A neuroprotective agent, T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate), prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice

• Published in: Neuropharmacology 2008-10, Vol.55 (5), p.654-660
• Main Authors: Kawasaki, Toshiyuki, Ago, Yukio, Kitao, Tatsuya, Nashida, Tetsuaki, Takagi, Akiko, Takuma, Kazuhiro, Matsuda, Toshio
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; Analysis of Variance; Animals; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dose-Response Relationship, Drug; Lipid Peroxidation - drug effects; Male; Maleates - pharmacology; Mice; Mice, Inbred C57BL; Microglia; Motor Activity - drug effects; MPTP Poisoning - chemically induced; MPTP Poisoning - pathology; MPTP Poisoning - prevention & control; Neuroprotective Agents - pharmacology; Neurotoxicity; Parkinson's disease; Rotarod Performance Test; T-817MA; Thiophenes - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2008.05.032

T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate) is a candidate therapeutic agent for Alzheimer's disease that inhibits oxidative stress and nitric oxide-induced neurotoxicity and acts as a neurotrophic factor. The present study examines the effect of T-817MA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6J mice. MPTP treatment (10 mg/kg, s.c. × 4 at 2-h intervals) impaired rotarod performance, and T-817MA improved this deficit. MPTP treatment also decreased dopamine levels and tyrosine hydroxylase immunostaining in the substantia nigra (SNc) and striatum. Pretreatment with T-817MA (10 and 30 mg/kg as T-817, p.o.) attenuated these decreases in dopamine levels and tyrosine hydroxylase immunoreactivity, but did not affect brain levels of 1-methyl-4-phenylpyridinium ion, an active metabolite of MPTP. The protective effect was almost complete in the SNc, but only partial in the striatum. MPTP increased levels of the lipid peroxidation product, thiobarbituric acid reactive substance, only in the midbrain, which could be blocked by T-817MA. MPTP caused microglial activation both in the SNc and striatum, but T-817MA did not affect the activation of microglia. These results suggest that T-817MA protects against MPTP-induced neurotoxicity by blocking lipid peroxidation in the SNc, and imply that this compound may be useful for treating neurodegenerative disorders related to oxidative stress, such as Parkinson's disease.