Glutamate excitotoxicity

Nicholls, DG and Ward, MW (2000) Mitochondrial membrane potential and neuronal glutamate excitotoxicity mortality and millivolts. Trends Neurosci. 23 166-174. 

Glutamate that is a major neurotransmitter in the mammalian nervous system not only plays a role in the development of the brain and learning but is also a potent neurotoxin when present in excess at synapses (Plaitakis and Shashidharan, 2000 Rausch et ah, 2006). Glutamate excitotoxicity has been shown to contribute to neuronal degeneration in acute conditions such as stroke, epilepsy, h) oglycemia, and chronic... 

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

Hornig-Rohan M, Amsterdam JD Clinical and biological correlates of treatment-resistant depression an overview. J Clin Psychiatry 24 220-227, 1994 Horowski R, Wachtel L, Turski L, et al Glutamate excitotoxicity as a possible pathogenetic mechanism in chronic neurodegeneration, in Neurodegenerative Diseases. Edited by Caine DB. Philadelphia, PA, WB Saunders, 1994, pp 163-174... 

N-methyl-D-aspartate glutamate antagonists Inhibit glutamate excitotoxicity 1 drug approved... 

To review the neuropathology of Alzheimer s disease, and its relationship to the amyloid cascade hypothesis and the glutamate excitotoxic hypothesis of Alzheimer s disease. 

Nicholls D. G. (2004). Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr. Mol. Med. 4 149-177. 

Lombardi G., Szekely A. M., Bristol L. A., Guidotti A., and Manev H. (1993). Induction of ornithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons. J. Neurochem. 60 1317-1324. 

Shaw P J. and Ince P G. (1997). Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J. Neurol. 244 Suppl 2 S3-S14. 

Ligand-operated Ca2+ channels (LOCCs), known also as ionotropic receptors, are important progressors of pathological Ca2+ entry, especially in the brain tissue. The best example of toxic plasmalemmal Ca2+ entry is represented by glutamate-induced excitotoxic death of neural cells (or glutamate excitotoxicity) in damaged... 

Nitric oxide synthase. The NO synthase (NOS) can generate both pro- and anti-apoptotic effects. The deleterious effects of excessive NO production are well documented in neuronal damage following ischemia and glutamate excitotoxicity (Dawson et al., 1991 Huang et al., 1994). 

Corona, J.C., Tovar-y-Romo, L.B., Tapia, R. (2007). Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis. Expert Opin. Ther. Targets 11 1415-28. 

Many events occuring during and after cerebral ischemia are well known, but they are not known enough to fully elucidate the mechanisms of brain damage. Factors responsible for the extension of infarction into the penumbral zone include acidosis, edema formation, acute local inflammation, dissipative ion fluxes, calcium overload, glutamate excitotoxicity, free radical formation, nitric oxide overproduction and programmed cell death [2,13-16]. 

Amacrine cells, an important class of interneurons of the inner retina, are also sensitive to ischemia and glutamate excitotoxicity. Ischemia upregulates expression of proinflammatory mediators such as COX-2 and iiNOS in amacrine cells (Ju et al., 2003). These molecules also are involved in ischemic injury to the ganglion cells, suggesting that common mechanisms of ischemic injury exist in different cells. Both of these cell types die by apoptosis (Singh et al., 2001). Amacrine cells are morphologically, functionally, and molecularly diverse, thus not all amacrine cells are equally susceptible to ischemia or excitotoxicity (Osborne and Larsen, 1996). 

---