Received for publication January 18, 2005.
Revised March 25, 2005.
Accepted for publication March 25, 2005.

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

Abstract

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 hydrogen peroxide (H₂O₂)-induced (100 µM for 24 h) neuronal death. T-817MA suppressed the decrease of reduced glutathione (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 (GAP-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 might have a potential for disease modification and to be useful for patients with neurodegenerative diseases, such as AD.

Key words: Alzheimer's disease, Glutathione, Growth-associated protein 43, Microtubule-associated protein 2, Neuroprotection, Oxidative stress