Endogenous Neuroprotection

Endogenous neuoprotection is a phenomenon where a brief episode of ischemia renders the brain resistant against a subsequent longer-asting ischemia event. Experimentally, the author was able to model hypoxic preconditioning in animal model. Increasing knowledge of this endogenous neuroprotectin by ischemic tolerance may help to minimize neuronal damage following ischemic stroke and hypoxic encephalopathy. This book is, therefore, the first overview of this important topic and will certainly influence further investigations in clinical and neuroscience research.

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.

Breathing must be robust and highly adaptable to maintain adequate oxygen and CO2 levels during birth, development, pregnancy, and disease. This is achieved by a delicate balance of inhibitory and excitatory neuronal signaling. Both sustained, and intermittent changes in respiratory neuron activity can create long-lasting changes in respiratory motor output (i.e., plasticity). As a constant requirement from birth until death, the respiratory control system must have endogenous mechanisms to maintain appropriate excitability during physiological or pathological stress, and express multiple types of plasticity. Reproduction is an example of an essential biological function with serious maternal and fetal risks. During late pregnancy, maternal brain allopregnanolone levels increase and augment the function of inhibitory GABAA receptors (GABAARs), posing the risk of excessively inhibiting respiratory neurons. Here, we show that respiratory-related hypoglossal motoneurons increase epsilon subunit incorporation into GABAA receptors, which confers insensitivity to allopregnanolone. Similarly, brain allopregnanolone levels increase during the critical period in respiratory control development (occurs during the second postnatal week). We also found that epsilon subunit-containing GABAARs dynamically change in respiratory-related brain regions during the second postnatal week. Thus, increased epsilon subunit incorporation in GABAARs appears to protect breathing from excessive inhibition during pregnancy and postnatal development under physiological conditions. Thus, these studies suggest that adjusting GABAAR subunit composition may be a little recognized, fundamental property of the respiratory control network. On the other hand, pregnancy and the neonatal period are also associated with pathological events, such as ischemic stroke. One potential strategy for protecting neurons from ischemia is to apply principles learned from ischemia-hypoxia resistant extremophile vertebrates, such as activating delta opioid receptors (DORs). We hypothesized that activating spinal DORs would prolong respiratory output (i.e., provide neuroprotection) during oxygen-glucose deprivation (OGD; in vitro stroke model). We found that spinal DOR activation provides flexible neuroprotection against OGD, regardless of whether DOR drugs are applied to the spinal cord before, during or after the onset of OGD. These studies suggest that understanding and controlling endogenous protective mechanisms is a compelling strategy for developing novel therapies and treatments to protect neuronal function against ischemia.

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.

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.

As clinical trials of pharmacological neuroprotective strategies in stroke have been disappointing, attention has turned to the brain's own endogenous strategies for neuroprotection. Two endogenous mechanisms have been recently characterized, ischemic preconditioning and ischemic postconditioning. In the present topic newly characterized mechanisms involved in preconditioning- and postconditioning- neuroprotection will be discussed. The understanding of the mechanisms involved in the neuroprotective pathways induced by preconditioning and postconditioning will be clinically relevant for identifying new druggable target for neurodegenerative disorder therapy. Furthermore, the importance of these neuroprotective strategies resides in that it might be easily translatable into clinical practice. Therefore, the data presented here will highlight the capacity of ischemic preconditioning and postconditioning to be of benefit to humans.

Neurotrophic factors play central roles in the developing and mature nervous system by promoting neuronal survival. The discovery in 1990 that an exogenously supplied neurotrophic factor could slow the progression of photoreceptor loss in an animal model of retinal degeneration has given rise to an active field of research whose ultimate goal is to develop neuroprotective therapy for patients with blinding diseases. At the same time, a growing body of evidence suggests that endogenously expressed neurotrophic factors maintain retinal health and mediate retinal responses to stress throughout life. This thesis investigates both the requirement for retinal expression of neurotrophic factors in a model of endogenous neuroprotection, and the activity of exogenous factors in a clinically relevant new model of retinal injury.

Although the genomic era is no longer in its infancy, the life sciences are still facing questions about the role of endogenous proteins and peptides in homeostasis and pathologies. Delving into one of the most current fields of interest in biology and medicine, Neuropeptides in Neuroprotection and Neuroregeneration describes the impact of neuropeptides on neuroprotection and neuroregeneration. The book begins with chapters describing important features of the endogenous neuropeptide systems related to their formation, receptor signaling, and inactivation. It includes chapters focused on the design and development of peptide-like drugs (peptidomimetics). In addition, the book covers: General aspects regarding the biosynthesis, structures, and distribution of neuroactive peptides and their receptors Basic mechanisms for neuropeptide action, metabolism, as well as techniques for their detection and aspects essential for the cellular mechanisms underlying brain pathology Neuropeptides known for their impact in neurodegenerative and neuroprotective processes Fundamental aspects as well as recent progress in the development of peptidomimetics of neuroprotective and cognition-enhancing peptides

Given the very limited capacity of regeneration in the brain, protecting neurons that are on the brink of death is a major challenge for basic and clinical neuroscience, with implications for a broad spectrum of acute and chronic neurological and psychiatric diseases. This book brings together leading experts from neurobiology, neurophysiology, neuropharmacology, neuroimmunology and clinical neuroscience to highlight the most recent milestones in this rapidly evolving field. The book will serve as a reference for both basic neuroscientists and clinicians interested in an authoritative update on the molecular and cellular biology of neuroprotection and its promises for new therapeutic strategies.