Excitotoxicity

The excitotoxicity is a pathological process of deterioration and neuronal destruction or neurotoxicity, by hyperactivation by the Glutamic acid and its analogues, gathered under the Amino-acid denomination of exiting, of the neuronal exiting receivers like receiving NMDA and AMPA ( $\ alpha$ -Amino-3-hydroxy-5-méthylisoazol-4-propionate). These excitotoxines like the NMDA 5 (N-methyl-D-ASPARTATe)) and the kainic Acid , or the glutamates in too great concentration, while binding to these receivers causes a massive entry in the cell of ion calcium. Ca⁺⁺ activates in its turn a certain number of Enzyme S of which Phospholipase C M, Endonucléase S and Protéase S the such Calpaïne. These enzymes degrade the cellular structures then: Cytosquelette, cellular Membrane, DNA.

This physiopathological mechanism is accused in a certain number of diseases neurological like the epilepsy and the cerebral vascular accidents, or neurodégénératives of the central Nervous system like the Multiple sclerosis, the Maladie of Alzheimer, the amyotrophic side Sclérose, the Fibromyalgie, the Parkinson's disease or finally the Chorée de Huntington.

History

The toxicity of glutamate was observed for the first time by D.R. Lucas and J.P. Newhouse in 1957, when after having nourished Souris newborns with Glutamate monosodic, they noted the destruction of neurons in the internal layer of their Rétine. About 1969, John Olney discovered that this phenomenon was not limited to the retina, but related to all the Cerveau, and it named then it excitotoxicity . It also establishes that this cellular death related to only the neurons post-synaptic S, that the neurotoxicity of the agonists of glutamate was proportional to their effectiveness to activate the receivers with glutamates, and that the antagonistic S of glutamates could inhibit this neurotoxicity.

Physiopathology

The excitotoxicté can be caused by substances synthesized by the organization (excitotoxines Endogène S). The glutamate is a first example of excitotoxine in the brain, but it is also, paradoxically, the principal exiting neuro-transmitter in the central nervous system of the Mammifère S. Under normal conditions the concentration of glutamate in the synaptic slit can reach 1 mm, to decrease then quickly in a few milliseconds. If this concentration does not decrease or on the contrary increases, the neuron car-is destroyed by Apoptose.

This pathogenic mechanism is also likely to occur after cerebral lesion. A cerebral Traumatism or a Cerebral vascular accident can be at the origin of an insufficiency of blood irrigation called Ischémie. Ischaemia is followed of an accumulation of glutamates and Aspartate S in the extracellular Liquide, which worsened by a deficiency in Oxygène and Glucose causes cellular death then. One calls ischemic Cascade the cascade of biochemical events resulting from ischaemia and implying the excitotoxicity. To limit the consequences of the ischaemia and the activation of the receivers to glutamate, the patient carrying a cerebral lesion can be put in major artificial coma to decrease the cerebral Métabolisme, therefore his consumption in glucose and oxygen, and to preserve energy necessary to eliminate glutamates by active transport. Note: the main aim of the induced coma is to decrease the intracranial pressure and not to decrease the cerebral metabolism (to be checked).

One of the fatal consequences of the excess of Calcium in the Cytosol is the opening of the membrane pores] of type PMT when this Organite absorbs too much calcium. This opening causes salting out by mitochondrion, of proteins being able to lead to the apoptose, its swelling and the excretion of more than calcium still. Moreover the production of Adenosine triphosphate or ATP can stop and the Enzyme ATP synthase can be put at to hydrolize the ATP instead of synthesizing it.

The production of unsuited ATP resulting from the traumatism encephalic is capable to disturb the gradient some Ion S. But these ionic gradients are necessary to the activity of the glutamate conveyers who eliminate it from intercellular space. The loss of these gradients not only will stop the elimination of glutamate, but still to reverse the direction of the conveyers and will thus lead to a larger rise still in the concentrations in aspartate and glutamate of the intercellular medium, and thus a raised and harmful activation of the receivers to glutamate.

The molecular mechanism biological of entry of calcium is not the only person in charge of the apoptose induced by the excitotoxicity. Recently, it was noticed that the activation of the extrasynaptic receivers with NMDA, started by the exposure to glutamate or conditions of ischaemia or Hypoxie, inactive the factor transcriptionnel CREB (Cyclic adenosine monophosphate response element binding protein) who in his turn causes the suppression of the potential of membrane of mitochondrion and the apoptose. On the other hand, the activation of the synaptic receivers with the NMDA activates only the metabolic way CERB which activates in its turn BDNF (brain-derived neurotrophic Factor) without starting apoptose. One the other hand, activation off synaptic NMDA receptors only activated the CREB pathway which activates BDNF (brain-derived neurotrophic Factor), not activating apoptosis. -->

The aspartame

The current debate concerning the most known phenomenon of excitotoxicity of the general public, is that relating to the Aspartame. Approximately 40% (in mass) of the absorptive aspartame are metabolized in Aspartic acid, a excitotoxine. As the aspartame is quickly absorbed, (contrary to the aspartic acid contained in food proteins), the aspartame is known like being able to cause peaks of concentration of aspartate in the Blood plasma.

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