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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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| − | ===Ischaemic Damage===
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| − | * The CNS is particularly sensitive to ischaemia, because it has few energy reserves.
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| − | * The CNS is protected by its bony covering.
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| − | ** Despite offering protection, the covering also makes the CNS vulnerable to certain types of damage, for example:
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| − | *** Damage due to fractures and dislocation.
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| − | *** Damage due to raised intracranial pressure.
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| − | **** Raised intracranial stimulates a compensatory increase in blood flow, further raising intracranial pressure. This stimulates a further increase in blood flow, and the cycle continues until intracranial pressure is so high that blood flow is impeded.
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| − | ***** The result of this is '''ischaemia'''.
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| − | * Survival of any cell is dependent on having sufficient energy.
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| − | ** Ischaemia causes cell death by impeding energy supply to cells.
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| − | *** Cells directly affected by ischamia die rapidly.
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| − | **** For example, those suffering a failure of pefusion due to an infarct.
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| − | *** Neurons surrounding this area of complete and rapid cell death exist under sub-optimal conditions and die over a more prolonged period.
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| − | **** This area of gradual death is known as the '''lesion penumbra'''.
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| − | **** There are several mechanisms implicated in cell death in the penumbra:
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| − | ****# Increase in intracellular calcium
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| − | ****# Failure to control free radicals
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| − | ****# Generation of nitrogen species (e.g NO and ONOO) are the main damaging events.
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| − | ===Oedema===
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| − | * There are three types of cerebral oedema:
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| − | *# '''Vasogenic oedema'''
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| − | *#* Vasogenic oedema follows vascular injury.
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| − | *#* Oedema fluid gathers outside of the cell.
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| − | *#* This is the most common variation of cerebral oedema.
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| − | *# '''Cytotoxic oedema'''
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| − | *#* Cytotoxic oedema is due to an energy deficit.
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| − | *#** The neuron can’t pump out sodium and water leading to swelling within the cell.
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| − | *# '''Interstitial oedema'''
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| − | *#* Associated with hydrocephalus.
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| − | *#* This type of cerebral oedema is of lesser importance.
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| − | * One serious consequence of oedema is that the increase in size leads to the brain trying to escape the skull.
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| − | ** This causes herniation of the brain tissue.
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| − | ** The most common site of herniation is at the foramen magnum.
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| − | *** The medulla is compressed at the site of the respiratory centres, leading to death.
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| − | ===Demyelination===
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| − | * Demyelination is the loss of initially normal myelin from the axon.
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| − | * Demyelination may be primary or secondary.
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| − | ====Primary Demyelination====
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| − | * Normally formed myelin is selectively destroyed; however, the axon remains intact.
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| − | * Causes of primary demyelination:
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| − | ** Toxins, such as hexachlorophene or triethyl tin.
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| − | ** Oedema
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| − | ** Immune-mediated demyelination
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| − | ** Infectious diseases, for example canine distemper or caprine arthritis/encephalitis.
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| − | ====Secondary Demyelination====
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| − | * Myelin is lost following damage to the axon.
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| − | ** I.e. in [[CNS Response to Injury - Pathology#Wallerian Degeneration|wallerian degeneration]]
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| − | ===Vascular Diseases===
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| − | * Vascular diseases can lead to complete or partial blockage of blood flow which leads to ischaemia.
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| − | ** Consequences of ischaemia depend on:
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| − | **# Duration and degree of ischaemia
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| − | **# Size and type of vessel involved
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| − | **# Susceptibility of the tissue to hypoxia
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| − | * Potential outcomes of vascular blockage include:
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| − | ** Infarct, and
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| − | ** Necrosis of tissue following obstruction of its blood supply.
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| − | * Causes include:
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| − | ** Thrombosis
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| − | *** Uncommon in animals but may be seen with DIC or sepsis.
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| − | ** Embolism. e.g.
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| − | *** Bone marrow emboli following trauma or fractures in dogs
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| − | *** Fibrocartilaginous embolic myelopathy
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| − | ** Vasculitis, e.g.
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| − | *** Hog cholera (pestivirus)
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| − | *** Malignant catarrhal fever (herpesvirus)
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| − | *** Oedema disease (angiopathy caused by E.coli toxin)
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| − | ===Malacia===
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| − | * Malacia may be used:
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| − | ** As a gross term, meaning "softening"
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| − | ** As a microscopic term, meaning "necrosis"
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| − | * Malacia occurs in:
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| − | ** Infarcted tissue
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| − | ** Vascular injury, for example vasculitis.
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| − | ** Reduced blood flow or hypoxia, e.g.
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| − | *** Carbon monoxide poisoning, which alters hemoglobin function
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| − | *** Cyanide poisoning, which inhibits tissue respiration
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| − | [[Category:CNS Response 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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