The Role of Iron Induced Oxidative Stress in Acute Ischemic Stroke and the Potential Role for Fasciculations in their Therapy

Hdl Handle:
http://hdl.handle.net/10675.2/552234
Title:
The Role of Iron Induced Oxidative Stress in Acute Ischemic Stroke and the Potential Role for Fasciculations in their Therapy
Authors:
Mehta, Shyamal H.
Abstract:
(Introductory Paragraphs) Stroke accounts for about one of every 15 deaths in the United States. It is the third leading cause of death behind heart disease and cancer in the United States and the second most common cause of death worldwide, according to the National Center for Health Statistics (1,2). Stroke is also the leading cause of serious disability in the United States; four million people are coping with the debilitating consequences of surviving a stroke which adds to the significant public financial burden (3). Based on the Framingham Heart Study 500,000 people suffer a new or recurrent stroke each year, of whom one third die over the next year, one-third remain permanently disabled and the remaining one-third make a reasonable recovery (1,4). Stroke is a sudden loss of brain function resulting from a disruption in the supply of blood and oxygen to the central nervous system (CNS) giving rise to hypoxic-ischemic conditions within the tissue. Acute stroke can be classified either as: 1. Ischemic stroke involves an interruption in blood supply to the CNS secondary to a vaso-occlusive phenomenon, accounting for 80% of the stroke cases. On basis of its etiology it can be further arbitrarily classified to extra-cranial or intracranial thrombosis and embolism (5). 2. Hemorrhagic stroke involves an interference in blood supply secondary to vascular disruption, accounting for 20% of the cases, which can be further classified to intracranial hemorrhage and subarachnoid hemorrhage (5). A progressing stroke or a stroke in evolution is an extremely complex event whose etiopathogenesis is poorly understood. Its multifactorial etiology makes it difficult to predict and treat by means of clinical, imaging and laboratory data currently available in clinical practice. The hemodynamic changes in the cerebral milieu and the biochemical mechanisms that hasten the progression of neurological injury are crucial to understand in order to reduce neurological morbidity and to design clinically effective interventions. In cerebral ischemia there is an ischemic gradient which can be divided into the core, which is the central ischemic zone and the penumbra, which is the area peripheral to the core. In the penumbra, functional impairment occurs in the neurons and the glia, with the neurons being more susceptible to ischemic injury due their dependence on oxidative metabolism (5). A better understanding of the pathologic mechanisms in ischemic injury would help limit the neurological injury in the penumbra through therapeutic intervention. The major pathogenic mechanisms include energy failure and excitotoxicity, loss of protein translation in the susceptible neurons, apoptotic mechanisms, inflammation and lastly, injury mediated by oxidative stress through the generation of reactive oxygen species (ROS) (6). Many of the above mentioned mechanisms are influenced by the generation of ROS. It has been directly demonstrated in numerous studies that ROS are involved in oxidative damage through peroxidation of lipids, proteins and nucleic acids in ischemic tissues (7). In addition, ROS also function as signaling molecules in cellular ischemia and reperfusion. In this dissertation we tried to elucidate the role of ROS in exacerbation of neurological injury in acute ischemic stroke. In order to gain a better understanding of the pathophysiological mechanisms underlying oxidative stress, we studied iron induced oxidative stress, as iron generates ROS through the Fenton reaction. We believe that ROS exacerbate ischemic injury, hence we wanted to demonstrate the neuroprotective ability of various antioxidants. In the end, we present a model of neuronal behavior in vitro that may have possible implications in post-injury remodeling and repair. Chapter 1 will review the literature in the field of antioxidants and ROS in stroke. In addition, the prevailing theories on the role of iron-induced oxidative stress and the various antioxidant agents used in stroke will be critically reviewed.
Affiliation:
Department of Physiology
Issue Date:
Jul-2003
URI:
http://hdl.handle.net/10675.2/552234
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/305295892?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorMehta, Shyamal H.en
dc.date.accessioned2015-05-05T02:43:04Zen
dc.date.available2015-05-05T02:43:04Zen
dc.date.issued2003-07en
dc.identifier.urihttp://hdl.handle.net/10675.2/552234en
dc.description.abstract(Introductory Paragraphs) Stroke accounts for about one of every 15 deaths in the United States. It is the third leading cause of death behind heart disease and cancer in the United States and the second most common cause of death worldwide, according to the National Center for Health Statistics (1,2). Stroke is also the leading cause of serious disability in the United States; four million people are coping with the debilitating consequences of surviving a stroke which adds to the significant public financial burden (3). Based on the Framingham Heart Study 500,000 people suffer a new or recurrent stroke each year, of whom one third die over the next year, one-third remain permanently disabled and the remaining one-third make a reasonable recovery (1,4). Stroke is a sudden loss of brain function resulting from a disruption in the supply of blood and oxygen to the central nervous system (CNS) giving rise to hypoxic-ischemic conditions within the tissue. Acute stroke can be classified either as: 1. Ischemic stroke involves an interruption in blood supply to the CNS secondary to a vaso-occlusive phenomenon, accounting for 80% of the stroke cases. On basis of its etiology it can be further arbitrarily classified to extra-cranial or intracranial thrombosis and embolism (5). 2. Hemorrhagic stroke involves an interference in blood supply secondary to vascular disruption, accounting for 20% of the cases, which can be further classified to intracranial hemorrhage and subarachnoid hemorrhage (5). A progressing stroke or a stroke in evolution is an extremely complex event whose etiopathogenesis is poorly understood. Its multifactorial etiology makes it difficult to predict and treat by means of clinical, imaging and laboratory data currently available in clinical practice. The hemodynamic changes in the cerebral milieu and the biochemical mechanisms that hasten the progression of neurological injury are crucial to understand in order to reduce neurological morbidity and to design clinically effective interventions. In cerebral ischemia there is an ischemic gradient which can be divided into the core, which is the central ischemic zone and the penumbra, which is the area peripheral to the core. In the penumbra, functional impairment occurs in the neurons and the glia, with the neurons being more susceptible to ischemic injury due their dependence on oxidative metabolism (5). A better understanding of the pathologic mechanisms in ischemic injury would help limit the neurological injury in the penumbra through therapeutic intervention. The major pathogenic mechanisms include energy failure and excitotoxicity, loss of protein translation in the susceptible neurons, apoptotic mechanisms, inflammation and lastly, injury mediated by oxidative stress through the generation of reactive oxygen species (ROS) (6). Many of the above mentioned mechanisms are influenced by the generation of ROS. It has been directly demonstrated in numerous studies that ROS are involved in oxidative damage through peroxidation of lipids, proteins and nucleic acids in ischemic tissues (7). In addition, ROS also function as signaling molecules in cellular ischemia and reperfusion. In this dissertation we tried to elucidate the role of ROS in exacerbation of neurological injury in acute ischemic stroke. In order to gain a better understanding of the pathophysiological mechanisms underlying oxidative stress, we studied iron induced oxidative stress, as iron generates ROS through the Fenton reaction. We believe that ROS exacerbate ischemic injury, hence we wanted to demonstrate the neuroprotective ability of various antioxidants. In the end, we present a model of neuronal behavior in vitro that may have possible implications in post-injury remodeling and repair. Chapter 1 will review the literature in the field of antioxidants and ROS in stroke. In addition, the prevailing theories on the role of iron-induced oxidative stress and the various antioxidant agents used in stroke will be critically reviewed.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/305295892?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectStrokeen
dc.subjectCentral Nervous Systemen
dc.subjectTherapeutic Interventionen
dc.subjectEnergy Failureen
dc.subjectExcitotoxicityen
dc.titleThe Role of Iron Induced Oxidative Stress in Acute Ischemic Stroke and the Potential Role for Fasciculations in their Therapyen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorWebb. R. C.en
dc.description.committeeNot Listeden
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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