Amlexanox Ameliorates Traumatic Brain Injury by Restoring Autophagy-Lysosomal Function via cAMP Signaling Modulation

Oct 6, 2026

Uploaded by Jasmine

Traumatic brain injury (TBI) disrupts cellular homeostasis through lysosomal dysfunction, oxidative stress, and impaired autophagy, driving neuronal degeneration and limiting effective therapies. This study evaluates amlexanox (AMX), a broad-spectrum phosphodiesterase (PDE) inhibitor, for TBI-induced neuronal damage. AMX elevates cAMP by inhibiting multiple PDE isoforms and suppresses neuroinflammation via NF-κB and STAT3 pathway inhibition. High-throughput screening identifies AMX restoring lysosomal acidity via PKA activation. In vitro and in vivo results show improved lysosomal function, reduced dendritic loss, alleviated oxidative and ER stress, reduced glial activation, and preserved hippocampal neuronal viability, with improved behavioral outcomes after TBI.

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CategoryHealthcare

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Ivyspring International Publisher InternationalJournal of Biological Sciences 2025; 21(10): 4467-4484. doi: 10.7150/ijbs.111216 Research Paper Amlexanox Ameliorates Traumatic Brain Injury by Restoring Autophagy-Lysosomal Function via cAMP Signaling Modulation Seo Young Woo1, Min Kyu Park1, A Ra Kho2,3, Hyun Wook Yang1, Hyun Ho Jung1, Jaewoo Shin4, Minwoo Lee5, Ha Na Kim6, Jae Young Koh6, Bo Young Choi7,8,􀀍, Sang Won Suh1,􀀍 1. Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea. 2. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 4. Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea. 5. Department of Neurology, Hallym Neurological Institute, Hallym University Sacred Heart Hospital, Anyang 14068, Republic of Korea. 6. Neural Injury Lab, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. 7. Department of Physical Education, Hallym University, Chuncheon 24252, Republic of Korea. 8. Institute of Sport Science, Hallym University, Chuncheon 24252, Republic of Korea. 􀀍 Corresponding authors: Bo Young Choi, PhD, Department of Physical Education, Hallym University, College of Natural Sciences, 1 Hallymdaehak-gil, Chuncheon 24252, Republic of Korea; Phone: (82) 10-8888-0646; Fax: (82) 33-248-2258; E-mail: [bychoi@hallym.ac.kr. Sang Won Suh](bychoi@hallym.ac.kr. Sang Won Suh), MD, PhD, Department of Physiology, Hallym University College of Medicine, 1 Hallymdaehak-gil, Chuncheon 24252, Republic of Korea; Phone: (82-10) 8573-6364; Fax: (82-33) 256-3426; E-mail: [swsuh@hallym.ac.kr](swsuh@hallym.ac.kr). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.01.27; Accepted: 2025.06.17; Published: 2025.07.06 Abstract Traumatic brain injury (TBI) disrupts cellular homeostasis through lysosomal dysfunction, oxidative stress, and impaired autophagy, contributing to neuronal degeneration. Despite advances in our understanding of these mechanisms, effective therapeutic options remain limited. This study investigatesamlexanox (AMX), a broad-spectrum phosphodiesterase (PDE) inhibitor, as a potential treatment for TBI-induced neuronal damage. AMX not only increases cyclic adenosine monophosphate (cAMP) levels by inhibiting multiple PDE isoforms but also exhibits anti-inflammatory properties by suppressing pro-inflammatory cytokine production and glial activation via NF-κB and STAT3 pathway inhibition. This dual pharmacological profile suggests a multifaceted therapeutic potential for brain injury. High-throughput screening of an FDA-approved drug library identified AMX as an agent that restores lysosomal acidity through protein kinase A (PKA) activation in primary neuron cultures. In vitro scratch assays demonstrated that AMX enhances lysosomal function, reduces dendritic loss, and promotes neuronal survival. Using a controlled cortical impact model, in vivo experiments revealed that AMX alleviates oxidative and endoplasmic reticulum stress, suppresses neuroinflammation by reducing microglial and astrocytic activation, and preserves neuronal viability in the hippocampus. Behavioral assessments confirmed significant improvements in cognitive and neurological deficits following TBI. These findings establish that AMX is a promising therapeutic agent that restores lysosomal function and mitigates TBI-induced neuronal damage through multi-target PDE inhibition and anti-inflammatory actions. Ke

FAQs

What therapeutic mechanism does amlexanox (AMX) target in traumatic brain injury?

AMX restores autophagy-lysosomal function by modulating cAMP signaling through PDE inhibition and enhancing protein kinase A (PKA) activity to improve lysosomal acidity and function.

How does AMX influence inflammation-related pathways in the study?

AMX suppresses neuroinflammation by inhibiting pro-inflammatory signaling through NF-κB and STAT3 pathway modulation, reducing cytokine production and glial activation.

What evidence supports AMX’s effects in vitro and in vivo?

In primary neuron cultures and scratch assays, AMX improves lysosomal function and neuronal survival while reducing dendritic loss. In a controlled cortical impact model, AMX reduces oxidative and ER stress, decreases microglial and astrocytic activation, preserves hippocampal neuronal viability, and improves cognitive and neurological deficits.

Oct 6, 2026

Uploaded by Jasmine