Single injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis.

Single injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis.

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.

Open Access PDF

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.

Concepts Keywords
ALS Apoptosis
Amyotrophic Lateral Sclerosis Alpha
Analog Excitotoxicity
Apoptosis Hypoxia in fish
ATP Amyotrophic lateral sclerosis
BDNF Spinal cord
Blood Flow SOD1
EPO Hypoxia-inducible factors
Erythropoietin Oxygen
G93A Transcription factors
Glutamate Toxicity Neurology
Hypoxia Nervous system
Hypoxic Organ systems
Ischemia Branches of biology
Mice ALS
Motor Neurons MS
Murine
Mutation
Neurodegenerative
ONO
Oxidative Stress
Pathogenesis
Pathologies
Progressive
Prostacyclin
Sci
SOD1
Spinal Cord
Subcutaneous
Sustained Release
Toxicity
Transgenic
Vasodilator
VEGF

Semantics

Type Source Name
pathway BSID Reproduction
disease MESH Diagnosis
gene UNIPROT TNFSF13B
drug DRUGBANK Sulfasalazine
disease DOID pulmonary fibrosis
disease MESH pulmonary fibrosis
drug DRUGBANK Bleomycin
gene UNIPROT MBNL1
disease DOID nephritis
disease MESH nephritis
disease DOID motor neuron disease
gene UNIPROT CD40
disease MESH demyelination
gene UNIPROT INTU
pathway BSID Angiogenesis
disease MESH tumor
disease MESH metastasis
gene UNIPROT ACTA1
gene UNIPROT DUOXA1
gene UNIPROT GRB2
gene UNIPROT FUS
disease MESH Renal
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
gene UNIPROT USB1
gene UNIPROT POSTN
disease MESH heart failure
disease MESH middle cerebral artery occlusion
gene UNIPROT MAGEE1
pathway BSID Glucose metabolism
disease MESH neuron degeneration
gene UNIPROT APPL1
drug DRUGBANK (S)-Des-Me-Ampa
disease MESH cognitive dysfunction
gene UNIPROT BRD2
disease MESH death
gene UNIPROT PHB2
gene UNIPROT KIT
gene UNIPROT CES2
gene UNIPROT CASP1
drug DRUGBANK Albendazole
drug DRUGBANK Aspartame
drug DRUGBANK Aprotinin
gene UNIPROT SDS
gene UNIPROT SBDS
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Dextran
gene UNIPROT MBOAT4
gene UNIPROT TSPO
gene UNIPROT CHRM3
gene UNIPROT FBN1
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Water
drug DRUGBANK Ethanol
drug DRUGBANK Sulodexide
drug DRUGBANK Polyvinyl alcohol
gene UNIPROT FAP
gene UNIPROT GLMN
disease DOID familial amyloid polyneuropathy
gene UNIPROT TPO
disease DOID multiple system atrophy
disease MESH multiple system atrophy
gene UNIPROT AKAP5
gene UNIPROT RXFP2
gene UNIPROT PROC
gene UNIPROT APC
gene UNIPROT ERBB2
gene UNIPROT NEU1
gene UNIPROT NEURL1
gene UNIPROT LARGE1
disease MESH B cell lymphoma
gene UNIPROT APAF1
pathway BSID Peroxisome
gene UNIPROT KDR
disease MESH growth
drug DRUGBANK Nitric Oxide
gene UNIPROT PTGS2
gene UNIPROT CASP3
gene UNIPROT BCL2
gene UNIPROT BAX
gene UNIPROT RYR1
gene UNIPROT PTGS1
gene UNIPROT HGF
gene UNIPROT IL6
gene UNIPROT SOS1
gene UNIPROT IGF1
gene UNIPROT IFNG
gene UNIPROT ANXA11
drug DRUGBANK Thiocolchicoside
gene UNIPROT RBM8A
gene UNIPROT SIGMAR1
disease DOID ALS16
gene UNIPROT TUBA4A
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
gene UNIPROT AIF1
gene UNIPROT GFAP
disease MESH weight loss
gene UNIPROT CASP9
gene UNIPROT PPARGC1A
gene UNIPROT CREB1
gene UNIPROT CHAMP1
gene UNIPROT CAMP
drug DRUGBANK Cyclic Adenosine Monophosphate
disease MESH inflammation
gene UNIPROT SPP1
disease MESH cerebral ischemia
gene UNIPROT TNFRSF11A
gene UNIPROT NOVA2
gene UNIPROT SNAP25
gene UNIPROT HERPUD1
gene UNIPROT NT5E
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Glycolic acid
disease DOID pulmonary hypertension
disease MESH pulmonary hypertension
drug DRUGBANK Oxygen
gene UNIPROT CEP55
gene UNIPROT COL9A3
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT SCN8A
gene UNIPROT COL9A2
gene UNIPROT MENT
drug DRUGBANK Trestolone
disease MESH defects
pathway BSID Neurodegenerative Diseases
disease MESH neurodegenerative diseases
gene UNIPROT SSRP1
disease MESH risk factor
disease DOID ALS13
pathway BSID Brain derived neurotrophic factor
disease DOID lateral sclerosis
disease MESH lateral sclerosis
drug DRUGBANK Coenzyme M
gene UNIPROT ATP8A2
drug DRUGBANK ATP
gene UNIPROT BDNF
gene UNIPROT VEGFA
gene UNIPROT EPX
gene UNIPROT TIMP1
gene UNIPROT EPO
drug DRUGBANK Erythropoietin
disease MESH familial
gene UNIPROT SETD2
disease MESH disease progression
disease MESH hypoxia
disease DOID ischemia
disease MESH ischemia
disease MESH multiple
pathway BSID Apoptosis
pathway BSID Oxidative Stress
disease MESH oxidative stress
gene UNIPROT SOD1
gene UNIPROT IGFALS
disease DOID amyotrophic lateral sclerosis
disease MESH amyotrophic lateral sclerosis
drug DRUGBANK Epoprostenol
pathway BSID Release

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *