Key Takeaways & Executive Findings
- •• Tetramethylpyrazine attenuates iron accumulation and ferroptosis after spinal cord injury by modulating the Keap-1/Nrf2 signaling pathway. • Treatment with tetramethylpyrazine upregulates Nrf2, ferritin heavy chain 1, and ferritin light chain expression while downregulating Keap-1, thereby restoring iron homeostasis. • Tetramethylpyrazine improves neuronal structural integrity and reduces iron deposition in a rat model of spinal cord injury. • The Keap-1/Nrf2 pathway represents a promising therapeutic target for spinal cord injury, and tetramethylpyrazine may serve as a potential neuroprotective agent.
Abstract
BACKGROUND: The clinical management of spinal cord injury remains a global medical challenge, with no currently available ideal treatment. Traditional Chinese medicine has therapeutic advantages for spinal cord injury. Notably, tetramethylpyrazine, an active component of Chuanxiong rhizome, has been shown to significantly suppress pathological responses including neuroinflammation and apoptosis after spinal cord injury, exhibiting promising therapeutic potential. However, its mechanisms require further elucidation. OBJECTIVE: To investigate the regulatory effects of tetramethylpyrazine on the Kelch-like ECH-associated protein 1/nuclear factor-erythroid 2-related factor 2 (Keap-1/Nrf2) signaling pathway and iron metabolism following spinal cord injury, and to elucidate its neuroprotective mechanisms. METHODS: Thirty-six Sprague-Dawley rats were randomly allocated into: sham group (laminectomy+saline, n=12), model group (spinal cord injury+saline, n=12), and tetramethylpyrazine group (spinal cord injury+tetramethylpyrazine, n=12). After 4 weeks, neuronal morphology was assessed by Nissl staining; iron deposition by Prussian blue staining; iron content by iron assay kit; expression of Keap-1, ferritin heavy chain 1 (FTH1), and ferritin light chain (FTL) by immunohistochemistry; Nrf2 expression by immunofluorescence; protein levels of Nrf2, FTH1, and FTL by western blot; and mRNA levels of Nrf2, Keap-1, FTH1, and FTL by RT-PCR. RESULTS AND CONCLUSION: Compared with the sham group, the model group showed disrupted neuronal structure, increased iron deposition and iron content, increased Keap-1 expression, and decreased Nrf2, FTH1, and FTL expression at both protein and mRNA levels (P < 0.01). Tetramethylpyrazine treatment significantly ameliorated these changes, as evidenced by improved neuronal structure, reduced iron deposition and content, decreased Keap-1 expression, and increased Nrf2, FTH1, and FTL expression compared with the model group (P < 0.01). These findings indicate that tetramethylpyrazine can regulate the Keap-1/Nrf2 signaling pathway and its downstream targets FTH1 and FTL, thereby improving iron metabolism disorders and facilitating spinal cord injury repair.
1. Introduction
Spinal cord injury (SCI) is a severe central nervous system injury and a worldwide medical challenge, with no ideal treatment currently available. Traditional therapies, such as high-dose methylprednisolone, have limited efficacy and are associated with complications. Other drugs, including gangliosides and edaravone, have not gained clinical acceptance. The pathological cascade following SCI is complex, and iron metabolism disorders can trigger lipid peroxidation via the Fenton reaction, leading to ferroptosis of neural cells, which exacerbates injury and impedes repair. Therefore, maintaining iron homeostasis is crucial for SCI recovery.
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a widely expressed transcription factor in the nervous system that plays a key role in antioxidant defense. Its negative regulator, Kelch-like ECH-associated protein 1 (Keap-1), controls Nrf2 activity. Under normal conditions, Keap-1 binds Nrf2 and promotes its degradation. Upon oxidative stress, Nrf2 dissociates and translocates to the nucleus, activating the transcription of antioxidant genes, including ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL), which are critical for iron storage and detoxification. Thus, the Keap-1/Nrf2 pathway is a potential target for modulating iron metabolism after SCI.
Tetramethylpyrazine (TMP), an active alkaloid from the traditional Chinese medicine Chuanxiong (Ligusticum chuanxiong), has demonstrated neuroprotective effects in various neurological disorders. Previous studies have shown that TMP can suppress neuroinflammation and apoptosis after SCI, but its effects on iron metabolism and the underlying mechanisms remain unclear. This study aimed to investigate whether TMP improves iron metabolism disorders after SCI via the Keap-1/Nrf2 signaling pathway, using a rat model.
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ZHENG Peng, JIA Xiaoning, TAO Jingwei, FAN Xiao (2026). Tetramethylpyrazine improves iron metabolism disorders in a rat model of spinal cord injury via the Keap-1/Nrf2 signaling pathway. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21277
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Frequently Asked Questions
What is the role of tetramethylpyrazine in spinal cord injury?
Tetramethylpyrazine, an active component of Chuanxiong, has been shown to improve iron metabolism disorders after spinal cord injury by modulating the Keap-1/Nrf2 signaling pathway, thereby reducing iron accumulation and ferroptosis, and promoting neuronal repair.
How does tetramethylpyrazine affect the Keap-1/Nrf2 pathway?
Tetramethylpyrazine downregulates Keap-1 expression and upregulates Nrf2 expression, leading to increased expression of downstream antioxidant proteins such as ferritin heavy chain 1 and ferritin light chain, which help restore iron homeostasis.
What is the significance of iron metabolism in spinal cord injury?
Iron metabolism disorders after spinal cord injury can trigger Fenton reactions, leading to lipid peroxidation and ferroptosis of neural cells, which exacerbates injury. Maintaining iron homeostasis is crucial for functional recovery.
What were the main findings of this study?
The study demonstrated that tetramethylpyrazine treatment significantly reduced iron deposition and content, improved neuronal structure, and modulated the expression of Keap-1, Nrf2, ferritin heavy chain 1, and ferritin light chain in a rat model of spinal cord injury, indicating its potential as a therapeutic agent.
What is the clinical relevance of this research?
This research provides experimental evidence supporting the use of tetramethylpyrazine as a potential treatment for spinal cord injury, offering a novel approach targeting iron metabolism and the Keap-1/Nrf2 pathway, which could be translated into clinical applications.
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