RESUMEN
Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.
Asunto(s)
Apoferritinas/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Melatonina/uso terapéutico , Animales , Apoferritinas/genética , Western Blotting , Ferroptosis/efectos de los fármacos , Inmunohistoquímica , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Brain injury is accompanied by serious iron metabolism disorder and oxidative stress. As a novel form of regulated cell death (RCD) depending on lipid peroxidation caused by iron overload, ferroptosis (FPT) further aggravates brain injury, which is different from apoptosis, autophagy and other traditional cell death in terms of biochemistry, morphology and genetics. Noteworthy, transcriptional regulator NRF2 plays a key role in the cell antioxidant system, and many genes related to FPT are under the control of NRF2, including genes for iron regulation, thiol-dependent antioxidant system, enzymatic detoxification of RCS and carbonyls, NADPH regeneration and ROS sources from mitochondria or extra-mitochondria, which place NRF2 in the key position of regulating the ferroptotic death. Importantly, NRF2 can reduce iron load and resist FPT. In the future, it is expected to open up a new way to treat brain injury by targeting NRF2 to alleviate FPT in brain.
Asunto(s)
Apoptosis , Lesiones Encefálicas , Factor 2 Relacionado con NF-E2 , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Sistemas de Liberación de Medicamentos , Regulación de la Expresión Génica , Humanos , Hierro/metabolismo , Peroxidación de Lípido , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Traumatic brain injury (TBI) is one of the most significant health care problems worldwide, causing disability and death especially among young individuals. Although a large range of agents and therapies have been proved beneficial to lesions post-TBI to some extent, effective treatments have not been translated to the clinic. As a newly discovered form of iron-dependent regulated cell death, ferroptosis has been implicated in TBI. In this review, we update the current state of knowledge related to second injuries post-TBI, including ferroptosis, oxidative stress, mitochondrial dysfunction, neuroinflammation and so on, which often lead to chronic symptoms and long-term disability. This review systematically summarizes the latest progress in the pathophysiological mechanisms of TBI, with a focus on providing references for proposing new multi-molecular targets for comprehensive therapeutic strategies based on ferroptosis-relevant mechanisms. In addition, biomarkers are essential diagnostic and prognostic tools in TBI. Several biomarkers associated with the outcome of TBI have been listed in this article, such as Pde10a, MDA, UCH-L1, S100A9, S100B, ALDOC, ACSL4, MBP and F2-Isoprostane. Therefore, the understating of ferroptosis-relevant mechanisms and biomarkers may contribute to development of promising therapies for TBI clinical trials.