Excitotoxic and excitoprotective mechanisms

Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, 21224 Baltimore, MD; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 21205 Baltimore, MD
NeuroMolecular Medicine (Impact Factor: 4.49). 3(2):65-94. DOI: 10.1385/NMM:3:2:65

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.

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