The role of excitotoxicity in neurodegenerative disease: Implications for therapy

Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory ami no acid receptors, which are ligand gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation, In n ormal synaptic functioning, activation of excitatory amino acid receptors i s transitory. However, if, for any reason, receptor activation becomes exce ssive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to invo lve sustained elevations of intracellular calcium levels. Impairment of neu ronal energy metabolism may sensitise neurones to excitotoxic cell death. T he principle of excitotoxicity has been well established experimentally, bo th in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetio logy or progression of several human neurodegenerative diseases has been pr oposed, which has stimulated much research recently. This has led to the ho pe that compounds that interfere with glutamatergic neurotransmission may b e of clinical benefit in treating such diseases. However, except in the cas e of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurolo gical sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions obser ved. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis , neurolathyrism, and human immunodeficiency virus dementia complex, severa l lines of circumstantial evidence suggest that excitotoxicity may contribu te to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotro phic lateral sclerosis. Parkinson's disease and Huntington's disease are ex amples of neurodegenerative diseases where mitochondrial dysfunction may se nsitise specific populations of neurones to excitotoxicity from synaptic gl utamic acid. The first clinical trials aimed at providing neuroprotection w ith antiglutamate drugs are currently in progress for these two diseases. ( C) 1999 Elsevier Science Inc. All rights reserved.