Fig. 1.

Proposed mechanism underlying the preservation of white matter by HDAC inhibition. Microglia/macrophages respond to TBI with proinflammatory changes that increase active, dephosphorylated PTEN. Active PTEN then converts phosphatidylinositol (3,5)-triphosphate (PIP3) to phosphatidyl (4,5)-biphosphate (PIP2), thereby inactivating the prosurvival kinase Akt and leading to microglial and oligodendroglial toxicity. HDAC inhibition counterbalances this inflammatory effect by increasing GSK3β, perhaps by relieving transcriptional repression of its mRNA. Active GSK3β then phosphorylates PTEN at Thr366, leading to a loss of PTEN activity. This loss of PTEN function results in activation of Akt, because PIP3 is no longer converted to PIP2. Activated Akt can now shift microglia from the destructive M1 phenotype toward the beneficial M2 phenotype and thereby elicit the protection of neighboring oligodendrocytes. Activated Akt also phosphorylates GSK3β, thereby disabling its pro-death effect. Knockdown of GSK3β or the PI3K/Akt inhibitor LY294002 each blocks the protective effects of HDAC inhibition, whereas the PTEN inhibitor bpV(pic) fails to provide any additional effect over that of HDAC inhibition.