Journal of integrative neuroscience · 2026
FPS-ZM1 Exerts Neuroprotection in Cardiac-Arrest Mice through Inhibiting Oxidative Stress and Pyroptosis via the HMGB1/RAGE Axis.
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Zhu Ying, Lin Qianhui, Wu Yanping, Hou Jing, Lu Liping, Xu Song, Li Ling, Yu Zhui
Аннотация
BACKGROUND: Cardiac arrest (CA) is a widespread public health problem with high mortality, severe neurological sequelae, and limited pharmacological therapies. We investigated the neuroprotective effect of a novel drug, FPS-ZM1 (FPS), on CA and explored its potential mechanism.
METHODS: A potassium chloride-induced CA was induced for 9.5 min in mice, with i.p. injections of FPS or vehicle administered 24 and 1 h before induction. Postoperative assessments included survival rate, body weight change, neurological scores, and neuronal pathological damage. The expression levels of the high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) axis, pyroptosis-related molecules, oxidative stress markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis were evaluated.
RESULTS: Post-CA brain injury (PCABI) activated the HMGB1/RAGE axis, triggering intensified oxidative stress and aggravated pyroptosis. In contrast, pretreatment with FPS attenuated CA-induced injuries. FPS pretreatment was found to suppress the activation of the HMGB1/RAGE axis, alleviate pyroptosis and the release of associated inflammatory mediators, and enhance the Nrf2/HO-1 antioxidant axis after PCABI.
CONCLUSION: FPS pretreatment mitigated PCABI by concurrently modulating the HMGB1/RAGE inflammatory axis and the Nrf2/HO-1 antioxidant pathway, suggesting that RAGE antagonism represents a promising therapeutic strategy for PCABI.
METHODS: A potassium chloride-induced CA was induced for 9.5 min in mice, with i.p. injections of FPS or vehicle administered 24 and 1 h before induction. Postoperative assessments included survival rate, body weight change, neurological scores, and neuronal pathological damage. The expression levels of the high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) axis, pyroptosis-related molecules, oxidative stress markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis were evaluated.
RESULTS: Post-CA brain injury (PCABI) activated the HMGB1/RAGE axis, triggering intensified oxidative stress and aggravated pyroptosis. In contrast, pretreatment with FPS attenuated CA-induced injuries. FPS pretreatment was found to suppress the activation of the HMGB1/RAGE axis, alleviate pyroptosis and the release of associated inflammatory mediators, and enhance the Nrf2/HO-1 antioxidant axis after PCABI.
CONCLUSION: FPS pretreatment mitigated PCABI by concurrently modulating the HMGB1/RAGE inflammatory axis and the Nrf2/HO-1 antioxidant pathway, suggesting that RAGE antagonism represents a promising therapeutic strategy for PCABI.