SUMMARY
Excitatory amino acids (EAA) represent major brain neurotransmitters. They are present in
numerous neuronal systems and thus are involved in almost all aspects of normal and pathological
brain activity. Changes in EAA transmission have been associated with the functional impairments
characterizing major neurological disorders, including epilepsy and schizophrenia. There is also a
suspicion that EAA systems underlie the neuronal death associated not only with acute CNS insults,
such as in ischemia or post-traumatic lesions, but also with neurodegenerative diseases such as ALS,
Huntington's disease and Parkinson's disease. The neurotoxicity of EAA, referred to as
excitotoxicity, is presumably mediated primarily through an excess of EAA synaptic receptor
stimulation. Indeed, overstimulation of the ionotropic NMDA or AMPA/kainate receptor subtypes
has been shown to produce an intense membrane depolarisation and further a massive increase in
intracellular calcium leading to cell damage. The extreme diversity and specific pattern of
expression of EAA receptor subunits could account for the differential vulnerability of certain brain
areas to such excitotoxic processes. In addition, it is now believed that besides abnormalities in
receptor functioning or in release processes, alterations in EAA transmission may result from
dysfunction of the EAA uptake system, which represents the mechanism for EAA removal from the
synapse. From the five transporter proteins cloned, termed EAAT1-5, the primarily glial transporters
EAAT1 and EAAT2 have been shown to mediate the bulk of EAA uptake in the brain and it has
then been suggested that they play a major role in the prevention of excitotoxic processes. In this
respect, the degeneration of motor neurons in ALS has been associated with altered expression or
inactivation of EAAT2. Moreover, recent evidence has been provided that pharmacological
alteration of glutamate transport can also induce astrocyte degeneration, as observed in
neurodegenerative insults, but through a mechanism independent of stimulation of EAA receptors.
Thus, one can obviously consider that these EAATs can represent a key target for further
development of new neuroprotective agents.
KEY WORDS
neurodegenerative diseases; signalling pathways; excitatory amino acids; neurotoxicity; striatal neurodegeneration
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