[goldmine848]

Fingolimod (FTY720) & Velcade-related neuropathy

by goldmine848 on Thu May 10, 2018 7:50 pm

As we all know, peripheral neuropathy from Velcade can be a difficult issue to deal with. This abstract can be difficult to read but the bottom line is that drugs in same class as fingolimod (FTY720), a drug currently used to treat multiple sclerosis, may alleviate neuropathy from Velcade.

Reference:

Stockstill, K, et al., "Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain," Journal of Experimental Medicine, Apr 2018 (full text of article)

Abstract:

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.