| Line 23: |
Line 23: |
| | | | |
| | ==[[Excitotoxicity]]== | | ==[[Excitotoxicity]]== |
| − |
| |
| − | * The term "excitotoxicity" is used to describe the process by which neurons are damaged by glutamate and other similar substances.
| |
| − | * Excitotoxicity results from the overactivation of excitatory receptor activation.
| |
| − |
| |
| − | ===The Mechanism of Excitotoxicity===
| |
| − |
| |
| − | * '''Glutamate''' is the major excitatory transmitter in the brain and spinal cord.
| |
| − | ** There are four classes of postsynaptic glutamate receptors for glutamate.
| |
| − | *** The receptors are either:
| |
| − | **** Directly or indirectly associated with gated ion channels, '''OR'''
| |
| − | **** Activators of second messenger systems that result in release of calcium from intracellular stores.
| |
| − | *** The receptors are named according to their phamacological agonists:
| |
| − | **** '''NMDA receptor'''
| |
| − | ***** The NMDA receptor is directly linked to a gated ion channel.
| |
| − | ***** The ion channel is permeable to Ca<sup>++</sup>, as well as Na<sup>+</sup> and K<sup>+</sup>.
| |
| − | ***** The channel is also voltage dependent.
| |
| − | ****** It is blocked in the resting state by extracellular Mg<sup>++</sup>, which is removed when membrane is depolarised.
| |
| − | ***** I.e. both glutamate and depolarisation are needed to open the channel.
| |
| − | **** '''AMPA receptor'''
| |
| − | ***** The AMPA receptor is directly linked to a gated ion channel.
| |
| − | ***** The channel is permeable to Na<sup>+</sup> and K<sup>+</sup> but NOT to divalent cations.
| |
| − | ***** The receptor binds the glutamate agonist, AMPA, but is not affected by NMDA.
| |
| − | ***** The receptor probably underlies fast excitatory transmission at glutamatergic synapses.
| |
| − | **** '''Kainate receptor'''
| |
| − | ***** Kainate receptors work in the same way as AMPA receptors, and also contribute to fast excitatory transmission.
| |
| − | **** '''mGluR''', the '''metabotropic receptor'''
| |
| − | ***** Metabotropic receptors are indirectly linked to a channel permeable to Na<sup>+</sup> and K<sup>+</sup>.
| |
| − | ***** They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca<sup>++</sup> stores.
| |
| − | ***** The physiological role ot mGluR is not understood.
| |
| − |
| |
| − | * Under normal circumstances, a series of glutamate transporters rapidly clear glutamate from the extracellular space.
| |
| − | ** Some of these transporters are neuronal; others are found on astrocytes.
| |
| − | * This normal homeostatic mechanism fails under a variety of conditions, such as ischaemia and glucose deprivation.
| |
| − | ** This results in a rise in extracellular glutamate, causing activation of the neuronal glutamate receptors.
| |
| − | * Two distinct events of excitiotoxicity arise from glutamate receptor activation:
| |
| − | *# The depolarisation caused mediates an influx of Na<sup>+</sup>, Cl<sup>-</sup> and water. This give '''acute neuronal swelling''', which is reversible.
| |
| − | *# There is a '''rise in intracellular Ca<sup>++</sup>'''.
| |
| − | *#* This is due to:
| |
| − | *#** Excessive direct Ca<sup>++</sup> influx via the NMDA receptor-linked channels
| |
| − | *#** Ca<sup>++</sup> influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
| |
| − | *#** Release of Ca<sup>++</sup> from intracellular stores.
| |
| − | *#* The rise in neuronal intracellular Ca<sup>2+</sup> serves to:
| |
| − | *#** 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.
| |
| − | *#** Activats a number of enzymes, including phospholipases, endonucleases, and proteases.
| |
| − | *#*** These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
| |
| − | * Excitotoxicity is, therefore, a cause of acute neuron death.
| |
| − |
| |
| − |
| |
| − | [[Category:CNS Response to Injury]]
| |