2. Academic Validation
  3. TrkB agonist N-acetyl serotonin promotes functional recovery after traumatic brain injury by suppressing ferroptosis via the PI3K/Akt/Nrf2/Ferritin H pathway

TrkB agonist N-acetyl serotonin promotes functional recovery after traumatic brain injury by suppressing ferroptosis via the PI3K/Akt/Nrf2/Ferritin H pathway

  • Free Radic Biol Med. 2022 Dec 7;194:184-198. doi: 10.1016/j.freeradbiomed.2022.12.002.
Ying Cheng 1,  Yuan Gao 1,  Jing Li 1,  Tongyu Rui 1,  Qianqian Li 2,  Huan Chen 1,  Bowen Jia 1,  Yiting Song 1,  Zhiya Gu 1,  Tao Wang 1,  Cheng Gao 1,  Ying Wang 1,  Zufeng Wang 1,  Fudi Wang 3,  Luyang Tao 4,  Chengliang Luo 5
Affiliations

Affiliations

  • 1 Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, 215123, China.
  • 2 School of Forensic Medicine, Wannan Medical College, Wuhu, 241002, China.
  • 3 The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. Electronic address: [email protected].
  • 4 Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, 215123, China. Electronic address: [email protected].
  • 5 Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, 215123, China. Electronic address: [email protected].
PMID: 36493983 DOI: 10.1016/j.freeradbiomed.2022.12.002
Abstract

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.

Keywords

Ferritin H; Ferroptosis; Lipid peroxidation; N-Acetyl serotonin; Neurodegeneration; Traumatic brain injury.

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