PMID- 30918303 OWN - NLM STAT- MEDLINE DCOM- 20201005 LR - 20210109 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Mar 27 TI - Single injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis. PG - 5252 LID - 10.1038/s41598-019-41771-4 [doi] LID - 5252 AB - 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-1alpha), 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(G93A) mice) compared to controls. Single subcutaneous administration of sustained-release prostacyclin analog ONO-1301-MS to mSOD1(G93A) mice abrogated the expression of HIF-1alpha in their spinal cords, as well as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), both of which are downstream to HIF-1alpha. Furthermore, ONO-1301-MS increased the level of mature brain-derived neurotrophic factor (BDNF) and ATP production in the spinal cords of mSOD1(G93A) mice. At late disease stages, the motor function and the survival of motor neurons of ONO-1301-MS-treated mSOD1(G93A) mice was significantly improved compared to vehicle-treated mSOD1(G93A) mice. Our data suggest that vasodilator therapy modulating local blood flow in the spinal cord has beneficial effects against ALS disease progression. FAU - Tada, Satoru AU - Tada S AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. AD - Department of Neurology, Tanaka Naika Medical Clinic, 2-7-28, Matsunohama-cho, Izumiotsu, Osaka, 595-0072, Japan. FAU - Okuno, Tatsusada AU - Okuno T AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. okuno@neurol.med.osaka-u.ac.jp. FAU - Shimizu, Mikito AU - Shimizu M AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Sakai, Yoshiki AU - Sakai Y AD - Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Sumi-Akamaru, Hisae AU - Sumi-Akamaru H AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Kinoshita, Makoto AU - Kinoshita M AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Yamashita, Kazuya AU - Yamashita K AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Sanda, Eri AU - Sanda E AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Choong, Chi-Jing AU - Choong CJ AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Namba, Akiko AU - Namba A AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Sasaki, Tsutomu AU - Sasaki T AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Koda, Toru AU - Koda T AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Takata, Kazushiro AU - Takata K AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Miyagawa, Shigeru AU - Miyagawa S AD - Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Sawa, Yoshiki AU - Sawa Y AD - Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Nakatsuji, Yuji AU - Nakatsuji Y AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. FAU - Mochizuki, Hideki AU - Mochizuki H AUID- ORCID: 0000-0002-0874-7542 AD - Department of Neurology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190327 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Pyridines) RN - 176391-41-6 (ONO 1301) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - DCR9Z582X0 (Epoprostenol) RN - Amyotrophic lateral sclerosis 1 SB - IM MH - Adenosine Triphosphate/metabolism MH - Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology MH - Animals MH - Blotting, Western MH - Disease Models, Animal MH - Epoprostenol/*analogs & derivatives MH - Immunohistochemistry MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Motor Neurons/drug effects/metabolism/pathology MH - Pyridines/*therapeutic use PMC - PMC6437213 COIS- The authors declare no competing interests. EDAT- 2019/03/29 06:00 MHDA- 2020/10/06 06:00 PMCR- 2019/03/27 CRDT- 2019/03/29 06:00 PHST- 2018/02/28 00:00 [received] PHST- 2019/03/15 00:00 [accepted] PHST- 2019/03/29 06:00 [entrez] PHST- 2019/03/29 06:00 [pubmed] PHST- 2020/10/06 06:00 [medline] PHST- 2019/03/27 00:00 [pmc-release] AID - 10.1038/s41598-019-41771-4 [pii] AID - 41771 [pii] AID - 10.1038/s41598-019-41771-4 [doi] PST - epublish SO - Sci Rep. 2019 Mar 27;9(1):5252. doi: 10.1038/s41598-019-41771-4.