4'-O-β-D-Glucosyl-5-O-Methylvisamminol, A Natural Histone H3 Phosphorylation Epigenetic Suppressor, Exerts a Neuroprotective Effect Through PI3K/Akt Signaling Pathway on Focal Cerebral Ischemia in Rats.

Abstract

A bursting inflammation has been observed that compromises neurologic function in patients who experience stroke. We sought to examine the neuroprotective efficacy of 4'-O-β-D-glucosyl-5-O-methylvisamminol (OGOMV), a novel histone H3 phosphorylation epigenetic suppressor) in a transient middle cerebral artery occlusion (tMCAO). A rodent tMCAO model was used. Administration with 400 μg/kg/day OGOMV was initiated 12 hours before (prevention) and 1 hour after animals were subjected to tMCAO (reversal). The cerebral cortex was harvested to examine protein kinase B (PI3D/Akt), 5-bromo-2'-deoxyuridine (Western blot), and caspases (reverse-transcription polymerase chain reaction). In addition, cerebrospinal fluid samples were collected to examine interleukin 1-β, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α (reverse-transcription polymerase chain reaction). Cortical 5-bromo-2'-deoxyuridine and phospho-PI3D/Akt were reduced in tMCAO animals, compared with the healthy controls but increased in the OGOMV treatment and prevention groups. Activated cortical caspase-3,-6, and -9a as well as increased IL-1β and TNF-α levels were observed in the tMCAO animals (P < 0.05). Both prevention and treatment with OGOMV significantly reduced cleaved caspase-3 and -9a groups, but no significant change in caspase-6 was noted. Perifosine, an Akt inhibitor, was added to reduce the bioexpression of phospho-P13D/Akt, and Bcl-2 level and increased cleaved caspase-9a level in both OGOMV prevention and treatment tMCAO groups (P > 0.05). Our study suggests that OGOMV could exert a neuroprotective effect by inhibiting the P13D/Akt protein, attenuating inflammation, and cleaved caspase-3- and -9a-related apoptosis. This study also lends credence to support the notion that the prevention of OGOMV could attenuate proinflammatory cytokine mRNA and late-onset caspases in tMCAO and merits further study.