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Excitotoxic neuronal death has been clearly documented in the adult brain following status epilepticus (SE), a state of uninterrupted seizure activity that may last for hours. The severity and duration of SE determine the extent of neuronal injury; in most animal models damage is observed with durations of one hour or longer. Severity, duration and rate of onset may also influence the extent to which...
The hypothesis that cerebral ischemia may recognize an excitoxic pathophysiological component is supported by a number of consolidated arguments, including the neuroprotective activity of glutamate receptor antagonists in experimental animal models and the use of anti-excitotoxic agents in clinical trials for stroke. Despite the dramatic results in the preclinical setting, phase III clinical trials...
Traumatic brain injury (TBI) is a major health problem in the industrialized world where survivors suffer major physical, psychological and economical consequences. Despite numerous clinical trials investigating pharmaceutical compounds with promising pre-clinical efficacy, no pharmacological treatment has been developed with proven clinical efficacy. The present chapter reviews the pathophysiology...
Excessive glutamate concentration is toxic to motor neurons in vitro, thus suggesting the possibil ity that glutamate excitotoxicity plays a role in motor neuron degeneration in Amyotrophic Lateral Sclerosis. Indeed high glutamate levels are found in the cerebrospinal fluid of about 40% of patients, possibly related to the decrese in glutamate uptake and EAAT2 transporter. Studies in vitro and in...
Parkinson’s disease (PO), a progressive neurodegenerative disorder, is a common cause of disability. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. The current pathophysiological concept of PD postulates a multifactorial origin, where alterations in neurotransmitter content are combined with genetic...
There is a large body of evidence implicating excitotoxicity in Huntington’s Disease (HD) pathogenesis. The concept that excitotoxicity might playa role was developed after the observation that kainic acid induced striatal lesions which mimic many of the neuropathologic features of HD. We and others subsequently showed that quinolinic acid lesions, which spare NADPH-diaphorase neurons, produced an...
Excitotoxic mechanisms of neuronal death can occur in the presence of excess glutamate. Hence, means to remove or convert extra-neuronal glutamate exist in brain. However, in Alzheimer’s disease (AD) brain, the glutamate transporter and glutamine synthestase function with considerably reduced activity. Consistent with the observed oxidative stress in AD brain and the oxidative stress induced by amyloid...
Prion diseases are characterised by the conversion of a normal glycoprotein, the prion protein, to an abnormal protease resistant form, which is suggested to be both the infectious agent and the cause of neuronal cell death in the disease. Death of the patient results from neurodegeneration. In this review, we present data arguing that neurodegeneration in prion diseases is a complex process, involving...
Multiple sclerosis (MS) is a disease of central white matter with prominent demyelination and oligodendrocyte loss. Recent data on MS pathogenesis has implicated disruption of glutamate homeostasis as a disease mechanism, at the center of which, molecules of the glutamate clearance pathway are selectively downregulated on oligodendrocytes. Thus, oligodendrocytes are unable to process extracellular...
Dementia constitutes one devastating consequence of infection with human immunodeficiency virus-1 (HIV-1). While the mechanism of the HIV-1 induced neuropathology remains incompletely understood, several lines of evidence suggest the involvement of chemokine receptors, inflammatory factors and NMDA receptor-mediated excitotoxicity. All of these can in tum trigger several downstream mechanisms, including...
The role of excitotoxicity in single patients affected by neurological disorders is difficult to assess, but it may provide useful indications as far as prognosis and response to therapy. Glutamate levels could be measured in biological fluids, such as plasma and cerebrospinal fluid. Increased levels of the amino acid have been demonstrated in cerebrovascular diseases, amyotrophic lateral sclerosis...
To counteract excitotoxic mechamisms involved in a great deal of acute and chronic neurodegenerative disorders, efforts have been addressed, over the last decade, to search for drugs that either reduce glutamate synaptic levels or block its postsysnaptic effects. Among the large amount of compounds tested, riluzole and the NMDA receptor antagonist memantine have proved to be quite efficacious in amyotrophic...
Although glial cells have been traditionally viewed as supportive partners of neurons, recent studies demonstrated that astrocytes possess functional receptors and are able to release transmitters by regulated pathways. Astrocytes were found to react to synaptically released neurotransmitters by undergoing intracellular calcium elevation which subsequently triggers an exocytosis-like glial transmitter...
Glutamate uptake is mediated by a family of glutamate transporter proteins present in the plasma membranes of glial cells and neurons. These proteins enable the nervous system to maintain low extracellular concentrations of glutamate. This is important to avoid harmful overactivation of glutamate receptors and to secure a high signal to noise ratio in synaptic transmission. In addition to this simple,...
The N-methyl-D-aspartate (NMDA) type glutamate receptors are abundant, ubiquitously distributed throughout the CNS, fundamental to excitatory glutamatergic transmission and critical for normal brain function. Activation of NMDA receptor is complex; both glutamate and glycine are required to open the ion channel and allow calcium entry. NMDA receptor is voltage dependently blocked by magnesium and...
AMPA receptors mediate the majority of excitatory synaptic transmission in the brain. Thus, the mechanisms that control the developmental and activity-dependent changes in the functional synaptic expression of AMPA receptors are of fundamental importance. Recent advances have shown a critical role for AMPA receptor trafficking in long-term potentiation (LTP) and in long-term depression (LTD). Here...
Metabotropic glutamate (mGlu) receptors, which exert a modulatory effect on excitatory synaptic transmission, are considered as potential targets for neuroprotective drugs and the advent of potent and centrally available subtype-selective ligands has lead to an extensive investigation of the role of individual mGlu receptor subtypes in neurodegeneration. Pharmacological blockade of mGlu1 or -5 receptors...
All neurons in the central nervous system of mammals express receptors for the excitatory amino acid glutamate. Although glutamatergic neurotransmission is therefore essential for the functioning of neuronal circuits in the brain and spinal cord, under certain conditions activation of glutamate receptors can trigger the death of neurons. Such excitotoxicity most often occurs when cells are coincidentally...
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