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NEUROPHARMACOLOGY

A Novel Neurotrophic Agent, T-817MA [1-{3-[2-(1-Benzothiophen-5-yl) Ethoxy] Propyl}-3-azetidinol Maleate], Attenuates Amyloid--Induced Neurotoxicity and Promotes Neurite Outgrowth in Rat Cultured Central Nervous System Neurons

Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan (K.H., H.Y., Y.T., A.T., T.F., N.I., A.S., M.N.); and Fifth Department of Internal Medicine, School of Medicine, Fukuoka University, Fukuoka, Japan (T.Y.)

Progressive neuronal loss in Alzheimer's disease (AD) is considered to be a consequence of the neurotoxic properties of amyloid- peptides (A). 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-induced neurotoxicity and its effect of enhancing axonal regeneration in the sciatic nerve axotomy model. The neuroprotective effect of T-817MA against A(1-42) or oxidative stress-induced neurotoxicity was assessed using a coculture of rat cortical neurons with glia. T-817MA (0.1 and 1 µM) was strongly protective against A(1-42)-induced (10 µM for 48 h) or H₂O₂-induced (100 µM for 24 h) neuronal death. T-817MA suppressed the decrease of GSH levels induced by H₂O₂ exposure (30 µM 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 µM) 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.

Address correspondence to: Kazunari Hirata, Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, 930-8508, Japan. E-mail: kazunari_hirata{at}toyama-chemical.co.jp