Excitotoxic and excitoprotective mechanisms
ABSTRACT Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells
are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative
stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death
involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed
cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability
changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several
subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in
excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity
of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of anti-excitotoxic
mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein
chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity
in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related
disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease and amyotrophic lateral sclerosis. A better understanding
of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders,
but also to unexpected insight into mechanisms of synaptic plasticity.
- Future Neurology 01/2006; 1(4):349-352.
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ABSTRACT: Mitochondria main function is cellular respiration. In recent years the study of the role of the mitochondria in ageing and disease pathophysiology has increased providing new knowledge in animal models as well as in human beings. Objective: in this review we present a brief descritption of the mitocondria, its DNA and its role in ageing and in particular in neurodegenrative diseases. Method: along the review we cover the mitochondrial function and dysfunction in neurodegenerative diseases such as Huntington, Parkinson, Alzheimer and amyotrophic lateral sclerosis emphasizing on recent advances. Conclusion: the mitochondria plays a relevant role in the pathogenesis of various neurodegenerative diseases, the understanding of the cellular mechanisms involved would allow the development of new therapeutic interventions.Arch Neurocien (Mex). 01/2010; 15(1):39-46.
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ABSTRACT: Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.Pharmaceuticals 01/2013; 7(1):29-45.