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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]