Figure 6.

The mechanisms of CIPN induced by protease inhibitors: Protease inhibitors increase the metabolism of sphingolipids in astrocytes, which leads to the formation of ceramide, sphingosine-1 phosphate (S1P) and dihydrosphingosine-1-phosphate (DH-S1P), which by binding to astrocyte receptors, increase the release of presynaptic glutamate at the level of the dorsal horn, which leads to the development of neuropathic pain. Moreover, bortezomib-induced mitochondrial damage increases the production of reactive oxygen species (ROS), which results in enzyme, protein and lipid damage within the neurons as well as induces apoptotic changes in peripheral nerves. These processes alter the excitability of peripheral neurons, whereas the attraction and activation of T-lymphocytes and monocytes, as well as the increases in the production of reactive oxygen species (ROS) induce the release and elevation of pro-inflammatory cytokines (interleukins and chemokines). These processes lead to nociceptor sensitization, the hyperexcitability of peripheral neurons and the development of neuroinflammation.