J Pineal Res: Luo Chengliang/俤/Tao Luyang team has made important breakthroughs in the field of brain trauma and iron death

Recently, Associate Professor Luo Chengliang of Suzhou University Medical Department and Professor Wang Fu of Zhejiang University School of Medicine published a research paper entitled "Deletion of Ferritin H in neurons counteracts" online in the internationally renowned academic journal Journal of Pineal Research (Impact Factor: 14.528).
The results first systematically illustrate the time-varying laws of iron-related protein expression and iron deposition after brain trauma, the first in the world to construct a genetic mouse model of cerebral iron death (Ferritin H-KO) to provide a new model for targeting neuron iron death, and the first to reveal melatonin as a potential iron-death inhibitor in animal models of brain trauma, and to clarify the new mechanism of melatonin in the treatment of brain trauma, and its anti-iron death is expected to be a new target for brain injury treatment.
The study first revealed the time-varying patterns of iron-related protein expression and iron deposition after traumatic brain injury, and found that xCT, Cox2, Tfr1, Nox2, and Fpn protein expression peaked at 12h to 24h after trauma, and then gradually declined to near or slightly below normal levels.
, Fth, Ftl and 4HNE proteins were significantly increased three days after trauma, with a slight decrease from 3d to 14d (Figure 1).
of the Surusland confirmed a significant increase in iron deposits seven days after trauma, followed by a trend towards increases.
With the intervention of melatonin and iron death-specific inhibitor liproxstatin-1 respectively, the expression levels of the above-mentioned iron death and iron metabolism-related proteins were significantly reversed, iron deposition and neurodegenerative changes were reduced, and neurological dysfunction caused by brain trauma was reduced.
results suggest that melatonin may play a neuroresistant role by suppressing iron death.
the study also used melatonin-like antagonists to further demonstrate that melatonin's iron-resistant death mechanism works primarily through melatonin-infested 2 (MT2).
1 Time-varying mechanisms for iron death expression associated with iron death protein expression after brain trauma in mice include iron stabilization disorders, glutathione (GSH) depletion, and lipid peroxide.
abnormal iron steady state is associated with iron death and can lead to a pathological state of the central nervous system.
can be observed in patients with brain trauma, suggesting that iron stability damage may be an important pathophysiological process for brain trauma.
regulates the intake, transport and storage of iron in the maintenance of cell iron stability.
iron intake is regulated by the trans-ferr protein complex-1 (Tfr1), and the iron output is regulated by a unique iron output protein (Fpn).
ferritin, the main iron storage protein, has elevated serum levels associated with a lower GCS score when a patient with a severe TBI is admitted to the hospital and an increased death rate in the intensive care unit (ICU).
can also be used as an important post-mortem biomarker to infer the time of injury after brain trauma and the survival time of the deceased from brain trauma.
ferrine consists of two sub-base of heavy chain (Fth) and light chain (Ftl) to form the cavity structure of the globular cavity, which is the most important iron storage protein in the cell.
ions of unused or excreted cells in cells are stored in ferrine, thus maintaining iron stability in cells and reducing oxidative stress caused by Fenton reactions to protect cells.
although TBI post-iron overload and Fth expression have been confirmed in both experimental animals and the human cerebral cortique, the specific mechanism of Fth's role in the brain is not yet clear.
previous studies have found that knocking out the Fth gene directly can lead to embryo fatality.
Taking into account that Fth is mainly expressed in neurons in brain tissue, in order to explore the mechanism of Fth's effect on iron death after TBI, this study used mice expressing Cre recombinant enzyme to interbreed with Fth-floxed mice, and obtained mice with mature neurons with conditions to knock out the Fth gene to explore the mechanism of iron death in brain trauma.
team used Cre/LoxP technology to build neuron-specific knock-out mice (Fth-KO) that encode the Ferritin H, Fth gene.
the specific knock-off of Fth by mature neurons, the cerebral cortical cortical in mice developed mild disorders in iron metabolism under physiological conditions, as shown by a significant decrease in the expression of Fth-KO mouse cortical Tfr1, while the expression of Fpn Significant increases; Fth-KO mice had no significant increase in the cortical Fe2 plus, while Fe3 plus and total cortical iron levels increased significantly; and Prussia blue staining showed no significant increase in the number of positive cells in the Fth-KO group.
above results show that under physiological conditions, Fth-KO mouse cortical iron metabolism is broken, which in turn shows that the iron storage function of neuron ferrite played an important role in maintaining iron stability in the brain.
To further explore the role of neuron Fth in brain trauma, the researchers detected differences in iron metabolism and iron death-related indicators in the control group and Fth-KO group, and found significant changes in iron overload, iron transfer, lipid peroxidation, neurodegenerativeity, etc.
suggests that Fth-KO can increase iron death from brain trauma compared to wild mice (Figure 2).
At this point, if melatonin is treated in Fth-KO mice, the above-mentioned melatonin anti-iron death effect in wild mice will be largely eliminated, suggesting that melatonin may play a neuroprotective role by inhibiting iron death mediated by the neuron Fth (Figure 3).
2 Fth-KO can aggravate iron death caused by brain trauma Figure 3: This study schematic has become a serious health problem worldwide due to the remarkable characteristics of high occurrence, mortality and disability rate of brain trauma.
Given that iron death may play an important role in the physical process of brain trauma, finding new ways to block cell death may help reduce the risk of brain trauma and increase the likely recovery. the
results reveal the mechanism of Fth's role in iron death caused by brain trauma, prove that melatonin is a feasible iron death inhibitor, and provide a new way of thinking for understanding the various biological functions of melatonin.
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