Excitotoxicity in Neurological Diseases

It can be reasonably anticipated that, over the next generations, the proportion of elderly people will remarkably increase and, with this, the number ofpersons suffering from acute (e.g. cerebral ischemia) or chronic neurodegenerative disorders. To date, approved drugs only alleviate the symptoms ofthese diseases (for instance, acetylcholinesterase inhibitors in Alzheimer disease and L-dopa and dopamine-agonists in Parkinson disease), while none seems to stop the progression of the degenerative processes underlying them. The development of effective preventive or protective therapies has been impeded by the limitations of our knowledge of the causes and the mechanisms by which neurons die in neurodegenerative disorders. Evidence accumulated in the past 20 years indicated that the major excitatory neurotransmitter glutamate may play a role as neurotoxin in several conditions. In particular, the glutamatergic system dysfunction seems to be an early event working as a common pathway in the pathogenesis ofa large number ofacute and chronic neurological disorders, in strict conjunction with other important mechanisms, such as oxidative stress and energetic failure, and probably triggered by different mechanisms in various diseases. In consideration of that, drug discovery efforts over the last decade have been focused on the search for drugs that either reduce glutamate synaptic levels or block its postsynaptic effects. Despite numerous reviews on basic mechanisms and clinical aspects ofthe excitotoxic phenomenon, so far no comprehensive book has covered the topic in all its complexity, starting from basic pharmacological mechanisms, to .animal models of diseases and finally to clinical pathogenic and therapeutic implications.

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The book is intended both for scientists already involved in the field, who may want a broader knowledge of all the aspects related to this complex mechanism, as well as for PhD or MD students, residents and neurologists wishing to learn more about a common mechanism involved in neuronal damage, driven by scientific curiosity or by the need to understand how new drugs, already on the market, may or may not work in various neurological disorders. With this aim, the book is basically divided into two parts, designed to be mutually integrated: - The first part covers all basic mechanisms of excitotoxicity, from glutamate metabolism, release, activity on various pre- and post-synaptic receptors, reuptake and their regulations, - The second part focuses on each neurologic disorder where this mechanism seems to play a major role, by examining in details pre-clinical and clinical evidences as well as treatment strategies in animal models and in patients. - To accomplish this complex task, world leaders in various fields, who did major contributions to define the problem and to open new avenues and are also actively working at present, agreed to put their expertise to launch the first complete and advanced level book on the role of excitotoxicity in neurologic diseases.

Contenu
and historical notes.- I: Basic mechanisms.- 1. Contribution of astrocyte glutamate release to excitotoxicity.- 2. Glutamate uptake and transporters.- 3. NMDA receptors.- 4. AMPA receptor and synaptic plasticity.- 5. Metabotropic glutamate receptors and neurodegeneration.- 6. Mechanisms of excitotoxicity and excitoprotection.- II: Acute and chronic neurological disorders.- 7. Epilepsy and seizures: excitotoxicity or excitotrophicity?.- 8. Excitotoxicity in cerebral ischemia.- 9. Excitotoxicity and traumatic brain injury.- 10. Excitotoxicity in amyotrophic lateral sclerosis: selective vulnerability of motor neurons.- 11. Glutamate transmission in the pathogenesis of Parkinson's disease.- 12. Excitotoxicity in Huntington's Disease.- 13. The glutamatergic system in Alzheimer's disease brain: dysfunction associated with amyloid ?-peptide and oxidative stress.- 14. Neurotoxicity and prion disease.- 15. Glutamate excitotoxicity in multiple sclerosis.- 16. HIV-1 associated dementia.- 17. Markers of excitotoxicity in patients: tool for diagnosis or therapy?.- 18. Anti-excitotoxic therapies in neurological diseases: current evidences and new perspectives.