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Oxidative and Nitrosative Stress

Oxidative stress plays a critical role in cerebral ischemic injury and occurs when there is an overproduction of free radicals and reactive oxygen species (ROS) beyond the ability of a biologic system to neutralize their adverse effects. ROS include oxygen ions, free radicals, and peroxides, and are products of cellular metabolism. Iron and its metabolites are crucial in the formation as well as destruction of ROS…

Excitotoxicity and Stroke

Introduction A long-standing goal of stroke research has been to elucidate the mechanisms responsible for the high vulnerability of brain tissue to hypoxic-ischemic insults. Understanding these mechanisms will aid the development of specific countermeasures that could be employed in the acute treatment of stroke victims. One such mechanism, “excitotoxicity,” was implicated in the 1980s as a prominent contributor to neuronal death after transient or permanent focal…

Mitochondrial Mechanisms During Ischemia and Reperfusion

Introduction The mitochondrion keeps a continuous workflow for oxidation of energy substances that are obtained from the blood to produce adenosine triphosphate (ATP) for cellular functions. Neural cells consume this energy derived from the ATP hydrolysis for maintaining ionic gradients across plasma membranes. During ischemia, oxygen supply and ATP production are rapidly impaired, followed by exhaustion of energy substances. This condition blocks mitochondrial respiration and glycolytic…

The Neurovascular Unit

Acknowledgments The neurovascular unit concept was developed by the entire research community, not just any one single scientist. The author apologizes to many colleagues who could not be included as coauthors and whose work could not be cited, due to space limitations. Introduction The concept of the “neurovascular unit” arose during a 2001 workshop convened by National Institute of Neurological Disorders and Stroke to address barriers…

Mechanisms of Endothelial Injury and Blood–Brain Barrier Dysfunction in Stroke

Acknowledgments This work was supported by grants from the National Institutes of Health to P.T.R. (R01 NS084941) and to T.P.D. (R01 NS42652 and R01 DA11271). Introduction The blood–brain barrier (BBB) is an essential physical and biochemical barrier that separates the CNS from the systemic circulation. It is formed by a monolayer of capillary endothelial cells that interact with each other as well as with other components…

Mechanisms of Glial Death and Protection

Introduction Cerebrovascular diseases cause tissue damage to both gray and white matter, which contribute about half of the CNS volume and differ in structure and cellular composition. White matter exclusively contains axons and their glial cell partners including fibrous astrocytes, oligodendrocytes (myelinating and nonmyelinating), and microglia. Gray matter harbors neurons and is rich in protoplasmic astrocytes, which shape synaptic transmission as they partner with nerve endings…

Mechanisms of Neuron Death (Necrosis, Apoptosis, Autophagy) After Brain Ischemia

Introduction Brain ischemia refers to a neurological condition that brain blood flow is insufficient to meet metabolic demand. There are two kinds of brain ischemia: (1) focal ischemia in which ischemia is confined to a specific region of the brain and (2) global ischemia, which affects the entire area of brain or forebrain tissue. Focal brain ischemia is a subtype of stroke along with subarachnoid hemorrhage…

Ischemic Tolerance: In Situ and Remote Pre- and Postconditioning

Introduction “Thus, when Heaven is about to confer a great office on any man, it first exercises his mind with suffering … it exposes his body to hunger … it stimulates his mind, hardens his nature, and supplies his incompetencies.” More than 2000 years ago, the Chinese philosopher Mencius believed that a person who experiences prior suffering is able to take on more responsibility throughout life.…

Drug Delivery to the Central Nervous System

Introduction The effective delivery of pharmaceutical agents into the central nervous system (CNS) still represents a significant challenge to modern drug delivery. Much of this can be attributed to the presence of the blood–brain barrier (BBB), which consists of a network of tight junctions formed between cerebral capillary endothelial cells along with the surrounding basal lamina, astrocytes, pericytes, and microglia. The integrity of these tight junctions…

Neuroprotectants: Temperature

Introduction The history of therapeutic hypothermia (HYPO) as a treatment for brain injury is quite a fascinating one. For millennia, cooling has been used to reduce edema and inflammation. Hippocrates recommended using ice packs on wounded soldiers. However, it was Napoleon’s surgeon Dominique-Jean Larrey (1766–1842) who noted the benefit of HYPO after he observed that wounded soldiers who stayed closer to the fire were likely to…

Comprehensive Concept of Regenerative Medicine for Ischemic Stroke With Bone Marrow Stromal Cells

Introduction Few drugs have been developed to effectively rescue the patients with ischemic stroke in spite of the huge efforts to develop them for longer than 50 years . As alternative approach, cell therapy has recently been expected as one of the promising strategies to enhance functional recovery after ischemic stroke. A variety of cells have been studied as the candidate donor cells for this purpose.…

Neuroprotectants: Cell-Death Based

Introduction Research in the 1990s provided fundamental discoveries of the molecular mechanisms of apoptosis, one type of cell death. In the nematode Caenorhabditis elegans , the genetic control of the programmed cell death during development was elucidated . Cloning of the cell death–related genes was completed. Among them, ced-3 and ced-4 are death-promoting genes and ced-9 is death inhibiting. The identification of their mammalian homologues suggested…

Neuroprotectants: Reactive Oxygen Species (ROS) Based

Introduction Oxygen-free-radical-induced membrane lipid peroxidation (LP) is a highly validated secondary injury mechanism that occurs in focal and global cerebral ischemia and subarachnoid hemorrhage (SAH). It has been firmly established as a major contributor to multiple aspects of ischemic, postischemic, and posthemorrhagic pathophysiologic conditions caused by the oxidative damage to lipids and proteins of the neural cell membrane. Sources of Reactive Oxygen Species in Cerebral Ischemia…

N-Methyl- d -Aspartate Receptors Remain Viable Therapeutic Targets for Stroke

Acknowledgments CP is the recipient of a postdoctoral fellowship granted by the regional council of Nord-Pas-De-Calais, France; and YTW is the holder of the Heart Stroke Foundation of British Columbia and Yukon Chair in Stroke Research. The authors also thank Ms. Rebecca Wiens for her excellent editorial assistance. Introduction Stroke is a major cause of morbidity and mortality in North America and worldwide . The mechanisms…

Mechanisms of Stroke Recovery

Introduction The consequences of stroke can be chronically disabling and overall represents the leading cause of long-term disability . A greater understanding of the mechanisms of stroke recovery will facilitate clinical, pharmacologic, and cell-based approaches to stroke recovery and rehabilitation. The infarct core at the center of the territory of occluded artery results in the cellular death of neurons and supporting cellular elements (glial cells) and…

Risk Factors: Gender and Sex

Introduction Reductions in stroke incidence and mortality are ongoing in the United States; however, the burden of stroke remains high for women. Stroke is the third leading cause of death for women, and roughly 60% of stroke deaths in the United States are in women. In part, this is due to the fact that women are frequently older at the time of stroke, display more nonclassical…

Risk Factors: Aging

Introduction Aging is the primary, nonmodifiable risk factor for cerebrovascular disease (CVD). Two of the most detrimental diseases related to aged cerebrovascular dysfunction are stroke and vascular dementia. Aging is associated with changes to the immune system, neural networks, and vascular regulation. Vascular compliance is impaired with aging, which may contribute to vascular dementia. Aging can produce numerous detrimental outcomes to multiple organ systems. Damaged organs…

Risk Factors : Diabetes

Introduction Diabetes is an endocrine disease with devastating vascular consequences . In the cerebrovasculature, accelerated atherosclerosis of the large vessels is believed to contribute to complications, such as stroke and transient ischemic attacks. There is growing body of evidence that microvascular disease also contributes to stroke and other neurological diseases including Alzheimer disease and vascular cognitive impairment . This chapter will summarize the epidemiological data on…

Hypertension

Acknowledgments Work summarized in this chapter was supported by research grants from the National Institute of Health (HL-62984, HL-113863, NS-09465), the Department of Veteran’s Affairs (BX001399), the Fondation Leducq (Transatlantic Network of Excellence), and the National Health and Medical Research Council of Australia (1053786). Introduction Normal brain function critically depends on adequate levels of perfusion under baseline conditions and in the face of changing cellular demands,…

Spreading Depolarizations

Spreading depolarizations (SDs) are recurrent waves of intense neuronal and glial depolarization that develop in apparently spontaneous fashion in ischemic stroke, intracranial hemorrhage, and trauma. Although Leão first described spreading depression, an SD wave in normal (i.e., uninjured) brain, in 1944, it was not until the late 1970s that periinfarct spreading depression-like waves were detected in experimental focal cerebral ischemia . Today we know that SDs…