Difference between revisions of "CNS Response to Injury - Pathology"

From WikiVet English
Jump to navigation Jump to search
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]]
 

Revision as of 12:34, 8 March 2011

Introduction

  • The CNS is composed of two major cell types:
    1. Neurons
    2. Glial cells, which include:
      • Astrocytes
      • Oligodendrocytes
      • Microglial cells
      • Ependymal cells
      • Choroid plexus epithelial cells
  • The response to injury varies with the cell type injured.

Neuron Response to Injury

Glial Cell Response to Injury

General CNS Responses to Injury

Excitotoxicity