부산대학교 도서관

Chronic neuropathic pain is often caused by peripheral nerve injury. We previously demonstrated that spinal expression of serum and glucocorticoid-inducible kinase-1 (SGK-1) is associated with exacerbation of pain hypersensitivity in nerve-injured mice, but there are no available strategies to inhibit SGK-1 in the spinal cord. In this study, we attempted to search for clinically approved drug that has the ability to inhibit SGK-1 activity. As result of screening 1,271 clinically approved drugs, sulfasalazine (SSZ) was identified as potent inhibitor of SGK-1. SSZ is a prodrug composed of 5-aminosalicylic acid and sulfapyridine linked by an azo bond, but the azo bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice alleviated mechanical pain hypersensitivity, no 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 breast cancer resistance protein (BCRP). Febuxostat (FBX) has been demonstrated to inhibit BCRP. Concomitant oral administration of SSZ with FBX increased the spinal concentrations of SSZ and allowed to exert its anti-neuropathic pain effects in nerve-injured mice, suggesting that FBX can improve the distribution of SSZ to the spinal cord after its oral administration by inhibiting the function of BCRP in intestinal epithelial cells and blood–cerebrospinal fluid barrier.