Excitotoxicity
Jump to navigation
Jump to search
- 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++, as well as Na+ and K+.
- The channel is also voltage dependent.
- It is blocked in the resting state by extracellular Mg++, 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+ and K+ 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+ and K+.
- They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca++ stores.
- The physiological role ot mGluR is not understood.
- NMDA receptor
- The receptors are either:
- There are four classes of postsynaptic glutamate receptors for glutamate.
- 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+, Cl- and water. This give acute neuronal swelling, which is reversible.
- There is a rise in intracellular Ca++.
- This is due to:
- Excessive direct Ca++ influx via the NMDA receptor-linked channels
- Ca++ influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
- Release of Ca++ from intracellular stores.
- The rise in neuronal intracellular Ca2+ 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.
- This is due to:
- Excitotoxicity is, therefore, a cause of acute neuron death.