Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.
Asiaticoside (AS) derivatives were tested for potential protective effects against Abeta-induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Abeta-induced death of B103 cells at 1 microM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H(2)O(2)-induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine-induced apoptosis. These results suggest that the three AS derivatives block Abeta toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n-methyl-D-aspartic acid (NMDA) or non-NMDA receptor-mediated synaptic transmission, paired-pulse facilitation or induction of long-term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Abeta-induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimer's disease drug that protects neurons from Abeta toxicity.
Mook-Jung
I
I
Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Shin
J E
JE
Yun
S H
SH
Huh
K
K
Koh
J Y
JY
Park
H K
HK
Jew
S S
SS
Jung
M W
MW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D009498:Neurotoxins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D014315:Triterpenes; C074636:amyloid beta-protein (25-35); D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D019311:Staurosporine; C004446:asiaticoside