PMID- 12362409
OWN - NLM
STAT- MEDLINE
DCOM- 20021029
LR  - 20240104
IS  - 0148-639X (Print)
IS  - 0148-639X (Linking)
VI  - 26
IP  - 4
DP  - 2002 Oct
TI  - Update on the glutamatergic neurotransmitter system and the role of 
      excitotoxicity in amyotrophic lateral sclerosis.
PG  - 438-58
AB  - Excitotoxicity may play a role in certain disorders of the motor system thought 
      to be caused by environmentally acquired toxins, including lathyrism and domoic 
      acid poisoning. Motor neurons appear to be particularly susceptible to toxicity 
      mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 
      (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic 
      toxicity as a contributory factor in the selective neuronal injury occurring in 
      amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated 
      toxicity is so far the only neuroprotective therapeutic strategy that has shown 
      benefit in terms of slowing disease progression in ALS patients. Biochemical 
      studies have shown decreased glutamate levels in central nervous system (CNS) 
      tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF 
      from ALS patients is toxic to neurons in culture, apparently via a mechanism 
      involving AMPA receptor activation. There is evidence for altered expression and 
      function of glial glutamate transporters in ALS, particularly excitatory amino 
      acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected 
      in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. 
      Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also 
      lead to significant interactions with regulation of the glutamate transmitter 
      system. Certain features of motor neurons may predispose them to the 
      neurodegenerative process in ALS, such as the cell size, mitochondrial activity, 
      neurofilament content, and relative lack of certain calcium-binding proteins and 
      molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by 
      calcium-permeable AMPA receptors. The relatively low expression of the glutamate 
      receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by 
      the large number and density of cell surface AMPA receptors are potentially 
      important factors that may predispose to such toxicity.
CI  - Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 438-458, 2002
FAU - Heath, Paul R
AU  - Heath PR
AD  - Academic Neurology Unit, E Floor, Medical School, University of Sheffield, Beech 
      Hill Road, Sheffield S10 2RX, United Kingdom.
FAU - Shaw, Pamela J
AU  - Shaw PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Muscle Nerve
JT  - Muscle & nerve
JID - 7803146
RN  - 0 (Amino Acid Transport System X-AG)
RN  - 0 (Excitatory Amino Acids)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, Glutamate)
RN  - 0 (Receptors, Kainic Acid)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Amino Acid Transport System X-AG/metabolism
MH  - Amyotrophic Lateral Sclerosis/*pathology
MH  - Animals
MH  - Excitatory Amino Acids/*physiology
MH  - Glutamic Acid/*physiology
MH  - Humans
MH  - Motor Neurons/physiology
MH  - Neural Pathways/pathology
MH  - Neurotransmitter Agents/*physiology
MH  - Receptors, AMPA/physiology
MH  - Receptors, Glutamate/physiology
MH  - Receptors, Kainic Acid/physiology
MH  - Receptors, Metabotropic Glutamate/physiology
MH  - Receptors, N-Methyl-D-Aspartate/physiology
RF  - 213
EDAT- 2002/10/04 04:00
MHDA- 2002/10/31 04:00
CRDT- 2002/10/04 04:00
PHST- 2002/10/04 04:00 [pubmed]
PHST- 2002/10/31 04:00 [medline]
PHST- 2002/10/04 04:00 [entrez]
AID - 10.1002/mus.10186 [doi]
PST - ppublish
SO  - Muscle Nerve. 2002 Oct;26(4):438-58. doi: 10.1002/mus.10186.