Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain
Traumatic brain injury (TBI) in the elderly is frequently associated with worsened neurological outcomes and prolonged recovery, yet the age-specific molecular mechanisms driving this vulnerability remain poorly understood. Aging is characterized by increased oxidative stress and chronic neuro-infla...
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MDPI AG
2025-06-01
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| Series: | Antioxidants |
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| author | Jui-Ming Sun Jing-Shiun Jan Ting-Lin Yen Yu-Hao Chen Ruei-Dun Teng Chih-Hao Yang Cheng-Ta Hsieh |
| author_facet | Jui-Ming Sun Jing-Shiun Jan Ting-Lin Yen Yu-Hao Chen Ruei-Dun Teng Chih-Hao Yang Cheng-Ta Hsieh |
| author_sort | Jui-Ming Sun |
| collection | DOAJ |
| description | Traumatic brain injury (TBI) in the elderly is frequently associated with worsened neurological outcomes and prolonged recovery, yet the age-specific molecular mechanisms driving this vulnerability remain poorly understood. Aging is characterized by increased oxidative stress and chronic neuro-inflammation, both of which may amplify the brain’s susceptibility to injury. In this study, we identify spermine oxidase (SMOX), a polyamine-catabolizing enzyme that produces reactive oxygen species, as a key mediator linking oxidative stress and neuro-inflammation to age-dependent TBI susceptibility. Using a mouse model of controlled cortical impact (CCI), we found that SMOX expression was significantly upregulated in aged brains, primarily in neurons and microglia, and this increase correlated with greater microglial activation, elevated pro-inflammatory cytokine expression, and widespread neuronal degeneration. Notably, SMOX upregulation also impaired astrocytic glutamate clearance by disrupting the membrane localization of the transporter GLT-1, contributing to excitotoxic stress. Importantly, analysis of postmortem human brain samples and transcriptomic data revealed a parallel age-related increase in SMOX expression, supporting its translational relevance. The pharmacological inhibition of SMOX with JNJ-9350 in aged mice reduced oxidative and inflammatory markers, preserved neuronal viability, and improved motor, cognitive, and emotional outcomes up to 30 days post-injury. These findings establish SMOX as a critical molecular driver of age-related vulnerability to TBI and highlight its inhibition as a promising therapeutic strategy for improving outcomes in elderly TBI patients. |
| format | Article |
| id | doaj-art-0579f5edbf75484482caea0f6738e198 |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj-art-0579f5edbf75484482caea0f6738e1982025-08-20T02:24:17ZengMDPI AGAntioxidants2076-39212025-06-0114670910.3390/antiox14060709Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging BrainJui-Ming Sun0Jing-Shiun Jan1Ting-Lin Yen2Yu-Hao Chen3Ruei-Dun Teng4Chih-Hao Yang5Cheng-Ta Hsieh6Section of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chia-Yi City 600, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanSection of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chia-Yi City 600, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDivision of Neurosurgery, Department of Surgery, Cathay General Hospital, Taipei 106, TaiwanTraumatic brain injury (TBI) in the elderly is frequently associated with worsened neurological outcomes and prolonged recovery, yet the age-specific molecular mechanisms driving this vulnerability remain poorly understood. Aging is characterized by increased oxidative stress and chronic neuro-inflammation, both of which may amplify the brain’s susceptibility to injury. In this study, we identify spermine oxidase (SMOX), a polyamine-catabolizing enzyme that produces reactive oxygen species, as a key mediator linking oxidative stress and neuro-inflammation to age-dependent TBI susceptibility. Using a mouse model of controlled cortical impact (CCI), we found that SMOX expression was significantly upregulated in aged brains, primarily in neurons and microglia, and this increase correlated with greater microglial activation, elevated pro-inflammatory cytokine expression, and widespread neuronal degeneration. Notably, SMOX upregulation also impaired astrocytic glutamate clearance by disrupting the membrane localization of the transporter GLT-1, contributing to excitotoxic stress. Importantly, analysis of postmortem human brain samples and transcriptomic data revealed a parallel age-related increase in SMOX expression, supporting its translational relevance. The pharmacological inhibition of SMOX with JNJ-9350 in aged mice reduced oxidative and inflammatory markers, preserved neuronal viability, and improved motor, cognitive, and emotional outcomes up to 30 days post-injury. These findings establish SMOX as a critical molecular driver of age-related vulnerability to TBI and highlight its inhibition as a promising therapeutic strategy for improving outcomes in elderly TBI patients.https://www.mdpi.com/2076-3921/14/6/709spermine oxidasetraumatic brain injuryaging brainoxidative stressneuro-inflammationneuronal cell death |
| spellingShingle | Jui-Ming Sun Jing-Shiun Jan Ting-Lin Yen Yu-Hao Chen Ruei-Dun Teng Chih-Hao Yang Cheng-Ta Hsieh Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain Antioxidants spermine oxidase traumatic brain injury aging brain oxidative stress neuro-inflammation neuronal cell death |
| title | Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain |
| title_full | Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain |
| title_fullStr | Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain |
| title_full_unstemmed | Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain |
| title_short | Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain |
| title_sort | targeting spermine oxidase to mitigate traumatic brain injury pathology in the aging brain |
| topic | spermine oxidase traumatic brain injury aging brain oxidative stress neuro-inflammation neuronal cell death |
| url | https://www.mdpi.com/2076-3921/14/6/709 |
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