Open AccessSingle injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis
Author(s) -
Satoru Tada,
Tatsusada Okuno,
Mikito Shimizu,
Yoshiki Sakai,
Hisae Sumi-Akamaru,
Makoto Kinoshita,
Kazuya Yamashita,
Eri Sanda,
ChiJing Choong,
Akiko Namba,
Tsutomu Sasaki,
Toru Koda,
Ken Takata,
Shigeru Miyagawa,
Yoshiki Sawa,
Yuji Nakatsuji,
Hideki Mochizuki
Publication year - 2019
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-019-41771-4
Subject(s) - amyotrophic lateral sclerosis , sod1 , medicine , spinal cord , hypoxia (environmental) , erythropoietin , pharmacology , neurotrophic factors , riluzole , neuroprotection , neuroinflammation , endocrinology , anesthesia , immunology , inflammation , chemistry , disease , organic chemistry , oxygen , receptor , psychiatry
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 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-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 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.