Woo Seo Young, Park Min Kyu, Kho A Ra, Yang Hyun Wook, Jung Hyun Ho, Shin Jaewoo, Lee Minwoo, Kim Ha Na, Koh Jae Young, Choi Bo Young, Suh Sang Won
Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Int J Biol Sci. 2025 Jul 6;21(10):4467-4484. doi: 10.7150/ijbs.111216. eCollection 2025.
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. scratch assays demonstrated that AMX enhances lysosomal function, reduces dendritic loss, and promotes neuronal survival. Using a controlled cortical impact model, 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.
创伤性脑损伤（TBI）通过溶酶体功能障碍、氧化应激和自噬受损破坏细胞内稳态，导致神经元变性。尽管我们对这些机制的理解有所进展，但有效的治疗选择仍然有限。本研究调查了氨来呫诺（AMX），一种广谱磷酸二酯酶（PDE）抑制剂，作为TBI诱导的神经元损伤的潜在治疗方法。AMX不仅通过抑制多种PDE同工型增加环磷酸腺苷（cAMP）水平，还通过抑制促炎细胞因子产生和通过NF-κB和STAT3途径抑制来抑制胶质细胞活化，从而表现出抗炎特性。这种双重药理学特性表明其对脑损伤具有多方面的治疗潜力。对一个FDA批准的药物库进行高通量筛选，确定AMX是一种通过激活原代神经元培养物中的蛋白激酶A（PKA）来恢复溶酶体酸度的药物。划痕试验表明，AMX增强溶酶体功能，减少树突损失，并促进神经元存活。使用控制性皮质撞击模型，实验表明AMX减轻氧化应激和内质网应激，通过减少小胶质细胞和星形胶质细胞活化来抑制神经炎症，并在海马体中维持神经元活力。行为评估证实TBI后认知和神经功能缺损有显著改善。这些发现表明，AMX是一种有前途的治疗药物，它通过多靶点PDE抑制和抗炎作用恢复溶酶体功能并减轻TBI诱导的神经元损伤。
