3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1- methylpyridine oxalate, a novel xanomeline derivative, improves neural cells proliferation and survival in adult mice

Abstract

The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M ₁/M ₄ receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up-regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression.