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Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain
Jia-You Wei1, Cui-Cui Liu2, Han-Dong Ouyang3
1Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Abstract:
Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment.
Insights
Bortezomib chemotherapy causes persistent pain by increasing methylglyoxal in the spinal cord. This activates RAGE/STAT3 signaling, leading to pain sensitization. Metformin and RAGE blockers reduce this pain.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Bortezomib is a key chemotherapy for multiple myeloma, but its mechanism causing persistent pain is unknown.
- Bortezomib-induced pain is a recognized clinical issue requiring mechanistic understanding.
Purpose of the Study:
- To elucidate the mechanism of bortezomib-induced persistent pain.
- To investigate the role of methylglyoxal, RAGE, and STAT3 in bortezomib-induced neuropathic pain.
Main Methods:
- A rat model using systemic bortezomib administration.
- Measurement of methylglyoxal, RAGE, and p-STAT3 in the spinal dorsal horn.
- Intervention with metformin, RAGE blockers, and STAT3 inhibitors/knockdown.
Main Results:
- Bortezomib induced mechanical allodynia and increased spinal methylglyoxal, RAGE, and p-STAT3.
- Methylglyoxal and RAGE activation were critical for central sensitization and allodynia.
- STAT3 inhibition or knockdown also attenuated bortezomib-induced pain.
Conclusions:
- Methylglyoxal accumulation in the spinal cord activates the RAGE/STAT3 pathway.
- This pathway contributes to central sensitization and persistent pain following bortezomib treatment.
- Targeting methylglyoxal or RAGE/STAT3 may offer therapeutic strategies for bortezomib-induced pain.
