Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Magnetic Resonance Imaging of Stroke

Introduction Neuroimaging methods have become indispensable tools for diagnosis of tissue status and aid in treatment decision making after stroke. Especially magnetic resonance imaging (MRI), which allows noninvasive and longitudinal measurement of multiple (early) biomarkers of brain tissue injury, can provide important insights in stroke lesion development. In addition to its diagnostic potential in the clinic, MRI offers a valuable method for in vivo studies on stroke…

Cerebral Blood Flow Methods

Introduction Although the brain represents only 2% of the total body mass in humans, it accounts for a fifth of the body’s basal O 2 consumption and a quarter of its glucose use. A continuous supply of blood and nutrients is essential for its functioning and cerebral blood flow (CBF) must constantly match the demands of brain activity. Because it lacks energy stores, the brain is…

Animal Models: Nonhuman Primates

Acknowledgment Supported by grants to MT from the Canadian Stroke Networks and the Heart and Stroke Foundation of Canada. MT is a Canada Research Chair (Tier 1) in Translational Stroke Research. Introduction The notion that stroke studies in nonhuman primates (NHPs) will enable the translation of a promising therapy to humans is theoretically sound, but unproven in the absence of a positive human study. Moreover, tissue…

Animal Models: Vascular Models of Cognitive Dysfunction

Introduction Convincing evidence supports a link between vascular disease, cognitive impairment and dementia, including Alzheimer disease (AD) . A compromised cerebral vasculature with structural alterations, impaired dilatory capacity, and failure to maintain brain perfusion and adjust flow in response to increased neuronal activity may result in cerebral dysfunctions that translate into cognitive failure. In human, a vasculopathology is a key factor in vascular cognitive impairment (VCI)…

Animal Models of Neonatal Stroke/Ischemia

Sources of Funding NINDS_NS80015, NINDS_NS44025, NINDS_NS76726, The Leducq Foundation DSRR_P34404. Introduction Development of age-appropriate models of cerebral ischemia and/or hypoxia has allowed knowledge that brain immaturity at the time of injury plays a key role in the pattern of brain damage. Furthermore, studies of ischemia in immature animals of differing ages have made apparent how rapidly changing the injury response is within the “immaturity spectrum,” in…

Animal Models: Cerebral Hemorrhage

Introduction Worldwide, stroke is the second leading cause of death, affecting approximately 6 million people in 2012. Intracerebral hemorrhage (ICH) accounts for 13% of all stroke cases and is associated with high mortality and morbidity. As many as 50% of patients die within 1 month after ICH onset, and only 20% of patients have functional independence at 6 months. However, preclinical research is less focused on…

Animal Models: Global Ischemia

Introduction Global cerebral ischemia (GCI) is a major factor in the high mortality following cardiac arrest, which causes around 300,000 fatalities per year in the United States. Among the survivors, most have lifelong cognitive deficits. To model GCI in animals, a number of global ischemia models were established in the 1970s. An initial focus lay on large animals, such as cats, dogs, and monkeys. With increasing…

Animal Models of Focal Ischemia

Ischemic stroke is a highly heterogeneous disease with variation in size, location, and cause of occlusion. In addition, differences in underlying comorbidities, including hypertension, diabetes, and aging, and sex-specific sensitivity to ischemia make replicating this condition in one animal model impossible. Yet animal models have and will continue to be an integral and important part of understanding stroke pathophysiology and in developing treatments. Understanding the strengths…

Matrix Metalloproteinases and Extracellular Matrix in the Central Nervous System

Introduction Brain cells are surrounded by extracellular matrix (ECM) made up of large protein molecules. Interstitial fluid (ISF) moves between the cells and along perivascular spaces, mixing with the cerebrospinal fluid (CSF) to act as the lymph of the brain. Early investigators realized that a mechanism to remove waste products of metabolism and to deliver nutrients to the cells was essential, and they postulated the ISF/CSF,…

Tissue Plasminogen Activator Signaling in the Normal and Diseased Brain

Tissue-type plasminogen activator (tPA) is currently the only U.S. Food and Drug Administration–approved therapy for the acute treatment of ischemic stroke . The most extensively studied function of tPA is its primary activity, namely, the proteolytic conversion of the zymogen plasminogen (plg) into the active protease plasmin, which in turn is essential for the lysis of blood clots . Human tPA is a serine protease composed…

Cytokines and Chemokines in Stroke

Introduction Cells involved in the immune system need to be tightly interconnected to elaborate a collaborative and well-organized response against noxious stimuli. With this aim, cells communicate either by direct contact mediated by different plasma membrane molecules or by the synthesis and release of small proteins called cytokines . These cytokines are produced in the earliest stages of cellular activation, alerting other cells of the existence…

Noncoding RNAs and Stroke

Acknowledgments This work was supported by NIH grant NS079585, VA merit review grant 1I01BX002985, and American Heart Association grant 15IRG23050015. Introduction Stroke (cerebral ischemia)-induced brain damage is a complex injury that begins with loss of oxygen and nutrient flow to the brain due to blockage of one or more cerebral arteries by plaque formation leading to embolism. This acute shortage of essential elements triggers a plethora…

Heat Shock Proteins and the Stress Response

Introduction In response to ischemia, cellular responses lead to the induction of a variety of stress proteins, included among them are the heat shock proteins (Hsps) and immediate early genes (IEGs). Hsps are a family of stress proteins thought to be involved in chaperone functions, such as protein folding, trafficking, and repair. Their expression can be constitutive or inducible depending on the family member. Constitutively expressed…

Akt-GSK3β Pro-survival Signaling Pathway in Cerebral Ischemic Injury

Introduction The balance between apoptotic signals and survival signals determines the fate of neurons after cerebral ischemia. Unobstructed activation of caspases in pathological conditions will lead to cell death; however, activation of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway may counteract the apoptotic process and support neuron survival and recovery from ischemic insults. Akt, also called protein kinase B (PKB), is a 57kD serine/threonine protein kinase that is…

Rho-Associated Kinases in Cerebrovascular Disease

Introduction More than two decades after their discovery, Rho-associated kinase (ROCK) is at the center stage of therapeutic development in many diverse diseases ranging from cardiovascular to neurological, metabolic, and ocular disorders. Because ROCK activity is pivotal in the regulation of numerous processes in virtually all cell types, the therapeutic indications have been wide ranging and growing. It is well established that upregulation of ROCK activity…

Mitogen-Activated Protein Kinase Signaling in Cerebrovascular Disease

Mitogen-Activated Protein Kinase Signaling Cells respond to their extracellular environment via common intracellular signaling systems. Mitogen-activated protein kinases (MAPKs) are serine–threonine kinases that mediate intracellular signaling involved in regulating protein and cell functioning related to membrane, intra- and intercellular processes and transformation, proliferation/growth, differentiation, survival, and death. The mammalian MAPK family consists of an extracellular signal–regulated kinase (ERK) signaling arm and the stress-activated protein kinases (SAPK)…

Lipid Mediators

Acknowledgment This work was supported by NIGMS grant GM103340 and NINDS grant NS046741 (NGB). Platelet-Activating Factor and Other Bioactive Lipids A target for cerebral ischemia is phospholipids from plasma membranes of neural cells. Phospholipid molecules of membranes from neurons, glial cells, and other neural cells store a variety of lipid messengers. Receptor-mediated events, or changes in intracellular events [Ca 2+ ], such as those that occur…

Ischemia Regulated Transcription Factors: Hypoxia Inducible Factor 1 and Activating Transcription Factor 4

Introduction Loss of blood flow during stroke creates significant cellular stress via a host of stresses including hypoxia, glucose deprivation, and oxidative stress. Preconditioning studies teach us that homeostatic programs to cell stress are rapidly engaged via activation of preexisting proteins and sustained via adaptive gene expression . Whether activated prior or after a stroke, if these adaptive mechanisms fail to restore homeostasis at a single…

Protein Kinases in Cerebral Ischemia

Introduction Protein kinases are key regulators of cell processes. Protein kinases are defined as enzymes that transfer a phosphate group onto an acceptor amino acid in a substrate protein. This process is called phosphorylation and can be reversed by phosphatases, enzymes that remove phosphoryl moieties from target proteins. Protein phosphorylation is an essential mechanism by which intracellular and extracellular signals are transmitted throughout the cell and…