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− | ==Introduction==
| + | #redirect[[:Category:Central Nervous System - Response to Injury]] |
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− | * The CNS is composed of two major cell types:
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− | *# Neurons
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− | *# Glial cells, which include:
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− | *#* Astrocytes
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− | *#* Oligodendrocytes
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− | *#* Microglial cells
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− | *#* Ependymal cells
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− | *#* Choroid plexus epithelial cells
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− | * The response to injury varies with the cell type injured.
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− | ==[[Neuron Response to Injury]]==
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− | ==[[Glial Cell Response to Injury]]==
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− | ==[[General CNS Responses to Injury]]==
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− | ==[[Excitotoxicity]]==
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− | * The term "excitotoxicity" is used to describe the process by which neurons are damaged by glutamate and other similar substances.
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− | * Excitotoxicity results from the overactivation of excitatory receptor activation.
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− | ===The Mechanism of Excitotoxicity===
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− | * '''Glutamate''' is the major excitatory transmitter in the brain and spinal cord.
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− | ** There are four classes of postsynaptic glutamate receptors for glutamate.
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− | *** The receptors are either:
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− | **** Directly or indirectly associated with gated ion channels, '''OR'''
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− | **** Activators of second messenger systems that result in release of calcium from intracellular stores.
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− | *** The receptors are named according to their phamacological agonists:
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− | **** '''NMDA receptor'''
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− | ***** The NMDA receptor is directly linked to a gated ion channel.
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− | ***** The ion channel is permeable to Ca<sup>++</sup>, as well as Na<sup>+</sup> and K<sup>+</sup>.
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− | ***** The channel is also voltage dependent.
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− | ****** It is blocked in the resting state by extracellular Mg<sup>++</sup>, which is removed when membrane is depolarised.
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− | ***** I.e. both glutamate and depolarisation are needed to open the channel.
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− | **** '''AMPA receptor'''
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− | ***** The AMPA receptor is directly linked to a gated ion channel.
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− | ***** The channel is permeable to Na<sup>+</sup> and K<sup>+</sup> but NOT to divalent cations.
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− | ***** The receptor binds the glutamate agonist, AMPA, but is not affected by NMDA.
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− | ***** The receptor probably underlies fast excitatory transmission at glutamatergic synapses.
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− | **** '''Kainate receptor'''
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− | ***** Kainate receptors work in the same way as AMPA receptors, and also contribute to fast excitatory transmission.
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− | **** '''mGluR''', the '''metabotropic receptor'''
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− | ***** Metabotropic receptors are indirectly linked to a channel permeable to Na<sup>+</sup> and K<sup>+</sup>.
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− | ***** They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca<sup>++</sup> stores.
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− | ***** The physiological role ot mGluR is not understood.
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− | * Under normal circumstances, a series of glutamate transporters rapidly clear glutamate from the extracellular space.
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− | ** Some of these transporters are neuronal; others are found on astrocytes.
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− | * This normal homeostatic mechanism fails under a variety of conditions, such as ischaemia and glucose deprivation.
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− | ** This results in a rise in extracellular glutamate, causing activation of the neuronal glutamate receptors.
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− | * Two distinct events of excitiotoxicity arise from glutamate receptor activation:
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− | *# The depolarisation caused mediates an influx of Na<sup>+</sup>, Cl<sup>-</sup> and water. This give '''acute neuronal swelling''', which is reversible.
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− | *# There is a '''rise in intracellular Ca<sup>++</sup>'''.
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− | *#* This is due to:
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− | *#** Excessive direct Ca<sup>++</sup> influx via the NMDA receptor-linked channels
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− | *#** Ca<sup>++</sup> influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
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− | *#** Release of Ca<sup>++</sup> from intracellular stores.
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− | *#* The rise in neuronal intracellular Ca<sup>2+</sup> serves to:
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− | *#** Uncouple mitochondrial electron transport and activate nitric oxide synthase and phospholipase A, leading to generation of reactive oxygen and nitrogen species which damage the neurone.
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− | *#** Activats a number of enzymes, including phospholipases, endonucleases, and proteases.
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− | *#*** These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
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− | * Excitotoxicity is, therefore, a cause of acute neuron death.
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− | [[Category:CNS Response to Injury]]
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