Abstract
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 (mSOD1G93A mice) compared to controls. Single subcutaneous administration of sustained-release prostacyclin analog ONO-1301-MS to mSOD1G93A 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 mSOD1G93A mice. At late disease stages, the motor function and the survival of motor neurons of ONO-1301-MS-treated mSOD1G93A mice was significantly improved compared to vehicle-treated mSOD1G93A mice. Our data suggest that vasodilator therapy modulating local blood flow in the spinal cord has beneficial effects against ALS disease progression.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by progressive degeneration of motor neurons in the brain and spinal cord, resulting in muscle weakness
Www.nature.com/scientificreports barrier (BSCB), which is composed of blood vessels and central nervous system (CNS), is damaged in human ALS patients and mSOD1G93A mice, and the findings in mice show that blood-spinal-cord barrier (BSCB) breakdown plays a role in early-stage disease pathogenesis
We investigated HIF-1α expression as a marker for hypoxia and ischemia in autopsied spinal cord specimens from ALS patients and spinal cord samples of mSOD1G93A mice
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by progressive degeneration of motor neurons in the brain and spinal cord, resulting in muscle weakness. Respiratory status is one of the prognostic factors for ALS patients, and respiratory impairment is an early sign of disease onset in mSOD1G93A mice[11,12]. It has been becoming more and more clear that vascular changes are deeply involved in the pathogenesis of ALS13–16. Www.nature.com/scientificreports barrier (BSCB), which is composed of blood vessels and central nervous system (CNS), is damaged in human ALS patients and mSOD1G93A mice, and the findings in mice show that BSCB breakdown plays a role in early-stage disease pathogenesis. To investigate the potential efficacy of anti-hypoxia therapy in ALS, we assessed the effect of ONO-1301-MS, a sustained-release form of ONO-1301, on disease progression in mSOD1G93A mice
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