Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in organotypic hippocampal cultures: protection by S-allyl-L-cysteine, a garlic compound.
We have assessed amyloid-beta (Abeta)-induced neurotoxicity, with and without added ibotenic acid (IBO), a potent N-methyl-D-aspartate (NMDA) agonist, in an organotypic hippocampal slice culture (OHC). In the OHC, there was little neurotoxicity after treatment with Abeta(25-35) (25 or 50 microM) alone for 48 h. However, with IBO alone neuronal death was observed in the pyramidal cell layer at low concentrations, and there was dramatic neuronal death at concentrations of 65 microM or more. When Abeta was combined with IBO (Abeta+IBO) there was more intense cell death than with IBO alone. S-Allyl-L-cysteine (SAC), one of the organosulfur compounds having a thioallyl group in aged garlic extract, was shown to protect the hippocampal neurons in the CA3 area and the dentate gyrus (DG) from the cell death induced by Abeta+IBO with no change in the CA1 area. Although L-glutamate (500 microM) potentiated the degree of IBO-induced neuronal death, it attenuated the Abeta+IBO-induced neuronal death in both the CA3 area and the DG with no obvious effect on the CA1 area. These results suggest that Abeta+IBO induces extensive neuronal death, and that SAC and L-glutamate protect cells from death in specific areas of the hippocampus. In addition, inhibition using a pan-caspase inhibitor, z-VAD-fmk, only provided partial protection from Abeta+IBO-induced toxicity for the neurons in the CA3 area. These results suggest that multiple mechanisms may be involved in Abeta+IBO-induced neuronal death in the OHC.
Ito
Yoshihisa
Y
Department of Pharmacology, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan. yoshiito@pha.nihon-u.ac.jp
Ito
Moriyuki
M
Takagi
Noritaka
N
Saito
Hiroshi
H
Ishige
Kumiko
K
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004148:Dioxolanes / Q000494:pharmacology; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005737:Garlic; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D007051:Ibotenic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; D004148:Dioxolanes; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D011687:Purines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; D007051:Ibotenic Acid; D018698:Glutamic Acid; C065299:S-allylcysteine; D003545:Cysteine