Pharmacological Inhibition of Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase Is Neuroprotective: Differential Effects on Astrocytes s

Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) inhibits protein kinase B (AKT) survival signaling in neurons. Small molecule pan-PHLPP inhibitors (selective for PHLPP1 and PHLPP2) may offer a translatable method to induce AKT neuroprotection. We test-ed several recently discovered PHLPP inhibitors (NSC117079 and NSC45586; benzoic acid, 5-[2-[4-[2-(2,4-diamino-5-methyl-phenyl)diazenyl]phenyl]diazenyl]-2-hydroxy-,sodium salt.) in rat cortical neurons and astrocytes and compared the biochemical response of these agents with short hairpin RNA (shRNA)-mediated PHLPP1 knockdown (KD). In neurons, both PHLPP1 KD and experimental PHLPP inhibitors activated AKT and ameliorated staurosporine (STS)-induced cell death. Unexpectedly, in astro-cytes, both inhibitors blocked AKT activation, and NSC11707