Naturally occurring marine steroid 24-methylenecholestane-3ß,5α,6ß,19-tetraol functions as a novel neuroprotectant.
Steroids
; 105: 96-105, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26631550
ABSTRACT
Steroids have been shown to have multiple effects on the nervous system including neuroprotective activities, and they have the potential to be used for the treatment of neurodegenerative diseases. In this current study, we tested the hypothesis that the marine steroid 24-methylenecholestane-3ß,5α,6ß,19-tetraol (Tetrol) has a neuroprotective effect. (1) We synthesized Tetrol through a multiple step reaction starting from hyodeoxycholic acid (HDCA). (2) We then evaluated the neuroprotective effect of Tetrol with a glutamate-induced neuronal injury model in vitro. Tetrol concentration dependently increased the survival rate of cerebellar granule neurons challenged with toxic concentration of glutamate. Consistently, Tetrol significantly decreased glutamate-induced lactate dehydrogenase (LDH) release with a threshold concentration of 2.5 µM. (3) We further evaluated the neuroprotective effect of Tetrol in a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in rat. Tetrol, at a dose of 12 mg/kg, significantly decreased MCAO-induced infarction volume by â¼50%. (4) Finally, we probed the mechanism and found that Tetrol concentration dependently attenuated N-methyl-d-aspartate (NMDA)-induced intracellular calcium ([Ca(2+)]i) increase with an IC50 of 7.8±0.62 µM, and inhibited NMDA currents in cortical neurons with an IC50 of 10.28±0.71 µM. Taken together, we have synthesized and characterized Tetrol as a novel neuroprotectant through negative modulation of NMDA receptors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Colestanóis
/
Fármacos Neuroprotetores
/
Organismos Aquáticos
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Steroids
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos