Dr. F. X. Sureda
a phenomenon that was
first described by Olney in the seventies, implies
the activation in the CNS of the so-called glutamate receptors.1
Glutamate, an excitatory amino acid, activates different types of ion channel
forming receptors (named ionotropic) and G-protein-coupled receptors ( named
metabotropic) to develop their essential role in the
functional activity of the brain. However, high concentrations of
glutamate, or neurotoxins acting at the same receptors, cause cell death
through the excessive activation of these receptors. In physiological
conditions, the presence of glutamate in the synapse is highly
regulated by very active, ATP-dependent
transporters in neurones and glia. For instance, in CNS ischaemia a decrease in
the levels of glucose exerts a
decrease in ATP production, leading to an impairment of glutamate uptake.
Moreover, the membrane potential of presynaptic neurones is lost and efflux of
excitatory amino acids occurs, contributing to the excessive activation of glutamate postsynaptic
As pointed out
glutamate and other amino acids can activate both ionotropic and metabotropic
receptors (for review, 3). The latter are subdivided in three main
families, and can be coupled to phospholipase C (PLC) or to adenylyl cyclase
(AC). The ion channel forming
receptors are subdivided in three different
receptor classes that are named by their selective agonists: AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid) receptors, kainate receptors and NMDA (N-methyl-D-aspartic acid)
receptors. AMPA and kainate receptors trigger rapid excitatory
neurotransmission in the CNS, by promoting entry of Na+ into neurones. However, a
subset of neurones in the hippocampus, cortex and the
retina express AMPA receptors that are also permeable to Ca2+. NMDA
receptors are associated to a high conductance Ca2+ channel that in resting,
non-depolarising conditions is blocked by Mg2+ in a
voltage-dependent manner. Their activation is secondary to AMPA or kainate
receptor activation that depolarises the
neurone, allowing for the relief
of the Mg2+ blockade.
The physiological role of the NMDA
receptor seems related to synaptic plasticity.
working together with metabotropic glutamate receptors, ensure
the establishment of the long-term potentiation phenomenon
(LTP), a process believed to be responsible for the acquisition of information.
These functions are mediated by calcium entry through the NMDA
receptor-associated channel. Calcium activates a number of Ca2+-dependent
enzymes that influence a wide variety of cellular components like
cytoskeletal proteins or second messenger synthases. However,
overactivation at NMDA receptors triggers an excessive entry of Ca2+,
initiating a series of cytoplasmic and nuclear processes that promote neuronal
cell death. For instance, Ca2+-activated proteolytic enzymes, like
calpains, can degrade essential proteins. Moreover, Ca2+/calmodulin
kinase II (CaM-KII) is activated, and a number of different enzymes
are phosphorilated, increasing their activity. Different
transcription factors such as c-Fos,
c-Jun or c-Myc are also expressed. Furthermore, Ca2+-dependent
endonucleases can degrade DNA. All of
these mechanisms, together with enhanced oxidative stress (see below) can
induce cell death through necrosis as well as apoptosis, a model of
programmed cell death that is described in several neurodegenerative diseases.
important role in the regulation of the intracellular calcium concentration. An
increased entry of Ca2+ into the mitochondria is believed to enhance
the mitochondrial electron transport, increasing the production of reactive
oxygen species (ROS) such as ·O2-. Although in the excitotoxic processmitochondria
is the major source of ROS, there are many enzymatic systems
that primarily or secondarily increase the presence of those
compounds in the CNS4. Calcium-dependent enzymes convert xanthine
dehydrogenase to xanthine oxidase, leading to the production of ·O2-
and H2O2. Moreover, Ca2+ activates the enzyme
phospholipase A2 (PLA2), which leads to the production of
arachidonic acid, that in turn, is transformed by cyclooxygenases,
increasing the formation of ·O2-. Calcium also
activates NO-synthase, increasing the presence of ·NO in the neurone
and also in surrounding areas. ·NO has a double effect, since activates
guanylylcyclases and also reacts with ·O2- to
form the highly toxic compound peroxynitrite (ONOO-). This is a
strong oxidizing agent that causes nitration in proteins and oxidation of
lipids, proteins and DNA, leading to a form of cell death that has the
characteristics of apoptosis. Lipid peroxidation causes a
disturbance in the structure of lipidic membranes,
and leakage in the cytoplasmic membrane occurs.
Apart from the loss of ionic gradients, enhanced
release of glutamate from presynaptic terminals take place,
worsening the previously mentioned effects.
Excitotoxicity has been related to
several acute neurological disorders, such as epileptic convulsions,
overactivity of excitatory synapses exists.
In ischaemic stroke and in post-traumatic lesions, the implication
of excitotoxicity is well established. As mentioned earlier, in
these particular pathologic situations a decrease in ATP production
evokes glutamate release through depolarisation of presynaptic terminals. In
neurodegenerative disorders like Parkinson or Alzheimer’s disease s,
Huntington’s chorea or in amyotrophic lateral sclerosis
(ALS), a role for excitotoxicity in the pathogenesis
of these diseases has also been postulated. Moreover, drugs that
block NMDA or other glutamate receptors, as well as compounds that decrease
glutamate release, attenuate some of the pathological manifestations in
experimental models of acute and chronic neurodegenerative diseases.
Due to the relevance of the
already mentioned and the
lack of existing, effective treatments,
the research in the field of NMDA
antagonists in the last decade has been extremely active. However, glutamate plays a very
important role in the CNS, and several clinical trials have been abandoned due
to psychomimetic or cardiovascular side-effects. Although the search for agents
active at NMDA receptors is
still on, other strategies like glutamate
release inhibitors or non-NMDA
receptor antagonists are leading the research oneld
1 Olney JW., Sharpe LG., Feigin RD. J. Neuropathol. Exp. Neurol., 31:464-88, 1972.
2 Dirnagl U., Iadecola C., Moskowitz MA. Trends Neurosci., 22:391-397, 1999.
3 Michaelis EK. Prog. Neurobiol., 54:369-415, 1998.
4 Greene JG., Greenamyre JT. Prog. Neurobiol., 48:613-634, 1996.
5 Baudy RB. Exp. Opin. Ther. Patents 6:983-1033, 1996.