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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. [ABSTRACT FROM AUTHOR]

Although traumatic brain injury (TBI) is a common cause of death and disability worldwide, there is currently a lack of effective therapeutic drugs and targets. To reveal the complex pathophysiologic mechanisms of TBI, we performed transcriptome analysis of the mouse cerebral cortex and immunohistochemical analysis of human cerebral tissues. The genes Mt1, Mt2, Il33, and Fth1 were upregulated post-TBI and enriched in pathways associated with the inflammatory response, oxidative phosphorylation, and ferroptosis. As an agonist of MT1/2, melatonin (MLT) confers anti-oxidant, anti-inflammatory, and anti -ferroptosis effects after TBI. However, whether these upregulated genes and their corresponding pathways are involved in the neuroprotective effect of MLT remains unclear. In this study, interventions to inhibit MT1/2, IL-33, and ferroptosis (i.e., ferritin H (Fth)- KO) were applied post-TBI. The results showed that MLT attenuated TBI-induced cerebral edema and neurological outcomes by inhibiting inflammation and ferroptosis. Mechanistically, MLT mainly suppressed inflammatory responses and ferroptosis via the activation of MT2 and IL-33 pathways. Building on the previous finding that Fth deletion increases susceptibility to ferroptosis post-TBI, we demonstrated that Fth depletion remarkably exacerbated the post-TBI inflammatory response, and abolished the anti-inflammatory effects of MLT both in vivo and in vitro. Furthermore, the post-TBI anti-inflammatory effect of MLT, which occurs by promoting the polarization of CD206+ macrophages, was dependent on Fth. Taken together, these results clarified that MLT alleviates inflammation- and ferroptosis-mediated brain edema and neurological deficits by activating the MT2/IL-33/Fth pathway, which provides a novel target and theoretical basis for MLT to treat TBI patients. [Display omitted] • The up-regulated genes Mt1, Mt2, Il33, and Fth1 post-TBI were identified by transcriptome. • Melatonin, an agonist of MT1/2, inhibited inflammation and ferroptosis via MT2 and IL-33 pathways. • Fth depletion exacerbated inflammation and ferroptosis, except for IL-33 expression post-TBI. • Melatonin promoted the activation of CD206+ macrophage to exert anti-inflammation dependent on Fth. • Melatonin alleviated post-TBI edema and neurological outcomes by the MT2/IL-33/Fth signaling. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of regulated cell death that is mainly triggered by iron-dependent lipid peroxidation. A growing body of evidence suggests that ferroptosis is involved in the pathophysiology of traumatic brain injury (TBI), and tropomyosin-related kinase B (TrkB) deficiency would mediate TBI pathologies. As an agonist of TrkB and an immediate precursor of melatonin, N-acetyl serotonin (NAS) exerts several beneficial effects on TBI, but there is no information regarding the role of NAS in ferroptosis after TBI. Here, we examined the effect of NAS treatment on TBI-induced functional outcomes and ferroptosis. Remarkably, the administration of NAS alleviated TBI-induced neurobehavioral deficits, lesion volume, and neurodegeneration. NAS also rescued TBI-induced mitochondrial shrinkage, the changes in ferroptosis-related molecule expression, and iron accumulation in the ipsilateral cortex. Similar results were obtained with a well-established ferroptosis inhibitor, liproxstatin-1. Furthermore, NAS activated the TrkB/PI3K/Akt/Nrf2 pathway in the mouse model of TBI, while inhibition of PI3K and Nrf2 weakened the protection of NAS against ferroptosis both in vitro and in vivo , suggesting that a possible pathway linking NAS to the action of anti-ferroptosis was TrkB/PI3K/Akt/Nrf2. Given that ferritin H (Fth) is a known transcription target of Nrf2, we then investigated the effects of NAS on neuron-specific Fth knockout (Fth -KO) mice. Strikingly, Fth deletion almost abolished the protective effects of NAS against TBI-induced ferroptosis and synaptic damage, although Fth deletion-induced susceptibility toward ferroptosis after TBI was reversed by an iron chelator, deferoxamine. Taken together, these data indicate that the TrkB agonist NAS treatment appears to improve brain function after TBI by suppressing ferroptosis, at least in part, through activation of the PI3K/Akt/Nrf2/Fth pathway, providing evidence that NAS is likely to be a promising anti-ferroptosis agent for further treatment for TBI. [Display omitted] • NAS reduces TBI-induced neurological deficits and neurodegeneration. • NAS is a potent anti-ferroptotic compound, and mitigates TBI-induced ferroptosis. • NAS prevents TBI-induced ferroptosis through the PI3K/Akt/Nrf2/Fth pathway. • Fth deletion abolishes the effects of NAS on TBI-induced ferroptosis and synaptic damage. [ABSTRACT FROM AUTHOR]

Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Our previous studies proved that the inhibition of Drp1 may help attenuate traumatic brain injury (TBI)-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. However, the molecular mechanisms of Drp1 after TBI remain poorly understood. In this study, we investigated the role of mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, in underlying mechanisms of general autophagy and mitochondria autophagy (mitophagy) after experimental TBI. In vivo , we found that autophagosomes accumulated in cortical neurons at 24 h after TBI, owing to the enhanced autophagy indicated by the accumulation of LC3 and the decrease of p62; but Mdivi-1 reversed the enhancement. Mdivi-1 also alleviated the number of LC3 puncta and TUNEL-positive structures in cells, indicating that autophagy maybe involved in Mdivi-1′s anti-apoptosis effects. Then, the expression level of mitochondrial dynamics related and mitophagy related proteins was assessed using the isolated mitochondria. The results showed that TBI-induced mitochondrial fission (represented by Drp1), mtDNA concentration down-regulation and PTEN induced putative kinase 1 (PINK1)-Parkin mediated mitophagy activation were all inhibited by Mdivi-1. In addition, TBI-induced blood-brain barrier (BBB) disruption and matrix metalloproteinases (MMP)-9 expression up-regulation were inhibited following Mdivi-1 treatment. In vitro , Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24 h both in the basal state and under the conditions of scratch cell injury. Together, these data demonstrate that Mdivi-1 mitigates TBI-induced BBB disruption and cell death at least in part by a mechanism involving inhibiting autophagy dysfunction and mitophagy activation. [ABSTRACT FROM AUTHOR]