Glutamate overstimulation

There is considerable evidence that overstimulation of glutamate receptors promotes cell death in a number of retinal disease processes. Glutamate overstimulation may be particularly important in acute ischemic injuries, but it also may play a role in diabetic retinopathy (16) and chronic neurodegenerative processes such as glaucoma (17). Evidence for this includes the observation that glutamate levels are elevated in the vitreous of patients with these conditions (16,17). 

Excitotoxicity. A pathological mechanism in the brain in which excess extracellular glutamate overstimulates receptors leading to cell death. 

N-Nitro-L-arginine methyl ester (L-NAME) is an inhibitor of NOS L-NAME reportedly reduces the volume of cortical and striatal infarct after middle cerebral artery occlusion in the rat. This protection can be reversed by co-injection of L-arginine. L-NAME also reduced the excitotoxic damage induced by NMDA injection. Finally, the authors showed that L-NAME reduced glutamate efflux produced by ischaemic injury in rats. The authors concluded that NOS induced by NMDA receptor overstimulation is a key event in the neuronal injury cascade (Buisson eta/., 1993). 

Figure 1.2 Serotonin is one of the brain s neurotransmitters. This image depicts serotonin transmission between neurons and the drug Ecstasy s effects on that transmission. Serotonin is normally removed from the synapse shortly after being released. Ecstasy blocks this mechanism, increasing the amount of serotonin in the synapse. This causes the postsynaptic neuron to be overstimulated by serotonin. Serotonin is one of many neurotransmitters that nerve cells can secrete. Other common neurotransmitters include dopamine, glutamate, gamma aminobutyric acid (GABA), noradrenaline, and endorphins.

The progression of glutamate neurotoxicity can be considered as a process of three sequential steps the overstimulation of postsynaptic glutamate receptors leading to the accumulation of Ca2+ the amplification of the detrimental signal through the additional Ca2+ influx and the release from intracellular stores the activation of catabolic pathways and the generation of free radicals (Choi, 1990). 

Of note, there have also been links between glutamate receptor stimulation and pathology. Excessive stimulation of glutamate receptors can cause seizure and it is hypothesized that NMDA overstimulation can cause neuronal cell death from an excessive influx of calcium. This has led to the development of NMDA antagonists like memantine to treat Alzheimer s Disease. 

HA also protects primary neuronal cell culture and animals from glutamate toxicity. Glutamate activates A-methyl-D-aspartate (NMDA) receptors and increases the flux of calcium ions into the neurons,whereas calcium at toxic levels can kill the cells. Pretreatment of primary neuronal cells with HA reduced glutamate- and OP-induced toxicity and decreased neuronal death.The consequence of excitatory amino-acid-induced overstimulation has been implicated in a variety of acute and... 

Retinal ischemic injury, for example, has been shown to result in the overstimulation of ionotropic glutamate receptors following the extracellular accumulation of glutamate (18,19). This effect appears to involve, in particular, the NMDA class of glutamate receptors. The subsequent excessive influx of calcium results in... 

The concept of excitotoxicity was proposed as early as 1957 by Lucas and Newhouse [62] who demonstrated that glutamate is toxic for retinal cells. In the 70s, the work published by Olney and Ho [63] proved that glutamate and similar compounds administered to rodents during the neonatal period lead to acute neurodegeneration in retinal neurones and periventricular structures. Excitotoxicity is related to an excessive flow of calcium into the neurone resulting from an overstimulation due to different categories of excitatory amino acid receptors [64]. An excess of neurotransmitters produces several effects ... 

---