Neuroprotection : Models, Mechanisms and Therapies > Neurology

Insults to the adult brain are regularly followed by degeneration of nerve tissue and an ensuing impairment of brain function. This process occurs in acute injury, such as brain or spinal cord trauma or cerebral ischemia (stroke), and in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Lou Gehrig's disease (amyotrophic lateral sclerosis). Except for thrombolysis in acute stroke, there are no treatments based on causative mechanisms for any of the aforementioned diseases, and symptomatic drug treatment is useful only for patients with Parkinson's disease and only for a limited period of time. This is where the idea of neuroprotection emerges. The concept may be defined as "pharmacological interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis and thereby forestalling onset of disease or clinical decline" (I. Shoulson. Science 1998;282:1072) or, in simple terms, as protection of nervous tissue at risk in a particular patient. This book addresses the topic in its many facets. The three sections -- covering the epidemiology, clinical overview, and model systems of neurologic disorders; cellular and molecular mechanisms; and therapies -- contain 17 chapters. The first section introduces specific clinical problems, including pathophysiological and epidemiologic data. In addition to injury, stroke, and chronic neurodegenerative disease, inflammation of the central nervous system is discussed. There is a particular focus on mechanisms of injury in stroke. The chapters on Parkinson's disease and Lou Gehrig's disease illustrate how advances in genetics that were derived from the few familial cases of these otherwise sporadic conditions have augmented our general understanding of the pathological cascades that lead to neuronal demise and have paved the way toward genetic models (in transgenic mice) of such conditions. The chapter on synucleinopathies demonstrates that, in addition to rodents and higher mammals, fruit flies and even the nematode Caenorhabditis elegans may be useful tools -- not primarily for imitating phenotypes in humans but for the rapid screening of potentially useful therapeutic compounds. By contrast, surgical (as opposed to genetic) models are well suited for mimicking the various aspects of cerebral ischemia and neurotrauma. In general, cell or tissue cultures are often well suited to investigating biochemical cascades of cell damage, whereas animals are needed for analyzing more complex sequelae in the entire brain and for preclinical testing of potential new treatments. These methodologic aspects of model systems are particularly well discussed in the chapters on the chronic neurodegenerative diseases and neurotrauma. The second section highlights mechanisms of cell death, including chapters on apoptosis, necrosis, excitotoxicity, inflammation, metabolic dysfunction, and protein misfolding. It emerges that most mechanisms play a role in many conditions to a variable extent and at various times. This concept raises hope that future treatments that are effective for one condition may also be effective in others. Beyond neuroprotection, various chapters address axonal regeneration (i.e., the outgrowth of processes from injured, and protected, neurons) as a prerequisite for regaining function; neurogenesis, the emergence of new neurons in certain brain regions; transplantation of new neurons into the lesioned brain, as an external replacement strategy; and gene-transfer approaches. The attempted translation of a vast number of promising results into clinical practice from in vitro, surgical, and transgenic models has failed. The reasons for this are addressed in the two final chapters of the last section. The chapters on spinal cord injury, axonal growth inhibition, and spinal cord trauma are particularly good examples of how models, mechanisms, and therapies can be brought together for a succinct overview. The book achieves similar success in regard to the chronic neurodegenerative diseases. Since most clinical trials of neuroprotection have been conducted in patients with acute stroke, a concise essay on the rationales and failures of these trials would have been welcome. Clearly, clinical neuroprotection is at its beginning stages. For it to go well, cooperative efforts are needed from basic researchers and experienced clinicians. With his expertise in both areas, Bahr has succeeded in bringing together experts from both sides to contribute to this book -- a collaboration that is also needed for advancement in the field. Stefan Isenmann, M.D.

Preface.
List of Contributors.
PART I: NEUROLOGICAL DISORDERS—EPIDEMIOLOGY, CLINICAL OVERVIEW, AND MODEL SYSTEMS.
1. Stroke (Andreas Meisel, Konstantin Prass, Tilo Wolf, Ulrich Dirnagl).
Abstract.
1.1 Introduction.
1.2 The Penumbra Concept.
1.3 Excitotoxicity.
1.4 Oxygen Free Radicals.
1.5 Tissue Acidosis.
1.6 Peri-infarct Depolarizations.
1.7 Inflammation.
1.8 Damage to the Blood–Brain-Barrier.
1.9 Programmed Cell Death and Apoptosis.
1.10 Ischemia-induced DNA Damage, DNA Repair, and p53 as Genotoxic Sensor.
1.11 Epigenetics.
1.12 Gene Expression.
1.13 Cell Replacement.
1.14 Endogenous Neuroprotection – Ischemic Tolerance.
1.15 Stroke Induced Immune Depression (SIDS).
1.16 Conclusion.
References.
2. Parkinson’s Disease (Marina Romero-Ramos, Matthew Maingay and Deniz Kirik).
2.1 Epidemiology of Parkinson’s Disease.
2.2 Oxidative Stress In Parkinson’s Disease.
2.3 Role of Alpha-Synuclein in Parkinson’s Disease.
2.4 The Involvement of Proteosome in PD.
2.5 Other Genes Involved in Familial Parkinson’s Disease.
2.6 Neurotoxic PD Models.
2.7 Genetic Models of Parkinson’s Disease.
Acknowledgements.
References.
3. Amyotrophic Lateral Sclerosis (Georg Haase).
3.1 Human Motor Neuron Diseases.
3.2 Cell Culture Models of Motoneuron Degeneration.
3.3 Animal Models of Motor Neuron Disease.
3.4 Future Neuroprotective Approaches.
3.5 Conclusion.
References.
4. Alzheimer’s Disease and Other Neurodegenerative Diseases (Philipp J. Kahle and Christian Haass).
Abstract.
4.1 Introduction.
4.2 Transgenic Invertebrates.
4.3 Transgenic Mice.
4.4 Viral Models.
4.5 Conclusion and Outlook.
References.
5. CNS Inflammation (Christine Stadelmann and Wolfgang Brück).
5.1 Introduction.
5.2 The Pathologic Characteristics of the MS Plaque.
5.3 Axonal Pathology in MS.
5.4 Neuronal Pathology in Multiple Sclerosis.
5.5 Lessons from Animal Models.
References.
6. Neurotrauma (Ibolja Cernak, Paul M. Lea IV, Alan I. Faden).
6.1 Introduction.
6.2 In Vivo Models.
6.3 In Vitro Models.
6.4 Conclusion.
References.
7. Spinal Cord Injury (Poonam Verma and James W. Fawcett).
7.1 Acute Neuroprotection (preventing neuronal death).
7.2 Regeneration of Nerve Fiber Tracts (initiating growth following injury).
7.3 Bridging Cysts and Scars and Cellular Replacement.
7.4 Replacing Lost Neurons.
7.5 Treating Demyelination.
7.6 Enhancing Plasticity.
7.7 Future Expectations.
References.
PART II: CELLULAR AND MOLECULAR MECHANISMS.
8. Apoptosis and Necrosis (Laura Korhonen and Dan Lindholm).
8.1 Introduction.
8.2 Apoptosis versus Necrosis.
8.3 Genetics of Apoptosis and the Proteins Involved.
8.4 Cellular Mechanisms of Apoptosis.
References.
9. Inflammation (Harald Neumann).
9.1 Introduction.
9.2 Innate Immune Responses in the CNS.
9.3 Dual Mechanism of Innate Immunity in the CNS.
9.4 Antigen Presentation for Adaptive Immune Responses in the CNS.
9.5 Regulation of Adaptive Immune Responses in the CNS.
9.6 Immune Surveillance of the CNS by T Lymphocytes.
9.7 Effector Mechanisms of Lymphocytes.
Acknowledgement.
References.
10. Metabolic Dysfunctions (Konstantin-A. Hossmann).
10.1 Introduction.
10.2 Disturbances of the Energy Metabolism.
10.3 Disturbances of Flow-coupling.
10.4 Mitochondrial Dysfunction.
10.5 Importance of Disturbed Energy Metabolism for Injury Evolution.
10.6 Disturbances of Protein Synthesis.
10.7 Importance of Disturbed Protein Synthesis on Injury Evolution.
10.8 Therapeutical Implications.
References.
11. Protein Misfolding (Milene Russelakis-Carneiro, Claudio Hetz, Joaquin Castilla and Claudio Soto).
Abstract.
11.1 Introduction.
11.2 Disease Propagation by Replication of Prion Protein Misfolding.
11.3 Prion Biology.
11.4 Prion Pathogenesis.
11.5 Neuronal Targeting.
11.6 Neuronal Apoptosis in Prion Diseases.
11.7 ER-Stress and Apoptosis in Prion Diseases.
11.8 Concluding Remarks.
References.
12. Axonal Growth Inhibition (Anne D. Zurn and Christine E. Bandtlow).
12.1 Introduction.
12.2 Intrinsic Properties of CNS Neurons.
12.3 Extrinsic Factors: The CNS as A Non-conducive Growth Environment.
12.4 Experimental Strategies to Overcome Growth Inhibition.
12.5 Conclusion.
References.
13. Neurogenesis (Sebastian Jessberger and Gerd Kempermann).
13.1 Introduction.
13.2 Neural Stem- and Precursor Cells in the Adult Brain.
13.3 Maturation and Migration of Adult-generated Neurons in the Adult Brain.
13.4 Neurogenesis in the Adult Brain – Age Dependency, Persistence and Genetic Determinants.
13.5 Regulation of Adult Neurogenesis.
13.6 Possible Functional Relevance of Neurogenesis in the Adult Brain.
13.7 Therapeutic Strategies for Neural Cell Replacement.
Acknowledgements.
References.
14. Excitotoxicity (Stuart A. Lipton, MD, PhD).
Abstract.
14.1 Introduction.
14.2 The Search for Clinically-Tolerated NMDA Receptor Antagonists.
14.3 Excitotoxicity.
14.4 Memantine.
14.5 NitroMemantines.
14.6 Summary.
Acknowledgments.
Appendix.
References.
PART III: THERAPIES.
15. Spinal Cord Trauma (V. Dietz).
Abstract.
15.1 Epidemiology.
15.2 Clinical Aspects.
15.3 Principles of Therapy.
15.4 Current Approaches in Motor Rehabilitation.
15.5 Search for Reliable Clinical Assessment.
15.6 Conclusion.
References.
16. Neurodegeneration (Jörg B. Schulz, MD).
16.1 What Is Neuroprotection?
16.2 Outcome Measures in Clinical Studies.
16.3 Specific Diseases.
16.4 Why Do So Many Clinical Studies Fail? What Do We Need?
References.
17. Perspectives for Neuroprotective Therapies in Basic Research and Clinical Application (Mathias Bähr and Pawel Kermer).
References.
Index.

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