Small synthetic hyaluronan disaccharides afford neuroprotection in brain ischemia-related models.
High molecular weight (HMW) glycosaminoglycanes of the extracellular matrix have been implicated in tissue repair. The aim of this study was to evaluate if small synthetic hyaluronan disaccharides with different degrees of sulfation (methyl 2-acetamido-2-deoxy-3-O-(β-d-glucopyranosyluronic acid)-O-sulfo-α-d-glucopyranoside, sodium salt (di0S), methyl 2-acetamido-2-deoxy-3-O-(β-d-glucopyranosyluronic acid)-6-di-O-sulfo-α-d-glucopyranoside, disodium salt (di6S) and methyl 2-acetamido-2-deoxy-3-O-(β-d-glucopyranosyluronic acid)-4,6-di-O-sulfo-α-d-glucopyranoside, trisodium salt (di4,6S)) could improve cell survival in in vitro and in vivo brain ischemia-related models. Rat hippocampal slices subjected to oxygen and glucose deprivation and a photothrombotic stroke model in mice were used. The three hyaluran disaccharides, incubated during the oxygen and glucose deprivation (15min) and re-oxygenation periods (120min), reduced cell death of hippocampal slices measured as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, being the most potent di4,6S; in contrast, high molecular hyaluronan was ineffective. The protective actions of di4,6S against oxygen and glucose deprivation were related to activation of the PI3K/Akt survival pathway, reduction of p65 translocation to the nucleus, inhibition of inducible nitric oxide oxidase induction and reactive oxygen species production, and to an increase in glutathione levels. Administered 1h post-stroke, di4,6S reduced cerebral infarct size and improved motor activity in the beam walk test. In conclusion, di4,6S affords neuroprotection in in vitro and in vivo models of ischemic neuronal damage. Our results suggest that its neuroprotective effect could be exerted through its capability to reduce oxidative stress during ischemia. Its small molecular size makes it a more potential druggable drug to target the brain as compared with its HMW parent compound hyaluronan.
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain.
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Egea
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain.
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Parada
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain.
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Gómez-Rangel
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain.
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Buendia
Departamento de Anatomía, Histología y Neurociencia, Universidad Autónoma de Madrid, Spain.
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Negredo
Pre-Clinical R&D Area, Pharmascience Division, BIOIBÉRICA, S.A., Barcelona, Spain.
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Montell
Pharmaceutical and Nutraceutical R&D Department, BIOIBÉRICA, S.A., Barcelona, Spain.
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Ruhí
Pre-Clinical R&D Area, Pharmascience Division, BIOIBÉRICA, S.A., Barcelona, Spain.
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Vergés
Hospital La Paz Health Research Institute-IdiPAZ, Madrid, Spain.
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JM
Roda
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain.
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García
Instituto Teófilo Hernando and Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain. Electronic address: manuela.garcia@uam.es.
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López
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004187:Disaccharides / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D004187:Disaccharides; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C000593378:methyl 2-acetamido-2-deoxy-3-O-(glucopyranosyluronic acid)-4,6-di-O-sulfoglucopyranoside; D006820:Hyaluronic Acid
hyaluronan disaccharides; ischemia; neuroprotection; oxidative stress