Background: Tetramethylpyrazine (TMP) is a natural alkaloid compound with antioxidant and neuroprotective effects. We hypothesized that TMP could exert neuroprotective effects by inhibiting ferroptosis through modulating iron metabolism, but its mechanism is unclear. Through in vivo and in vitro experiments, we have explored how TMP can regulate neurons’ iron metabolism through the NRF2/ARE pathway to Inhibit ferroptosis.Methods: In the in vivo experiment, the effects of TMP on nerve function and secondary spinal cord injury were observed through behavioral tests and morphology staining. Transmission electron microscopy, molecular biology tests and immunofluorescence staining were used to investigate the role of TMP in the regulation of iron metabolism and ferroptosis through the Nrf2/ARE pathway. Using in vitro experiments to investigate the mechanism of TMP in inhibiting ferroptosis through the Nrf2/ARE pathway.Results: Firstly, through in vivo experiments, we found that TMP improves motor function of rats with spinal cord injury, reduces spinal cord tissue damage and nerve cell death caused by secondary injury. Moreover, neuronal death and the formation of spinal cord cavities are inhibited by TMP. By regulating lipid peroxidation, TMP can inhibit mitochondrial damage and reduce ROS accumulation. Our study also demonstrated that TMP regulates iron metabolism through the NRF2/ARE pathway to inhibit ferroptosis and repair spinal cord injury. To further explore the regulatory mechanisms of TMP we down-regulating Nrf2 expression in subsequent in vitro experiments. We find that a key ferroptosis pathway, lipid peroxidation, can be regulated by TMP. Additionally, TMP inhibits iron overload-mediated ferroptosis by increasing Nrf2 transcriptional activity.Conclusion: A regulatory effect of TMP on the NRF2/ARE pathway was found in both in vitro and in vivo experiments. It promotes the transcription and translation of iron metabolizing and antioxidant molecules. Our study explored the inhibitory effect of TMP on ferroptosis from the iron metabolism pathway and provided new ideas for the treatment of SCI.

The tetramethylpyrazine-loaded conductive hydrogel could diminish the breakdown of the blood–spinal cord barrier and protect against neuronal cell death to synergistically restore neurological functions post spinal cord injury.

Objective: Biomaterials loaded with ingredients derived from traditional Chinese medicine (TCM) are viewed as a promising strategy for treating spinal cord injury (SCI). However, a comprehensive analysis of the existing literature on this topic has not yet been conducted. Therefore, this paper systematically reviews researches related to this approach, aiming to identify gaps and shortcomings in the field.Methods: PubMed, EMBASE, Web of Science, Chinese Biomedical Literature, Wanfang, and China National Knowledge Infrastructure (CNKI) were searched for retrieving studies on biomaterials loaded with TCM ingredients published from their inception to October 2024. Two reviewers performed screening of search results, information extraction, and literature quality assessment independently.Results: For this systematic review, 41 publications were included. Six TCM ingredients-paclitaxel, curcumin, tetramethylpyrazine, resveratrol, berberine, and tanshinone IIA were combined with biomaterials for treatment of SCI. Biomaterials were categorized into hydrogels, biodegradable scaffolds, nanoparticles, and microspheres according to the type of scaffold. These drug delivery systems exhibit commendable biocompatibility, drug-loading capacity, and drug-release capabilities, and in combination with TCM ingredients, synergistically contribute to anti-oxidative stress, anti-inflammatory, neuroprotective, and anti-apoptotic effects.Conclusion: These studies demonstrated the efficacy of biomaterials loaded with TCM ingredients in facilitating motor function recovery and neuroprotection in SCI rats, providing evidence for future research. However, in the complex microenvironment of SCI, achieving the maximum drug loading capacity of TCM ingredients within biomaterials, along with sustained and controlled release to fully exert their pharmacological effects, remains a major challenge for future research.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42024505000.

Background: This study is the first to summarize the evidence on how the use of anti-inflammatory drugs during acute pain has an impact on the development of chronic pain. Methods: Randomized controlled trials retrieved from nine databases included anti-inflammatory drugs (NSAIDs or steroids) versus non-anti-inflammatory drugs in patients with acute pain and reported the incidence of chronic pain. No specified date, age, sex, or language restrictions. Subgroup analyses were performed according to pain classification, follow-up time, and medication. The GRADE method was used to evaluate quality of evidence. Results: A total of 29 trials (5220 patients) were included. Steroids or NSAIDs did not reduce the incidence of chronic nociceptive pain. Steroid use in acute phase significantly reduced the incidence of chronic neuropathic pain. In subgroup analysis, benefits were observed for methylprednisolone and dexamethasone, with some adverse effects. Steroids or NSAIDs were statistically significant in reducing pain intensity over 1 year, but the effect size was too small, and whether the long-term effect is clinically relevant needs to be further studied. Conclusion: Quality of the evidence was low to moderate. No drug can be recommended to prevent chronic nociceptive pain. Injections of steroids (methylprednisolone or dexamethasone) during the acute phase reduce the incidence of chronic neuropathic pain, but most included studies also used local anesthetics. The results are indirect and need to be interpreted with caution. The pooled data effect sizes for pain intensity were small, so the clinical relevance was unclear. Study registration PROSPERO (CRD42022367030).