Publication date: Mar 27, 2019
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by several pathologies including oxidative stress, apoptosis, neuroinflammation, and glutamate toxicity. Although multiple reports suggest that ischemia and hypoxia in the spinal cord plays a pivotal role in the pathogenesis of ALS, the precise role of hypoxia in disease progression remains unknown. In this study, we detected higher expression levels of Hypoxia-inducible factor 1-alpha (HIF-1α), a key regulator of cellular responses to hypoxia, in the spinal cord of ALS patients and in the transgenic mice overexpressing the familial ALS-associated G93A SOD1 mutation (mSOD1 mice) compared to controls. Single subcutaneous administration of sustained-release prostacyclin analog ONO-1301-MS to mSOD1 mice abrogated the expression of HIF-1α in their spinal cords, as well as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), both of which are downstream to HIF-1α. Furthermore, ONO-1301-MS increased the level of mature brain-derived neurotrophic factor (BDNF) and ATP production in the spinal cords of mSOD1 mice. At late disease stages, the motor function and the survival of motor neurons of ONO-1301-MS-treated mSOD1 mice was significantly improved compared to vehicle-treated mSOD1 mice. Our data suggest that vasodilator therapy modulating local blood flow in the spinal cord has beneficial effects against ALS disease progression.
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Tada, S., Okuno, T., Shimizu, M., Sakai, Y., Sumi-Akamaru, H., Kinoshita, M., Yamashita, K., Sanda, E., Choong, C.J., Namba, A., Sasaki, T., Koda, T., Takata, K., Miyagawa, S., Sawa, Y., Nakatsuji, Y., and Mochizuki, H. Single injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis. 17614. 2019 Sci Rep (9):1.