期刊
BIOCHEMICAL PHARMACOLOGY
卷 185, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114411
关键词
Sulfasalazine (SSZ); Serine; threonine protein kinase; Serum-and glucocorticoid-inducible kinase-1; (Sgk-1); Neuropathic pain; ABC transporter G2; Circadian rhythm
资金
- Japan for the Promotion of Science [16H02636, 18H04019, 20K21484]
- AMED [JP18am0101091]
- Grants-in-Aid for Scientific Research [20K21484, 16H02636, 18H04019] Funding Source: KAKEN
Diurnal variations in pain hypersensitivity are common in chronic pain disorders, with exacerbation of neuropathic pain hypersensitivity depending on glucocorticoid secretion. The study found that the drug SSZ has inhibitory effects on SGK-1 in the spinal cord, and concomitant administration with FBX can enhance its anti-neuropathic pain effects.
Diurnal variations in pain hypersensitivity are common in chronic pain disorders. Temporal exacerbation of neuropathic pain hypersensitivity is dependent on diurnal variations in glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression of serum- and glucocorticoid-inducible kinase-1 (SGK-1) is associated with glucocorticoid- induced exacerbation of pain hypersensitivity, but there are no available strategies to inhibit SGK-1 in the spinal cord. By screening a clinically approved drug library (more than 1,200 drugs), we found that sulfasalazine (SSZ) has inhibitory effects on SGK-1. SSZ is a prodrug composed of 5aminosalicylic acid and sulfapyridine linked by N??N bond, which is therapeutically effective for inflammatory bowel diseases. However, the N??N bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice significantly alleviated mechanical pain hypersensitivity, no significant anti- neuropathic pain effects of SSZ were detected after oral administration due to its low bioavailability and limited spinal distribution, which were associated with efflux by the xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant oral administration of SSZ with febuxostat (FBX), which is an approved drug to inhibit BCRP, improved the distribution of SSZ to the spinal cord. The concomitant oral administration with FBX also increased the anti-neuropathic pain effects of SSZ. Our study revealed a previously unrecognized pharmacological effect of SSZ to alleviate SGK-1-induced painful peripheral neuropathy, and concomitant oral administration of SSZ with FBX may also be a preventative option for diurnal exacerbation of neuropathic pain hypersensitivity.
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