Circular RNA SMEK1 promotes neuropathic pain in rats through targeting microRNA-216a-5p to mediate Thioredoxin Interacting Protein (TXNIP) expression

Neuropathic pain (NP) is a disease induced by damage to the nervous system. A large number of studies have manifested that circular RNAs (circRNAs) are key in the development of neurological diseases. However, the role of circRNA in NP remains ambiguous. In this study, the biological function and molecular mechanism of circSMEK1 were investigated in NP. NP rat and cell models were established by chronic contractile injury (CCI) surgery and lipopolysaccharide (LPS) treatment, separately. The results exposed that circSMEK1 and TXNIP were up-regulated in NP, while miR-216a-5p was down-regulated. The claw retraction threshold and claw retraction latency in rats were elevated and reduced separately via knockdown circSMEK1 and miR-216a-5p. Meanwhile, knockout circSMEK1 or elevated miR-216a-5p declined inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL6 in spinal cord, and the activation of microglia, but promoted the polarization of microglia into anti-inflammatory type, while up-regulation of circSMEK1 or knockdown of miR-216a-5p was opposite. Mechanism studies demonstrated that circSMEK1 mediated TXNIP expression through competitive adsorption of miR-216a-5p. Functional rescue experiments manifested that the suppressive effect of circSMEK1 knockdown on NP was reversed by declined miR-216a-5p simultaneously. In conclusion, the results of this study affirmed that circSMEK1 facilitates NP inflammation and microglia M1 polarization by modulating miR-216a-5p/TXNIP axis, providing a new molecular target for the future treatment of NP.