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| + | ==Introduction== |
| + | |
| + | * The CNS is composed of two major cell types: |
| + | *# Neurons |
| + | *# Glial cells, which include: |
| + | *#* Astrocytes |
| + | *#* Oligodendrocytes |
| + | *#* Microglial cells |
| + | *#* Ependymal cells |
| + | *#* Choroid plexus epithelial cells |
| + | * The response to injury varies with the cell type injured. |
| + | |
| + | ==Response of Neurons to Injury== |
| + | |
| + | * Neurons are particularly vulnerable to injury, due to their: |
| + | ** High metabolic rate |
| + | ** Small capacity to store energy |
| + | ** Lack of regenerative ability |
| + | ** Axons being very dependent on the cell body. |
| + | *** Axons cannot make their own protein as they have no Nissl substance. |
| + | *** The cell body produces the axon's protein and disposes of its waste. |
| + | *** Death or damage of the cell body causes axon degeneration. |
| + | |
| + | * There are four ways in which neurons may react to insult: |
| + | *# Acute Necrosis |
| + | *# Chromatolysis |
| + | *# Wallerian Degeneration |
| + | *# Vacuolation |
| + | |
| + | ===Acute Necrosis=== |
| + | |
| + | * Acute necrosis is the most common neuronal response to injury. |
| + | * Causes of actue necrosis include: |
| + | ** Ischaemia |
| + | *** Diminution of the blood supply causes a lack of nutrients and oxygen, inhibiting energy production. A decrease in the levels of ATP leads to: |
| + | ***# Failure of the Na<sup>+</sup>/K<sup>+</sup>pumps, causing cell swelling and an increase in extracellular potassium. |
| + | ***# Failure to generate NAD required for DNA repair. |
| + | ** Hypoxia |
| + | ** Hypoglycaemia |
| + | ** Toxins, such as lead and mercury |
| + | |
| + | ====Laminar Cortical Necrosis==== |
| + | |
| + | * Laminar cortical necrosis refers to the selective destruction of neurons in the deeper layers of the cerebral cortex. |
| + | ** These neurons are the most sensitive to hypoxia. |
| + | * The laminar cortical pattern of acute necrosis occurs in several instances: |
| + | *# Ischaemia |
| + | *#* For example, seizure-related ischaemia in dogs. |
| + | *# Polioencephalomalacia in ruminants |
| + | *#* Also called cerebrocortical necrosis or CCN. |
| + | *# Salt poisoning in swine |
| + | *# Lead poisoning in cattle |
| + | * It is most likely that gross changes will not be seen. When they are visible, changes may be apparent as: |
| + | ** Oedema |
| + | *** Causes brain swelling, flattened gyri and herniation |
| + | ** A thin, white, glistening line along the middle of the cortex. |
| + | *** In ruminants, this fluoresces with UV-light. |
| + | * Ultimately the cortex becomes necrotic and collapses. |
| + | |
| + | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=POLIOENCEPHALOMALACIA View images courtesy of Cornell Veterinary Medicine] |
| + | |
| + | ===Chromatolysis=== |
| + | |
| + | * Chromatolysis is the cell body’s reaction to axonal insult. |
| + | * The cell body swells and the Nissl substance disperses. |
| + | ** Dispersal of the Nissl substance allows the cell body to produce proteins for rebuilding the axon. |
| + | * IT IS NOT A FORM OF NECROSIS. |
| + | ** It is an adaptive response to deal with the injury. |
| + | ** It can, however lead to necrosis. |
| + | * Seen, for example, in grass sickness in [[Hindgut Fermenters - Horse - Anatomy & Physiology|horses]] (equine dysautonomia). |
| + | |
| + | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=Display&imgID=13353 View images courtesy of Cornell Veterinary Medicine] |
| + | |
| + | ===Wallerian Degeneration=== |
| + | |
| + | * Wallerian degeneration is the axon’s reaction to insult. |
| + | * The axon and its myelin sheath degenerates distal to the point of injury. |
| + | * There are several causes of wallerian degeneration: |
| + | ** Axonal transection |
| + | *** This is the "classic" cause |
| + | ** Vascular causes |
| + | ** Inflamatory reactions |
| + | ** Toxic insult |
| + | ** As a sequel to neuronal cell death. |
| + | |
| + | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=WALLERIAN View images courtesy of Cornell Veterinary Medicine] |
| + | |
| + | ====The Process of Wallerian Degeneration==== |
| + | |
| + | # '''Axonal Degeneration''' |
| + | #* Axonal injuries initially lead to acute axonal degeneration. |
| + | #** The proximal and distal ends separate within 30 minutes of injury. |
| + | #* Degeneration and swelling of the axolemma eventually leads to formation of bead-like particles. |
| + | #* After the membrane is degraded, the organelles and cytoskeleton disintegrate. |
| + | #** Larger axons require longer time for cytoskeleton degradation and thus take a longer time to degenerate. |
| + | # '''Myelin Clearance''' |
| + | #* Following axonal degeneration, myelin debris is cleared by phagocytosis. |
| + | #* Myelin clearance in the PNS is much faster and efficient that in the CNS. This is due to: |
| + | #** The actions of schwann cells in the PNS. |
| + | #** Differences in changes in the blood-brain barrier in each system. |
| + | #*** In the PNS, the permeability increases throughout the distal stump. |
| + | #*** Barrier disruption in CNS is limited to the site of injury. |
| + | # '''Regeneration''' [[Image:neuronalvacuolation1.jpg|thumb|right|150px|Neuronal vacuolation. Image courtesy of BioMed Archive]] |
| + | #* Regeneration is rapid in the PNS. |
| + | #** Schwann cells release growth factors to support regeneration. |
| + | #* CNS regeneration is much slower, and is almost absent in most species. |
| + | #** This is due to: |
| + | #*** Slow or absent phagocytosis |
| + | #*** Little or no axonal regeneration, because: |
| + | #**** Oligodendrocytes have little capacity for remyelination compared to Schwann cells. |
| + | #**** There is no basal lamina scaffold to support a new axonal sprout. |
| + | #**** The debris from central myelin inhibits axonal sprouting. |
| + | |
| + | ===Vacuolation=== |
| + | [[Image:neuronalvacuolation2.jpg|thumb|right|150px|Neuronal vacuolation. Image courtesy of BioMed Archive]] |
| + | * Vacuolation is the hallmark of transmissible spongiform encephalopathies. |
| + | ** For example, BSE and Scrapie. |
| + | * Vacuolation can also occur under other circumstances: |
| + | ** Artefact of fixation |
| + | ** Toxicoses |
| + | ** It may sometimes be a normal feature. |
| + | |
| + | ==Glial Cell Response to Injury== |
| + | |
| + | * The order of susceptibility of CNS cells to injury runs, from most to least susceptible: |
| + | *# Neurons |
| + | *# Oligodendroglia |
| + | *# Astrocytes |
| + | *# Microglia |
| + | *# Endothelial cells |
| + | |
| + | ===Astrocytes=== |
| + | |
| + | * The response of astrocytes to insult include: |
| + | ** '''Necrosis''' |
| + | ** '''Astrocytosis''' |
| + | *** An increase in the number of astrocytes (i.e. astrocyte hyperplasia). |
| + | ** '''Astrogliosis''' |
| + | *** An increase in the size of astrocytes (i.e. astrocyte hypertrophy). |
| + | ** '''Gliosis''' |
| + | *** Formation of glial fibres. |
| + | *** This is a form of scarring in the CNS. |
| + | |
| + | ===Oligodendrocytes=== |
| + | |
| + | * Oligodendrocytes are prone to hypoxia and degeneration |
| + | * Oligodendrocytes proliferate around damaged neurons. |
| + | ** This is known as '''satellitosis'''. |
| + | * Death of oligodendrocytes causes demyelination. |
| + | |
| + | ===Microglial Cells=== |
| + | |
| + | * Microglial cells can respond in two ways to CNS injury. |
| + | *# They may phagocytose cell debris to transform to gitter cells. |
| + | *#* Gitter cells are large macrophages with foamy cytoplasm. [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=GITTER View images courtesy of Cornell Veterinary Medicine] |
| + | *# They may form glial nodules. |
| + | *#* These are small nodules that occur notably in viral diseases. |
| + | |
| + | ==General Responses to Injury== |
| + | |
| + | ===Ischaemic Damage=== |
| + | |
| + | * The CNS is particularly sensitive to ischaemia, because it has few energy reserves. |
| + | * The CNS is protected by its bony covering. |
| + | ** Despite offering protection, the covering also makes the CNS vulnerable to certain types of damage, for example: |
| + | *** Damage due to fractures and dislocation. |
| + | *** Damage due to raised intracranial pressure. |
| + | **** 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. |
| + | ***** The result of this is '''ischaemia'''. |
| + | * Survival of any cell is dependent on having sufficient energy. |
| + | ** Ischaemia causes cell death by impeding energy supply to cells. |
| + | *** Cells directly affected by ischamia die rapidly. |
| + | **** For example, those suffering a failure of pefusion due to an infarct. |
| + | *** Neurons surrounding this area of complete and rapid cell death exist under sub-optimal conditions and die over a more prolonged period. |
| + | **** This area of gradual death is known as the '''lesion penumbra'''. |
| + | **** There are several mechanisms implicated in cell death in the penumbra: |
| + | ****# Increase in intracellular calcium |
| + | ****# Failure to control free radicals |
| + | ****# Generation of nitrogen species (e.g NO and ONOO) are the main damaging events. |
| + | |
| + | ===Oedema=== |
| + | |
| + | * There are three types of cerebral oedema: |
| + | *# '''Vasogenic oedema''' |
| + | *#* Vasogenic oedema follows vascular injury. |
| + | *#* Oedema fluid gathers outside of the cell. |
| + | *#* This is the most common variation of cerebral oedema. |
| + | *# '''Cytotoxic oedema''' |
| + | *#* Cytotoxic oedema is due to an energy deficit. |
| + | *#** The neuron can’t pump out sodium and water leading to swelling within the cell. |
| + | *# '''Interstitial oedema''' |
| + | *#* Associated with hydrocephalus. |
| + | *#* This type of cerebral oedema is of lesser importance. |
| + | * One serious consequence of oedema is that the increase in size leads to the brain trying to escape the skull. |
| + | ** This causes herniation of the brain tissue. |
| + | ** The most common site of herniation is at the foramen magnum. |
| + | *** The medulla is compressed at the site of the respiratory centres, leading to death. |
| + | |
| + | ===Demyelination=== |
| + | |
| + | * Demyelination is the loss of initially normal myelin from the axon. |
| + | * Demyelination may be primary or secondary. |
| + | |
| + | ====Primary Demyelination==== |
| + | |
| + | * Normally formed myelin is selectively destroyed; however, the axon remains intact. |
| + | * Causes of primary demyelination: |
| + | ** Toxins, such as hexachlorophene or triethyl tin. |
| + | ** Oedema |
| + | ** Immune-mediated demyelination |
| + | ** Infectious diseases, for example canine distemper or caprine arthritis/encephalitis. |
| + | |
| + | ====Secondary Demyelination==== |
| + | |
| + | * Myelin is lost following damage to the axon. |
| + | ** I.e. in [[CNS - Response to Injury#Wallerian Degeneration|wallerian degeneration]] |
| + | |
| + | ===Vascular Diseases=== |
| + | |
| + | * Vascular diseases can lead to complete or partial blockage of blood flow which leads to ischaemia. |
| + | ** Consequences of ischaemia depend on: |
| + | **# Duration and degree of ischaemia |
| + | **# Size and type of vessel involved |
| + | **# Susceptibility of the tissue to hypoxia |
| + | * Potential outcomes of vascular blockage include: |
| + | ** Infarct, and |
| + | ** Necrosis of tissue following obstruction of its blood supply. |
| + | * Causes include: |
| + | ** Thrombosis |
| + | *** Uncommon in animals but may be seen with DIC or sepsis. |
| + | ** Embolism. e.g. |
| + | *** Bone marrow emboli following trauma or fractures in dogs |
| + | *** Fibrocartilaginous embolic myelopathy |
| + | ** Vasculitis, e.g. |
| + | *** Hog cholera (pestivirus) |
| + | *** Malignant catarrhal fever (herpesvirus) |
| + | *** Oedema disease (angiopathy caused by E.coli toxin) |
| + | |
| + | ===Malacia=== |
| + | |
| + | * Malacia may be used: |
| + | ** As a gross term, meaning "softening" |
| + | ** As a microscopic term, meaning "necrosis" |
| + | * Malacia occurs in: |
| + | ** Infarcted tissue |
| + | ** Vascular injury, for example vasculitis. |
| + | ** Reduced blood flow or hypoxia, e.g. |
| + | *** Carbon monoxide poisoning, which alters hemoglobin function |
| + | *** Cyanide poisoning, which inhibits tissue respiration |
| + | |
| + | ==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. |