Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders.
Alzheimer's disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury. The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of AD, and previous reports have demonstrated that the blockade of glutamate receptors prevents Abeta-induced neuronal death. We show that taurine, a beta-amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate receptor agonists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demonstrated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABA(A) receptors. GABA and the GABA(A) receptor agonists phenobarbital and melatonin also protect neurons against Abeta-induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may represent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.
Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brasil.
Paulo Roberto
PR
Louzada
Andréa C
AC
Paula Lima
Dayde L
DL
Mendonca-Silva
François
F
Noël
Fernando G
FG
De Mello
Sérgio T
ST
Ferreira
D000544:Alzheimer Disease / Q000188:drug therapy; D016564:Amyloid beta-Protein Precursor / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D002642:Chick Embryo; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005136:Eye Proteins / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010852:Picrotoxin / Q000494:pharmacology; D018091:Receptors, AMPA / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012160:Retina / Q000166:cytology / Q000196:embryology; D013654:Taurine / Q000494:pharmacology* / Q000627:therapeutic use; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D016291:Dizocilpine Maleate; D018690:Excitatory Amino Acid Agonists; D005136:Eye Proteins; D018698:Glutamic Acid; D007608:Kainic Acid; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D010852:Picrotoxin; D018091:Receptors, AMPA; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid