Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells

Post stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.

Rat primary cortical neurons (PCNs) were exposed to oxygen glucose deprivation (OGD) followed by increasing glucose concentration (0, 5, 10, 25 mM) at reoxygenation. In vivo, adult rats were subjected to two hours transient distal middle cerebral artery occlusion (t-dMCAO) and hyperglycemic reperfusion.

In PCN cultures, high glucose levels impaired normal neurite growth at 24 h I/R where it drastically depressed S6 ribosomal protein phosphorylation at serine 235/236 residues in 40S ribosomal subunit. This concurred with substantial hypoxia inducible factor-1α (HIF-1α) destabilization and sustained vascular endothelial growth factor (VEGF). Our immunoblotting findings indicated HIF-1α stabilization and AMPK activation rely on glucose availability. Incremental glucose concentrations above the physiological levels, induced a shift towards 4E-BP1, eIF-4E hypo-phosphorylated forms leading to reduced eIF-4E availability and efficacy, as the key to recruit the 40S ribosomal subunit to the 5' end of mRNA. In vivo, immunostaining of t-dMCAO rat brains showed remarkable decrease in phosphorylated 4E-BP1 and particularly s6 ribosomal protein in the marginal cortical tissue of hyperglycemic compared to normoglycemic animals.

These findings suggest a remarkable association between hyperglycemic I/R injury with dysregulated cap-dependent translation poststroke. Further loss/gain of function experiment may elucidate the potential therapeutic targets in regulation of HIF-1α/translation in hyperglycemic I/R injury.