A novel neurotrophic agent, T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate], attenuates amyloid-beta-induced neurotoxicity and promotes neurite outgrowth in rat cultured central nervous system neurons.
Progressive neuronal loss in Alzheimer's disease (AD) is considered to be a consequence of the neurotoxic properties of amyloid-beta peptides (A beta). T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate) was screened as a candidate therapeutic agent for the treatment of AD based on its neuroprotective potency against A beta-induced neurotoxicity and its effect of enhancing axonal regeneration in the sciatic nerve axotomy model. The neuroprotective effect of T-817MA against A beta(1-42) or oxidative stress-induced neurotoxicity was assessed using a coculture of rat cortical neurons with glia. T-817MA (0.1 and 1 microM) was strongly protective against A beta(1-42)-induced (10 microM for 48 h) or H2O2-induced (100 microM for 24 h) neuronal death. T-817MA suppressed the decrease of GSH levels induced by H2O2 exposure (30 microM for 4 h) in cortical neuron culture; therefore, T-817MA was likely to alleviate oxidative stress. Besides the neuroprotective effect, T-817MA (0.1 and 1 microM) promoted neurite outgrowth in hippocampal slice cultures and reaggregation culture of rat cortical neurons. T-817MA also increased the growth-associated protein 43 content in the reaggregation culture of cortical neurons. These findings suggest that T-817MA exerts neuroprotective effect and promotes neurite outgrowth in rat primary cultured neurons. Based on these neurotrophic features, T-817MA may have a potential for disease modification and be useful for patients with neurodegenerative diseases, such as AD.
Hirata
Kazunari
K
Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, 930-8508, Japan. kazunari_hirata@toyama-chemical.co.jp
Yamaguchi
Hidetoshi
H
Takamura
Yusaku
Y
Takagi
Akiko
A
Fukushima
Tetsuo
T
Iwakami
Noboru
N
Saitoh
Akihito
A
Nakagawa
Masaya
M
Yamada
Tatsuo
T
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008298:Maleates / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*
C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D016229:Amyloid beta-Peptides; D008298:Maleates; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D013876:Thiophenes; D006861:Hydrogen Peroxide; D005978:Glutathione