Glutamate Excitotoxicity Essay

2579 words - 11 pages

2.0 GLUTAMATE EXCITOTOXICITY
Despite being its global role as a neurotransmitter in the brain, at higher concentrations glutamate is highly toxic to neurons, a phenomenon known as excitotoxicity. Glutamate could kill the neuron cells at low concentration in culture and based on the finding in 1970s, glutamate was used extensively as a ‘taste-enhancing’ food additive which was given orally and causes neurodegeneration in vivo which is known as ‘The Chinese restaurant syndrome’ with symptoms of acute neck stiffness and chest pain. However, the possibility of more serious neurotoxicity is only hypothetical so far.1

Glutamate excitotoxicity is a process that triggers a number of injurious intracellular mechanisms. It stimulates the direct release of excessive excitatory amino acids (EAAs), such as glutamate and aspartate into the extracellular space. These EAAs bind to the suitable postsynaptic receptor N-methyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)2, and metabotropic (MGlu) receptors.1

2.1 Glutamate as a neurotransmitter

2.1.1 Glutamate
Glutamate is an amino acid and one of a group of amino acid neurotransmitters in the brain, it is the major excitatory neurotransmitter that can be found in the brain. Cerebral glutamate is derived exclusively from endogenous sources. Which mainly are from α ketoglutarate, a product of the tricarboxylic acid cycle (TCA Cycle).3

Figure 2.1.1: Glutamate

2.1.2 Glutamatergic processing and neurotransmission
Glutamate is synthesized by the endoplasmic reticulum before being transported to the Golgi apparatus for additional processing. Packaged in vesicles, glutamate is transported down the axon via a complex system of microtubules, the vesicle with the enclosed glutamate merges with the presynaptic membrane. Glutamate is then released into the synaptic cleft by exocytosis. The vesicular membrane is then recycled and transported back to the neuronal axon. Glutamate interacts with specific receptor sites on the postsynaptic membrane of the adjacent neuron to initiate a cascade of molecular events within that neuron.3

The termination of glutamatergic neurotransmission is by the removal of glutamate from the synaptic cleft by specific transporters. There are five of them (EAAT1 –EAAT5) expressed in the human CNS. In the brain, isoforms of EAAT1 and EAAT2 plays the main role in glutamate transport and they are mainly expressed in astroglial and microglial cells. Imbalances of extracellular sodium concentrations and insufficiency of energy may alter the activity of these proteins which may lead to retention of glutamate in the synaptic cleft and lead to prolonged neurotoxicity.5

2.1.3 Glutaminergic Postsynaptic receptors
There are three types of ionotropic receptors found in the postsynaptic membrane. They are N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors.4

There are three types of metabotropic G protein–coupled...

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