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

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 investigates amlexanox (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.