Restorative Neurology and Neuroscience - Volume 13, issue 1-2

Authors: Prass, Konstantin | Dirnagl, Ulrich

Article Type: Research Article

Abstract: It is well established that excitotoxicity is a key mechanism of tissue destruction in focal cerebral ischemia (stroke). Very soon after onset of a critical perfusion deficit energy failure leads to neuronal depolarization and release of excitatory aminoacids, most notably glutamate. At the same time, energy dependent reuptake of excitatory amino acids is impede. Overstimulation of glutamate receptors (NMDA, AMPA/kainate, metabotropic) induces dramatically increased intracellular Ca2+ concentrations, release of K+ into the …extracellular space, and cell swelling due to the passive movement of water with Na+ influx. The massively increased intracellular second messenger Ca2+ triggers numerous deleterious processes, including free radial formation and membrane degradation, mitochondrial dysfunction, inflammation, DNA-damage and apoptosis. A plethora of experimental studies have convincingly demonstrated the relevance of excitotoxicity in focal cerebral ischemia, and pointed to very effective experimental treatment strategies, many of which involve the blockade of glutamate receptors. Unfortunately, large clinical studies were so far unable to replicate the animal data in human stroke patients. This article, by reviewing excitotoxic damage of focal cerebral ischemia in the context of a complex pathophysiological cascade, aims at explaining this failure and stimulating further efforts in drug design and clinical evaluation to establish the first neuroprotective therapy of human stroke. Show more

Keywords: cerebral ischemia, excitotoxicity, inflammation, apoptosis, neuroprotection, clinical trials

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 3-10, 1998

Authors: Bittigau, Petra | Pohl, Daniela | Sifringer, Marco | Shimizu, Hiroki | Ikeda, Masuhiro | Ishimaru, Masahiko | Stadthaus, Daniel | Fuhr, Susanne | Dikranian, Krikor | Olney, John W. | Ikonomidou, Chrysanthy

Article Type: Research Article

Abstract: We have developed a model for head trauma in infant rats in an attempt to study mechanisms of neurodegeneration in the developing brain and were able to morphologically characterize two distinct types of brain damage. The first type or primary damage evolved within 4 hrs after trauma and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hrs and occured by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site …of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus, hippocampal dentate gyrus and striatum. Histological evidence of delayed cell death was preceded by decrease of bcl-2- in conjunction with increase of c-jun-mRNA-levels, already evident at 1 hr after trauma. Increase of CPP32-like activity and elevated concentrations of oligonucleosomes in affected brain regions represented additional findings to indicate that this secondary disseminated degenerative reaction is apoptotic in nature. At the age of 7 days, secondary apoptotic damage was more severe than primary excitotoxic damage, but its severity declined with increasing age. In 7-days-old rats, NMDA antagonists protected against primary excitotoxic damage but increased severity of secondary apoptotic damage whereas the free radical scavenger SPBN, the tumor necrosis factor (TNF) inhibitor pentoxifylline and the antioxidant N-acetylcystein mitigated apoptotic damage. These findings demonstrate that in the developing rat brain apoptosis and not excitotoxicity determines neuropathologic outcome following head trauma. Whereas radical scavengers and TNF-inhibitors may prove useful in treatment of pediatric head trauma, great caution should be applied in regards to the use of NMDA antagonists because of the inherent risk of apoptosis promotion. Show more

Keywords: apoptosis, excitotoxicity, traumatic head injury, neurodegeneration, free radicals, development, rats

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 11-23, 1998

Authors: Urbanska, Ewa M. | Czuczwar, Stanislaw J. | Kleinrok, Zdzislaw | Turski, Waldemar A.

Article Type: Research Article

Abstract: Epilepsy has been described as a neurological disorder with a prevalence rate estimated at approximately 0.5% of population. In recent years there have been significant advances in our understanding of the contribution of excitatory glutamatergic transmission to seizures. Glutamate appeared to participate in the initiation, propagation and maintenance of epileptic activity. In epileptic patients, changes in glutamate concentration and receptor function were found. Intracerebral or systemic administration of glutamate receptor agonists has …become a popular way to induce seizures in rodents. Glutamate antagonists were shown to be potent anticonvulsants in varying experimental seizure models determined genetically, induced chemically and electrically, or due to kindling. A potential therapeutic role for drugs affecting glutamatergic mechanisms in epilepsy has not yet been defined but is constantly attracting interest. In this review we summarize data from studies performed in humans and animals and focus on iono- and metabotropic excitatory amino acid receptor-mediated events in seizures and epilepsy. Show more

Keywords: seizure disorders, ionotropic receptors, metabotropic receptors, anticonvulsants

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 25-39, 1998

Authors: Tarnawa, István | Vize, E. Sylvester

Article Type: Research Article

Abstract: The 2,3-benzodiazepine GYKI 52466 (1-(4-aminophenyl)-4 methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) and its analogues represent a family of selective AMPA antagonists. They modulate AMPA channel functions through an allosteric site on the receptor, which is probably different from the ones involved in the actions of cyclothiazide and aniracetam. These compounds are frequently used as research tools to elucidate glutamate receptor-mediated functions. The most effective members of the family inhibit AMPA-induced currents in the submicromolar range. In addition, …they are active at low systemic doses in various in vivo experimental models and also possess a good oral bioavailability. In vitro and in vivo pharmacological results with 2,3-benzodiazepine AMPA antagonists indicate their potential therapeutical value in treating a great variety of central nervous system diseases, of which epilepsy and neurodegenerative disorders are regarded as the most important. Show more

Keywords: GYKI 52466, epilepsy, spasticity, pain disorders, neuroprotection, neurodegenerative disorders

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 41-57, 1998

Authors: Ludolph, Albert C. | Meyer, Thomas | Riepe, Matthias W. | Volkel, Helge

Article Type: Research Article

Abstract: Amyotrophic lateral sclerosis is a progressive fatal disorder devastating the spinal cord and brain in humans. Excitotoxicity has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis. This hypothesis has driven a wealth of basic research and stimulated development of neuroprotective therapies for chronic neurodegenerative disorders. As a result of these efforts, riluzole, an antiglutamatergic drug, has been established in the therapy of amyotrophic lateral sclerosis. A transgenic mouse …showing features of amyotrophic lateral sclerosis has been subsequently engineered enabling studies of the disease in vivo. However, despite considerable progress, the etiology of amyotrophic lateral sclerosis remains obscure and the disturbances in excitatory neurotransmission should by no means be regarded as exclusive to the pathogenesis of the disease. Show more

Keywords: amyotrophic lateral sclerosis, Cu/Zn SOD, EAAT2, excitotoxicity, neurolathyrism, riluzole

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 59-67, 1998

Authors: Wüllner, Ullrich | Evert, Bernd | Klockgether, Thomas

Article Type: Research Article

Abstract: Recent advances in molecular genetic and cellular biology have provided new insights into the mechanisms leading to neuronal dysfunction and cell death in the disorders of the cerebellum. Trinucleotide repeat expansions have been identified as an important cause of inherited cerebellar ataxias and mechanisms involved in apoptotic cell death have become centerstage of scientific interest. In the present article, we review the recent findings in trinucleotide repeat disorders and address the possible link of glutamate …neurotoxicity, impaired Ca2+ homeostasis and apoptosis. Show more

Keywords: spinocerebellar ataxia, trinucleotide repeats, calcium, apoptosis, glutamate

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 69-73, 1998

Authors: Olney, John W. | Wozniak, David F. | Farber, Nuri B.

Article Type: Research Article

Abstract: In this article we review the hypothesis that impaired function of the N-methyl-Daspartate (NMDA) glutamate receptor system may be an important mechanism for understanding the pathophysiology of Alzheimer's disease (AD). We propose a two stage process, the first involving amyloidopathy, oxidative stress and/or energy metabolic disturbances promoting neuronal sensitivity to glutamate-induced excitotoxic injury to an extent that even normal amounts of Glu become excitotoxic. As a consequence, NMDA receptor-bearing neurons (and their …NMDA receptors) are deleted from critical corticolimbic brain circuits, which leaves these circuits in an NMDA receptor hypofunctional (NRHypo) state. In the second stage this NRHypo state results in the disinhibition of a complicated neural circuitry that leads to widespread neurodegeneration in corticolimbic areas, consquent neurofibrillary tangle formation and cognitive decline. We propose that certain pharmacological methodes which have been found to protect against NRHypo-induced neurodegeneration in animal brain might be useful treatments for AD. Show more

Keywords: NMDA antagonists, amyloid processing, GABA, glutamate, acetylcholine

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 75-83, 1998

Authors: Cavalheiro, Esper A. | Schoepp, Darryle | Turski, Lechoslaw

Article Type: Abstract

Abstract: The past decade has led to many significant advances in the understanding of the function of excitatory amino acids in synaptic transmission. The cloning of the ionotropic and metabotropic glutamate receptor families has produced new strategies for the pharmacological modulation of glutamate transmission. The engineering of transgenic animals with modified expression of receptor proteins has created new insights into the function, dysfunction and possible pathology causally related to glutamate receptors. Advances in the pharmacology of glutamate receptors has lead to clinical research addressing multiple therapeutic applications of drugs that act on excitatory amino acid systems. A number of NMDA receptor …antagonists have now been studied in humans. AMPA/kainate and metabotropic receptor active compounds have left the preclinical realm of research and have moved towards or are in the clinic. Excitatory amino acid research has brought new therapeutic concepts and increased immensely our understanding of how the brain works. The pharmaceutical industry has explored the emerging concepts and therapy related principles in the clinic. Research on excitatory amino acids in the last ten years has produced a foundation for future therapeutic strategies that are highly innovative, and now hold considerable promise to deliver novel pharmaceuticals for both neurological and psychiatric disorders. November 1998, after a long ten year break, marks the second symposium on "Excitatory Amino Acids - Manaus '98". The conference is organized under the auspices of the Brazilian Academy of Sciences, the Federation of Brazilian Societies of Experimental Biology and the Brazilian League Against Epilepsy. The selection of the venue has a symbolic characteristic and addresses the research in South America and developing countries. The meeting addresses today's emerging questions and the new avenues which glutamate research is taking in to the future from the perspectives of molecular biology, physiology, pathology, pharmacology, and medicine. It is our goal that scientists from a variety of disciplines will benefit from the information provided. Show more

Keywords: glutamate, glutamate receptors, glutamate antagonists, neurodegenerative disorders, psychiatric disorders, clinical trials

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 1-2, pp. 85-115, 1998