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

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. This study was funded by the Hallym University Research Fund (grant number: MHC-2023-02-02-02). All authors thank Sang Won Suh for advice regarding the experimental design and statistical analysis.

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2025-00520396 to S.W.S.). Additional supported by the ANCHOR program(Glocal University30) through the Gangwon ANCHOR Center, funded by the Ministry of Education(MOE) and the Gangwon State(G.S.),Republic of Korea.(2026-ANCHOR-10-009 to S.W.S.). Department of Physiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea Se Wan Park, Song Hee Lee, Beom Seok Kang, Min Kyu Park, Chang Jun Lee, Hyun Wook Yang, Seo Young Woo, Dong Yeon Kim, Won Il Yang, Hyun Ho Jung & Sang Won Suh Department of Physical Education, Hallym University, Chuncheon, 24252, Republic of Korea Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, College of Medicine, Johns Hopkins University School, Baltimore, MD, 21205, USA Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA Department of Sport Industry Studies, Yonsei University, Seoul, Republic of Korea Department of Neurology, Hallym Neurological Institute, Hallym University Sacred Heart Hospital, Anyang, 14068, Republic of Korea All authors have read the journal’s policy on the disclosure of potential conflicts of interest and have no conflicts to declare.

All the authors have read the journal’s authorship agreements. Experimental procedures were conducted following the guidelines and regulations approved by the Institutional Animal Care and Use Committee of the College of Medicine, Hallym University (Protocol # Hallym 2022-28), as well as ARRIVE guidelines 2.0 for how to REPORT animal experiments. This manuscript does not include the results of human subjects.

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