Traumatic brain injury (TBI) is a universal leading cause of long-term neurological disability and causes a huge burden to an ever-growing population. Moderate intensity of treadmill exercise has been recognized as an efficient intervention to combat TBI-induced motor and cognitive disorders, yet the underlying mechanism is still unclear. Ferroptosis is known to be highly implicated in TBI pathophysiology, and the anti-ferroptosis effects of treadmill exercise have been reported in other neurological diseases except for TBI. In addition to cytokine induction, recent evidence has demonstrated the involvement of the stimulator of interferon genes (STING) pathway in ferroptosis. Therefore, we examined the possibility that treadmill exercise might inhibit TBI-induced ferroptosis via STING pathway. In this study, we first found that a series of ferroptosis-related characteristics, including abnormal iron homeostasis, decreased glutathione peroxidase 4 (Gpx4), and increased lipid peroxidation, were detected at 44 days post TBI, substantiating the involvement of ferroptosis at the chronic stage following TBI. Furthermore, treadmill exercise potently decreased the aforementioned ferroptosis-related changes, suggesting the anti-ferroptosis role of treadmill exercise following TBI. In addition to alleviating neurodegeneration, treadmill exercise effectively reduced anxiety, enhanced spatial memory recovery, and improved social novelty post TBI. Interestingly, STING knockdown also obtained the similar anti-ferroptosis effects after TBI. More importantly, overexpression of STING largely reversed the ferroptosis inactivation caused by treadmill exercise following TBI. To conclude, moderate-intensity treadmill exercise rescues TBI-induced ferroptosis and cognitive deficits at least in part via STING pathway, broadening our understanding of neuroprotective effects induced by treadmill exercise against TBI.
Neurofilament light chain (NF-L) plays critical roles in synapses that are relevant to neuropsychiatric diseases. Despite postmortem evidence that NF-L is decreased in opiate abusers, its role and underlying mechanisms remain largely unknown. We found that the microinjection of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) into the ventrolateral orbital cortex (VLO) attenuated chronic morphine-induced behavioral sensitization. The microinjection of TSA blocked the chronic morphine-induced decrease of NF-L. However, our chromatin immunoprecipitation (ChIP)-qPCR results indicated that this effect was not due to the acetylation of histone H3-Lysine 9 and 14 binding to the NF-L promotor. In line with the behavioral phenotype, the microinjection of TSA also blocked the chronic morphine-induced increase of p-ERK/p-CREB/p-NF-L. Finally, we compared chronic and acute morphine-induced behavioral sensitization. We found that although both chronic and acute morphine-induced behavioral sensitization were accompanied by an increase of p-CREB/p-NF-L, TSA exhibited opposing effects on behavioral phenotype and molecular changes at different addiction contexts. Thus, our findings revealed a novel role of NF-L in morphine-induced behavioral sensitization, and therefore provided some correlational evidence of the involvement of NF-L in opiate addiction.
As one form of stroke, intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease, which has high morbidity and mortality, and lacks of effective medical treatment. An increased in ltration of in ammatory cytokines coupled with pyroptotic cell death is involved in the pathophysiological process of ICH. However, little is known about whether concomitant fracture patients have the same progression of in ammation and pyroptosis. Hence, we respectively established mouse ICH model and ICH with bilateral tibial fracture model (MI) to explore the potential cross-talk between the above two injuries. We found that MI obviously reversed the expressions of pyroptosis-associated proteins, which were remarkably up-regulated at the acute phase after ICH. Similar results were observed in neuronal expressions via double immunostaining. Furthermore, brain edema was also signi cantly alleviated in mice who suffered MI, when compared with ICH alone. To better clarify the potent mechanisms mediated this cross-talk, recombinant mouse interleukin-13 (IL-13) was used to investigate its effect on pyroptosis in the mouse MI model, in which lower level of IL-13 was observed. Remarkably, IL-13 administration reawakened cell death, which was mirrored by the re-upregulation of pyroptosis-associated proteins and PI positive cell counts. The results of hemorrhage volume and behavioral tests further con rmed its critical role in regulating the neurological functions. Besides, IL-13-treated MI group showed poor outcomes of fracture healing. To sum up, our research indicates that controlling the IL-13 content in acute phase would be a promising target in in uencing the outcomes of brain injury and fracture, and meanwhile, provides new evidence in repairing compound injuries in clinics.
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