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.
neurodegenerative diseases; signalling pathways; excitatory amino acids; neurotoxicity; striatal neurodegeneration
Arriza JL, Eliasof S, Kavanaugh MP, Amara SG: Proc Natl Acad Sci USA 94:4155, 1997.
Arzberger T, Krampfl K, Leimgruber S, Weindl A: J. Neuropathol Exp Neurol 56:440, 1997.
Barks JDE and Silverstein FS: Mol Chem Neuropathol 23:201, 1994.
Bellochio EE, Hu H, Pohorille A, Chan J, Pickel VM, Edwards RH: J Neurosci 18:8648, 1998.
Bellochio EE, Reimer RJ, Freneau RT, Edwards RH: Science 289:847, 2000.
Bigge CF: Curr Opin Chem Biol 3:441, 1999.
Bristol LA and Rothstein JD: Ann Neurol 39:676, 1996.
Casado M, Bendahan A, Zafra F, Danbolt NC, Aragon C, Gimenez C, Kanner BI: J Biol Chem 268:27313, 1993.
Curtis DR, Phillips JW, Watkins JC: Nature 183:611, 1959.
Danbolt NC: Progr Neurobiol 65:1, 2001.
Doble A: Pharmacol Ther 81:163, 1999.
Had-Aissouni L, Re D, Ait-Mamar H, Samuel D, Shimamoto K, Kerkerian-Le Goff L, Birman S: Rev Neurol Spec issue 24-17 May, Abstract P202, 2000.
Kanai Y and Hediger MA: Nature 360:467, 1992.
Kim JP and Choi DW: Neuroscience 23:423, 1987.
Lee LY, Sawin ER, Chalfie M, Horvitz HR, Avery L: J Neurosci 19:159, 1999.
Lievens JC, Bernal F, Forni C, Mahy N, Kerkerian-Le Goff L: Glia 29:222, 2000.
Lortet S, Samuel D, Had-Aissouni L, Masmejan F, Kerkerian-Le Goff L, Pisano P: Neuropharmacology 38:395, 1999.
Lucas DR and Newhouse JP: AMA Arch Ophtalmol 58:193, 1957.
Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koelher R, Rothstein JD, Traystman RJ: Ann Neurol 42:335, 1997.
Nicholls D and Attwell D: Trends Pharmacol Sci 11:462, 1990.
Olney JW: In Lodge D (ed): Excitatory amino acids in health and disease. John Wiley 1988, p. 337.
Roberts PJ: Neuropharmacology 34:813, 1995.
Rossi DJ, Oshima T, Attwell D: Nature 403:316, 2000.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kunel R, Kanai Y, Hediger MA, Wang Y, Scielke J, Welty DF: Neuron 16:675, 1996.
Rothstein JD, Martin LJ, Kuncl RW: New England J Med 326:1464, 1992.
Takamori S, Rhee JS, Rosenmund C, Jahn R: Nature 407:141, 2000.
Vanderberg RJ: Clin Exp Pharmacol Physiol 25:393, 1998.