Administration of a phosphodiesterase 4B inhibitor reduces hippocampal neuronal cell death after global cerebral ischemia

Abstract Global cerebral ischemia (GCI) causes widespread neuronal injury, with hippocampal neurons being particularly vulnerable. This study examined whether post-GCI treatment with amlexanox (AMX), a phosphodiesterase 4B (PDE4B) inhibitor, reduces hippocampal neurodegeneration and modulates lysosome/autophagy-associated processes. In a mouse model of GCI, AMX (10 mg/kg, intraperitoneally) was administered daily, and hippocampal injury was evaluated using histological and molecular analyses. AMX treatment reduced neuronal degeneration and preserved neuronal integrity in the hippocampus. These effects were accompanied by reduced PDE4B expression, increased levels of proteins associated with lysosomal and autophagic processes, and changes in apoptosis-related protein expression. Overall, AMX treatment exerted neuroprotective effects and was associated with alterations in lysosome/autophagy-associated markers following GCI. Although the underlying signaling mechanisms and autophagic flux were not directly examined, these findings suggest that AMX may represent a potential therapeutic approach for reducing ischemia-induced neuronal injury.