Neuroprotection against Abeta and glutamate toxicity by melatonin: are GABA receptors involved?
The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of Alzheimer's disease (AD). Previous studies have suggested that the neurotoxicity of Abeta may be related to the overactivation of glutamatergic transmission and excitotoxicity, and that blockade of glutamate receptors prevents Abeta-induced cell death. Here, we show that melatonin, a pineal hormone, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate. Right-angle light scattering and thioflavin T fluorescence measurements, as well as light microscopy analysis, indicated that, under our experimental conditions, melatonin had no effect on the aggregation of Abeta. Interestingly, the neuroprotective action of melatonin against the toxicity of Abeta was significantly decreased in the presence of picrotoxin, an antagonist of GABA(A)-like receptors. By itself, picrotoxin had no effect. These results suggest that the neuroprotective effects of melatonin against Abeta neurotoxicity could be at least in part related to a decrease in the excitatory tonus, mediated by activation of GABA receptors and the resulting hyper-polarization of the neurons. Thus, selective pharmacological manipulation of neuronal excitatory/inhibitory tonus could be a potentially interesting new approach in the treatment of AD.
Paula-Lima
Andréa C
AC
Departamento de Bioquimica Medica, Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil.
Louzada
Paulo Roberto
PR
De Mello
Fernando G
FG
Ferreira
Sérgio T
ST
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D052160:Benzothiazoles; D002642:Chick Embryo; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005456:Fluorescent Dyes; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D008027:Light; D008550:Melatonin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010852:Picrotoxin / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects*; D012160:Retina / Q000166:cytology / Q000187:drug effects; D012542:Scattering, Radiation; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D052160:Benzothiazoles; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D018698:Glutamic Acid; D008550:Melatonin; D010446:Peptide Fragments; D010852:Picrotoxin; D018079:Receptors, GABA; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T