stroke and their application in clinical research , 2015, Drug design, development and therapy.

[7]  Mark D. Huffman,et al.  AHA Statistical Update Heart Disease and Stroke Statistics — 2012 Update A Report From the American Heart Association WRITING GROUP MEMBERS , 2010 .

[8]  David Kleinfeld,et al.  The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit , 2012, Nature Neuroscience.

[9]  S. Ashwal,et al.  Animal models of neonatal stroke , 2001, Current opinion in pediatrics.

[10]  I. Bilic,et al.  [Pathophysiology of ischaemia-reperfusion injury]. , 2006, Lijecnicki vjesnik.

[11]  Fred H. Gage,et al.  Local generation of glia is a major astrocyte source in postnatal cortex , 2012, Nature.

[12]  Anne L. van de Ven,et al.  Real-time intravital microscopy of individual nanoparticle dynamics in liver and tumors of live mice. , 2013, Protocol exchange.

[13]  Stephanie Taylor,et al.  Induction of ischemic stroke in awake freely moving mice reveals that isoflurane anesthesia can mask the benefits of a neuroprotection therapy , 2014, Front. Neuroenergetics.

[14]  Timothy H. Murphy,et al.  Hardware and methodology for targeting single brain arterioles for photothrombotic stroke on an upright microscope , 2008, Journal of Neuroscience Methods.

[15]  K. Nelson Perinatal Ischemic Stroke , 2007, Stroke.

[16]  J. Mcculloch,et al.  Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat , 1990, Neuroscience Letters.

[17]  C. Iadecola,et al.  Glial regulation of the cerebral microvasculature , 2007, Nature Neuroscience.

[18]  W. Golde,et al.  A rapid, simple, and humane method for submandibular bleeding of mice using a lancet , 2005, Lab Animal.

[19]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[20]  J. Mohr,et al.  Transient ischemic attack--proposal for a new definition. , 2002, The New England journal of medicine.

[21]  L. Schmued,et al.  Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons , 2005, Brain Research.

[22]  W. Jagust,et al.  Neuropathologic Substrates of Ischemic Vascular Dementia , 2000, Journal of neuropathology and experimental neurology.

[23]  Ricardo Prado,et al.  Cerebral Blood Flow Restoration and Reperfusion Injury After Ultraviolet Laser-Facilitated Middle Cerebral Artery Recanalization in Rat Thrombotic Stroke , 2002, Stroke.

[24]  J. J. Croat,et al.  Neodymium-iron-boron permanent magnets , 1991 .

[25]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[26]  G. Burnstock,et al.  DEMONSTRATION OF "GAP JUNCTIONS" BETWEEN SMOOTH MUSCLE CELLS , 1970, The Journal of cell biology.

[27]  Jaime Grutzendler,et al.  Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes , 2015, Neuron.

[28]  D. Kleinfeld,et al.  Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke , 2006, Nature Methods.

[29]  L. Pitts,et al.  Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. , 1986, Stroke.

[30]  Shaoqun Zeng,et al.  A Modified Mini-Stroke Model with Region-Directed Reperfusion in Rat Cortex , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  A. Sher,et al.  Analysis of Fractalkine Receptor CX3CR1 Function by Targeted Deletion and Green Fluorescent Protein Reporter Gene Insertion , 2000, Molecular and Cellular Biology.

[32]  M. Sands,et al.  Percutaneous intravenous injection in neonatal mice. , 1999, Laboratory animal science.

[33]  U. Dirnagl Bench to Bedside: The Quest for Quality in Experimental Stroke Research , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  M. Hoehn,et al.  Differences in Clot Preparation Determine Outcome of Recombinant Tissue Plasminogen Activator Treatment in Experimental Thromboembolic Stroke , 2003, Stroke.

[35]  J. M. Camacho,et al.  Alternative method to calculate the magnetic field of permanent magnets with azimuthal symmetry , 2013 .

[36]  G. Boysen,et al.  A Rat Model of Reproducible Cerebral Infarction Using Thrombotic Blood Clot Emboli , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[37]  B. Lévy,et al.  Smooth Muscle Cell Phenotypic Switching in Stroke , 2013, Translational Stroke Research.

[38]  Turgut Tatlisumak,et al.  Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia , 2007, Pharmacology Biochemistry and Behavior.

[39]  H. Shokrollahi,et al.  Nano-magnetic particles used in biomedicine: core and coating materials. , 2013, Materials science & engineering. C, Materials for biological applications.

[40]  C. Betsholtz,et al.  Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. , 2011, Developmental cell.

[41]  D. Ferriero Neonatal brain injury. , 2004, The New England journal of medicine.

[42]  X. Rabasseda,et al.  A report from the American Heart Association Scientific Sessions 2012 (November 3-7 - Los Angeles, California, USA). , 2013, Drugs of today.

[43]  Xiaoqin Zhu,et al.  NG2 cells generate both oligodendrocytes and gray matter astrocytes , 2007, Development.

[44]  Yoji Yoshida,et al.  Experimental studies of ischemic brain edema , 1986 .