Experimental neurology · 2025
Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury.
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Meng Lei, Song Bingyi, Shi Xuan, Duan Aojie, Lu Dengfeng, Ren Yubo, Zhang Yu, Shou Renjie, Li Haiying, Wang Zhong, Liu Jiangang, Wang Zongqi, Sun Xiaoou
Аннотация
BACKGROUND: Traumatic brain injury (TBI) induces oxidative stress, leading to secondary injury and neuronal apoptosis. The thioredoxin (Trx) system, a key regulator of redox homeostasis, and the pentose phosphate pathway (PPP), the primary source of NADPH, play critical roles in mitigating oxidative damage. This study investigates the neuroprotective effects of Trx1 in modulating oxidative stress through the Trx1-ATM-PPP axis.
METHODS: Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH.
RESULTS: Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression.
CONCLUSION: Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.
METHODS: Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH.
RESULTS: Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression.
CONCLUSION: Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.