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SS-31 improves post-cardiac arrest brain injury by inhibiting microglial ferroptosis and polarization
Tangxing Jiang1, Huidan Zhang2, Yijun Sun2
1Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China; Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China; Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Abstract:
Accumulating evidence suggests that ferroptosis and mitochondrial dysfunction contribute significantly to brain injury following cardiac arrest (CA) and resuscitation. SS-31, a novel mitochondria-targeting peptide, has demonstrated protective effects against mitochondrial dysfunction induced by ischemia/reperfusion injury. This study aimed to investigate the neuroprotective effects of SS-31 in post-CA brain injury and clarify the underlying signaling mechanisms. An in vivo rat model of CA and resuscitation was established. Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group. Survival rates, neurological deficit scores, serum neuronal injury markers (NSE and S100B), and histopathological changes were evaluated for up to 72 h post-resuscitation. Mechanistically, ferroptosis-related signaling pathways were examined, including glutathione peroxidase 4 (GPX4) expression, iron accumulation, oxidative stress markers, and pro-inflammatory cytokine levels, utilizing microglia-specific Sesn2 knockdown via adeno-associated virus vectors. In vitro experiments were performed on BV2 cells subjected to oxygen-glucose deprivation/reoxygenation, assessing cell viability, lipid peroxidation, ferroptosis-associated protein expression, and cytokine secretion following SS-31 intervention. Brain injury post-CA and resuscitation is significantly accompanied by ferroptosis of microglia. Treatment with SS-31 substantially improved survival rates, reduced neurological deficits, and lowered serum NSE and S100B levels. Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines. These effects were primarily mediated via the Sesn2 signaling pathway. SS-31 could effectively improve post-CA brain injury, in which the mechanism was potentially related to the inhibition of microglial ferroptosis and polarization through the regulation of Sesn2 signaling pathway.
Insights
SS-31 peptide protects the brain after cardiac arrest by reducing microglial ferroptosis and inflammation. This neuroprotective effect improves survival and neurological function by targeting the Sesn2 signaling pathway.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Cardiac arrest (CA) and resuscitation often lead to significant brain injury.
- Ferroptosis and mitochondrial dysfunction are key contributors to this post-CA brain damage.
- SS-31, a mitochondria-targeting peptide, shows promise in mitigating ischemia/reperfusion injury.
Purpose of the Study:
- To investigate the neuroprotective potential of SS-31 against brain injury following CA and resuscitation.
- To elucidate the underlying molecular mechanisms, focusing on ferroptosis and microglial activation.
- To examine the role of the Sesn2 signaling pathway in SS-31's effects.
Main Methods:
- Established a rat model of CA and resuscitation, treating with SS-31 or saline.
- Assessed survival rates, neurological scores, serum markers (NSE, S100B), and brain histology.
- Investigated ferroptosis markers (GPX4, iron, oxidative stress, cytokines) and Sesn2 signaling in vivo and in vitro (BV2 cells).
Main Results:
- SS-31 treatment significantly improved survival rates and neurological function post-resuscitation.
- SS-31 reduced markers of neuronal injury (NSE, S100B) and brain histopathology.
- SS-31 attenuated microglial ferroptosis by enhancing GPX4, reducing iron, oxidative stress, and pro-inflammatory cytokines, primarily via the Sesn2 pathway.
Conclusions:
- SS-31 demonstrates significant neuroprotective effects in a post-CA brain injury model.
- The mechanism involves inhibiting microglial ferroptosis and promoting an anti-inflammatory shift.
- Targeting microglial ferroptosis and polarization via the Sesn2 pathway represents a promising therapeutic strategy for post-CA brain injury.
