Design to neuroprotection: a blood brain barrier permeable selective HDAC3 inhibitor active against chemical and viral insults.

Abstract

Neuronal loss in neurodegenerative diseases is mediated by oxidative stress, neuroinflammation, and epigenetic dysregulation, with histone deacetylase 3 (HDAC3) playing a central role in inflammatory signaling and neuronal damage. We synthesized 12 compounds and identified the lead compound 9c as a potent and selective HDAC3 inhibitor, with an IC₅₀ of 0.75 μM and at least 27-fold selectivity over other HDAC isoforms. Compound 9c exhibited significant neuroprotection against hydrogen peroxide (H₂O₂) induced oxidative stress in N2A cells and Japanese encephalitis virus (JEV)-induced cell death in SH-SY5Y cells. Further western blot analysis revealed upregulation of neuronal markers (CREB, BDNF, and synaptophysin) and increased histone acetylation (Ac-H3K9, Ac-H3K27, and Ac-H4K8). Treatment of SH-SY5Y cells with 9c during JEV infection reduces virus-induced caspase-3/7 activity. In addition, quantitative real-time PCR analysis revealed that 9c reduces the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) during JEV infection. Neurite outgrowth and neuronal differentiation assays demonstrated that 9c promotes neuronal growth and maturation. Pharmacokinetic studies showed substantial brain penetration of 9c, with a C _max of 1.84 μg mL^-1 at 1 h and t _1/2 of 4 h. Collectively, these findings suggest that selective HDAC3 inhibition by 9c confers neuroprotection, supporting its potential as a promising therapeutic candidate for neurodegenerative disorders.