Despite compelling preclinical evidence from laboratory models of brain hypoxia suggesting potential neuroprotective strategies, only scattered data are available from clinical studies. A few candidate neuroprotectants have been studied regarding antioxidant, antiapoptotic, anti-excitotoxic, immunomodulatory, and neurotrophic effects. In parallel with clinical innovations, preclinical research initiatives are also identifying new animal models more closely resembling the clinical course and pathology of neurodegenerative diseases. Clarifying the specific mission of the brain cells involved in the damage/repair system in the examined animal models is important to define new therapeutic targets. Following hypoxic damage, detrimental events intermingle with the repairing events in both time- and cellular-dependent fashion. Identifying reliable post-hypoxia brain markers is mandatory to develop potential therapeutic interventions, improving translational research from the experimental observations to the clinical application. A deeper understanding of the precise participation of neurons, glia, and endothelial cells is expected to offer more clues for designing new therapeutic strategies to reduce the current gap among the experimental and the clinical data. One of the main issues should be to study the epigenetic mechanism of neuroprotective agents and their action on the genetic modification induced by hypoxia. Achieving this goal is presumed critical to obtain more conclusive results in patients that by now do not receive appropriate therapy for mitigating the several diseases generated by brain hypoxia. Although a few ongoing studies are evaluating interesting approaches, future research is necessary to come to a novel mechanism of neuroprotection. This book encompasses different chapters conveying the goals and aims of the pertaining research.

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It is with great pleasure that I present to you this book. At the present time, physicians and scientists are working feverishly to find novel strategies for neuroprotection in human preterm and term hypoxic newborns. Cerebral hypoxia-ischemia and asphyxia present a great challenge to all of us concerned with the deleterious consequences that manifest as cerebral dysfunction, mental retardation, and cerebral palsy. This book entitled Mechanisms of Hypoxic Brain Injury in the Newborn and Potential Strategies for Neuroprotection will be of great interest to physicians, clinician-scientists, and researchers in a number of disciplines including Pediatrics, Neonatal-Perinatal Medicine, Developmental Biology, Neurology, Pediatric Neurology, Obstetrics and Gynecology, Neuroscience, Developmental Neuroscience, Developmental Neurochemistry, and to everyone interested in the developing brain . The information presented in this book will be appropriate to residents, clinical fellows, pre- and post-doctoral fellows, faculty of basic science departments, faculty of clinical departments, and to the most advanced researchers in the field of hypoxic ischemic brain injury in the fetus and the newborn. I would like to thank sincerely my colleagues and contributors to this book for their excellent efforts and extremely valuable time. Each contributor to this book is a pioneer in his or her field: the contributions are superb. As a reader, you will find that the authors of this book are from different parts of the world and that this book presents the forefront of cutting-edge global research and developments in the field of hypoxic brain injury in newborns. Finally, I would like to thank my wife Ira Mishra, whose constant support and patience have been invaluable in helping to produce not just this book but thirty years of my research investigations on the mechanisms of hypoxic injury in the developing brain.

Traumatic brain injury (TBI) remains a significant source of death and permanent disability, contributing to nearly one-third of all injury related deaths in the United States and exacting a profound personal and economic toll. Despite the increased resources that have recently been brought to bear to improve our understanding of TBI, the developme

Cerebral preconditioning is a phenomenon wherein a mild insult or stress induces cellular and tissue adaptation or tolerance to a later, severe injury, therefore reflecting the efficacy of endogenous mechanisms of cerebrovascular protection. Initially identified for rapid cardiac protection, preconditioning has expanded to all aspects of CNS protection from ischemia, trauma and potentially neurodegeneration. Many different stimuli or stressors have been identified as preconditioning agents, suggesting a downstream convergence of mechanisms and underscoring the potential for translational application of preconditioning in the clinic. Moreover, the fundamental mechanisms responsible for preconditioning-induced tolerance will help in the design novel pharmacological approaches for neuroprotection. While stroke and many other brain injuries are not predictable, in some populations (e.g., metabolic syndrome, patients undergoing carotid endarterectomy, aneurysm clipping, or with recent TIAs) the risk for stroke is identifiable and significant, and preconditioning may represent a useful strategy for neuroprotection. For unpredictable injuries, post-conditioning the brain – or inducing endogenous protective mechanisms after the initial injury – can also abrogate the extent of injury. Finally, remote pre- and post-conditioning methods have been developed in animals, and are now being tested in clinical trials, wherein a brief, noninjurious stress to a noncerebral tissue (i.e., skeletal muscle) can provide protection to the CNS and thereby allows clinicians the opportunity to circumvent concerns regarding the direct preconditioning of neurological tissues.

SOLOMON H. SNYDER Receptor Research Reaches Neurology: Relevance to Neurodegenerative Diseases and Stroke President George Bush has heralded the 1990s as the decade of the brain, based largely on the rapid escalation of advances in the molecular neuro sciences and the likelihood that these will bear therapeutic fruit before the turn of the century. There is little doubt that the 1970s and 1980s have witnessed more remarkable advances in the molecular neurosciences than all of the preceding hundred years. Identification of receptor sites for drugs and neurotransmitters along with simple, sensitive, and specific means of monitoring them has made it possible to elucidate the mechanism of action for many known drugs and to identify new chemical entities as potential therapeutic agents. At the same time, the numbers of distinct neurotrans mitters have multiplied. Prior to 1970 only the biogenic amines were well accepted as transmitters. The early 1970s witnessed the gradual acceptance of amino acids as major excitatory and inhibitory neurotransmitters. Identification of opiate receptors and the subsequent identification of the enkephalins as their endogenous ligands led to an appreciation of peptides as putative transmitters and the accumulation of as many as a hundred neuropeptides by the decade's end. In the 1980s the revolutions of molecular biology have been applied aggressively to the neurosciences with molecular cloning for neuropeptide precursors, many important neurochemical en zymes, and receptors for numerous transmitters.