Inhibition of Notch pathway Alleviates nab-Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing HMGB1/TLR4 Signaling in Spinal Cord

Abstract

Paclitaxel is widely used in clinical treatment of cancer and peripheral neuropathy is a common adverse side effect of paclitaxel. Diverse mechanisms contribute to the development and maintenance of paclitaxel-induced peripheral neuropathy. However, the role of spinal notch pathway in paclitaxel-induced peripheral neuropathy is not completely understood. In this study, we established an animal model of paclitaxel-induced peripheral neuropathy using nab-paclitaxel. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of nab-paclitaxel, accompanied by increased expression of Notch pathway related proteins, enhanced apoptosis, neuronal and axonal injury, and glial responses. Using DAPT, an inhibitor for notch pathway, could restore the mechanical and thermal threshold and decrease apoptosis, neuronal and axonal injury, and glial responses induced by nab-paclitaxel. DAPT relieved paclitaxel-induced peripheral neuropathy by inhibiting activation of Notch pathway related proteins, then inhibited HMGB1/TLR4 signaling pathway, reduced the expression of inflammatory factor tumor necrosis factor-α and interleukin-1β and accelerated nerve regeneration. Taking together, our study demonstrated that Notch pathway may serve as a potential target for paclitaxel-induced peripheral neuropathy intervention.

Soluble Epoxide Hydrolase Inhibitor TPPU Alleviates Nab-Paclitaxel-Induced Peripheral Neuropathic Pain via Suppressing NF-κB Signalling in the Spinal Cord of a Rat

“…Microglia and astrocytes are also most affected by a reduction in the inflammatory response [ 26 ]. Our previous study also found that inhibition of the Notch pathway could reduce the expression of inflammatory factors accompanied by repressive glia response through the HMGB1/TLR4 signalling pathway in a rat model of nab-paclitaxel-induced peripheral neuropathy [ 27 ]. All the results suggested that TPPU may suppress the activation of the glial response through the regulation of inflammatory cytokines.…”