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Strategies of neuroprotection in an in vivo model of retinal degeneration induced by mitochondrial dysfunction.
Current approaches to treat neurodegenerative disease provide only mild symptomatic relief but do not modify the natural history of these conditions. A large body of evidence suggests that mitochondrial dysfunction is a key event in the pathophysiology of neurodegeneration. Supporting and improving mitochondrial function has a big potential as a strategy for neuroprotection. The goal of this dissertation was to test whether interventions that target mitochondrial function are effective at preventing neurodegeneration induced by mitochondrial failure in vivo. A rodent model of optic neuropathy induced by the mitochondrial toxin rotenone was used to test the neuroprotective effects of methylene blue (MB) and near-infrared light (NIL), two interventions with mechanisms of action localized to mitochondria. This work also tested the effects of memantine, an NMDA receptor blocker, to further characterize the relationship between excitotoxicity and mitochondrial dysfunction. Neuroprotective effects were evaluated via behavioral testing of visual function and histopathological analysis of the retina. The neurochemical effects of MB, NIL and memantine were analyzed in vitro and in vivo with indicators of oxidative stress, cell respiration and catalytic activity of respiratory enzymes, including NADH dehydrogenase and cytochrome oxidase. MB, a diaminophenothiazine with potent antioxidant and unique redox properties, prevented the changes in visual function and the retinal histopathology induced by rotenone. In vitro, MB increased oxygen consumption and prevented the increases in oxidative stress in brain tissue induced by rotenone. NIL prevented the behavioral impairment and the decrease in retinal and visual pathway metabolic activity, retinal nerve fiber layer thickness and ganglion cell layer cell density induced by rotenone in a dose-dependent manner. Whole-brain cytochrome oxidase and superoxide dismutase activities were also increased in NIL-treated subjects in a dose-dependent manner, suggesting an in vivo transcranial effect of NIL. Finally, uncompetitive NMDA receptor blockade with memantine displayed neuroprotection against rotenone-induced neurodegeneration in a dose-response manner, and this effect was associated with a decrease in retinal oxidative stress and a long-term increase in neuronal energy metabolism capacity. These data constitute a proof-of-principle that interventions that target the mitochondria and support the function of the respiratory chain are effective at preventing neurodegeneration in vivo.
This book provides a contemporary resource on one of the major players in retinal diseases – the Retinal Pigment Epithelium (RPE). Throughout the book, the physiological and the pathological function of the RPE are covered on equal terms, to help readers to understand the RPE as a whole. Moreover, the development of RPE in diagnostics and therapy are covered, as well as some practical knowledge about RPE experimental models. Retinal Pigment Epithelium in Health and Disease highlights new findings of RPE research and includes the state-of-the-art knowledge of each RPE topic presented. This important feature sets this book apart from other publications, with the chapters following a design which leads from the general to the specific, to give a precise collection of the facts known. The chapters are written by well-known experts that are currently active in the field as consultants, basic scientists, and group leaders, providing expert guidance on the current aspects and future outlooks of this topic.
The undisputed gold standard text in the field, Ryan's Retina is your award-winning choice for the most current, authoritative information on new technologies, surgical approaches, scientific advances and diagnostic and therapeutic options for retinal diseases and disorders. Packed with timely updates throughout, new illustrations, and a dedicated team of editors who extend Dr. Ryan’s legacy in retina, this outstanding 6th Edition is a must-have reference for retinal specialists, ophthalmologists, and fellows in training. Offers the most comprehensive content available on retina, balancing the latest scientific research and clinical correlations, covering everything you need to know on retinal diagnosis, treatment, development, structure, function, and pathophysiology. Provides a truly global perspective from five highly esteemed section editors and more than 350 other world authorities from across Europe, Asia, Australasia, and the Americas. Bullets Includes new chapters on widefield imaging, intraoperative OCT imaging, medical management of diabetes mellitus and age-related macular degeneration, and senile retinoschisis. Includes more than 1,150 brand-new illustrations, scans, and photographs throughout. Covers the explosion of new imaging options across optical coherence tomography (OCT), fundus imaging, and autofluorescence imaging, including a greatly expanded OCT imaging chapter that features crucial information on OCT-Angiography (OCT-A). Presents new pharmacotherapy data and the latest approaches in anti-VEGF therapy for age-related macular degeneration, diabetic retinopathy, and venous occlusive disease. Features an expanded online video library highlighting the latest surgical techniques and new coverage of complications of vitreoretinal surgery. Contains thorough content updates in every area of retina, including advanced imaging technologies, gene therapy, inflammation and immune responses, white dot syndromes, epigenetic mechanisms, transplantation frontiers to improve retinal function, macular hole, myopic eye disease, ocular trauma, drug delivery to the posterior segment, advances in macular surgery, vitrectomy and complex retinal detachment, tumors, and retinal genetics and biology. Expert ConsultTM eBook version included with purchase. This enhanced eBook experience allows you to search all of the text, figures, Q&As, and references from the book on a variety of devices.
The focus of this collection of illustrated reviews is to discuss the systems biology of free radicals and anti-oxidants. Free radical induced cellular damage in a variety of tissues and organs is reviewed, with detailed discussion of molecular and cellular mechanisms. The collection is aimed at those new to the field, as well as clinicians and scientists with long standing interests in free radical biology. A feature of this collection is that the material also brings insights into various diseases where free radicals are thought to play a role. There is extensive discussion of the success and limitations of the use of antioxidants in several clinical settings.
Neuroprotection has been placed on a firm scientific basis during the past decade due to an improved understanding of the molecular basis of neurological diseases and the knowledge that treatment of neurological disorders should not be merely symptomatic but preventative against the progression of the underlying disease, as well as regenerative. The Handbook of Neuroprotection serves as a comprehensive review of neuroprotection based on knowledge of the molecular basis of neurological disorders. Neuroprotective effects of older, established drugs, as well as new drugs in development, are well documented in this detailed volume, featuring the most cutting-edge and innovative methods currently in use. In-depth and authoritative, The Handbook of Neuroprotection features a compendium of vital knowledge aimed at providing researchers with an essential reference for this key neurological area of study.
Cottrell's Neuroanesthesia 5th Edition, edited by James E. Cottrell, MD, FRCA and William L. Young, MD, delivers the complete and authoritative guidance you need to ensure optimal perioperative safety for neurosurgical patients. Integrating current scientific principles with the newest clinical applications, it not only explains what to do under any set of circumstances but also why to do it and how to avoid complications. Comprehensive updates reflect all of the latest developments in neurosurgical anesthesia, and contributions from many new experts provide fresh insights into overcoming tough clinical challenges. New co-editor William L. Young, MD joins James E. Cottrell, MD, FRCA at the book's editorial helm, providing additional, complementary expertise and further enhancing the book's authority. New chapters keep you current on interventional neuroradiology, anesthetic management of patients with arteriovenous malformations and aneurysms, awake craniotomy, epilepsy, minimally invasive and robotic surgery, and pregnancy and neurologic disease. Comprehensive updates reflect all of the latest developments in neurosurgical anesthesia, and contributions from many new experts provide fresh insights into overcoming tough clinical challenges. Comprehensive and broad coverage of all important aspects of neuroanesthesia, including special patient populations, enables you to find reliable answers to any clinical question. Chapters written by neurointensivists, neurosurgeons, and radiologists provide well-rounded perspectives on each topic. A consistent, logical organization to every chapter makes answers easy to find quickly. Clear conceptual illustrations make complex concepts easier to understand at a glance.
The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.
This volume describes a broad spectrum of experimental approaches for investigating structure, function, and transport of neuronal mitochondria in health and disease. Most of these approaches were only recently developed and range from electron tomography-based 3D reconstruction of mitochondrial cristae to patch clamp recording from mitochondria in intact neurons. The chapters in this book cover topics such as mitochondrial proteomics, fluorescence lifetime imaging, respirometry and mitophagy, as well as optical approaches based on the use of genetically engineered fluorescent sensors for monitoring synaptic ATP and axonal ROS generation, mitochondrial Ca2+ cycling and pH changes, and mitochondrial dynamics and axonal trafficking in live neurons. Each chapter also discusses difficulties, tips, tricks, and precautions to take. Neuromethods series style chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and comprehensive, Techniques to Investigate Mitochondrial Function in Neurons is a valuable and useful resource for a broad range of investigators interested in the function of neuronal mitochondria in health and disease states.