Paclitaxel is a widely used chemotherapeutic agent for treating various solid tumors. However, resulting neuropathic pain, often a lifelong side effect of paclitaxel, can limit dosing and compromise optimal treatment. The choroid plexus, located in the brain ventricles, spreads peripheral inflammatory reactions into the brain. Our study is the first to analyze the effects of paclitaxel on inflammatory alterations in the choroid plexus. We hypothesized that the choroid plexus could respond directly to paclitaxel and simultaneously be indirectly altered via circulating damage-associated molecular patterns (DAMPs) produced by paclitaxel application. Using immunohistochemical and Western blot analysis, we examined the levels of toll-like receptor 9 (TLR9) and formyl peptide receptor 2 (FPR2), along with the pro-inflammatory cytokines interleukin 6 (IL6) and tumor necrosis factor α (TNFα) in choroid plexus epithelial cells of male Wistar rats following paclitaxel treatment. Moreover, we utilized an in vitro model of choroid plexus epithelial cells, the Z310 cells, to investigate the changes in these cells in response to paclitaxel and DAMPs (CpG ODN). Our results demonstrate that paclitaxel increases TLR9 and FPR2 levels in the choroid plexus while inducing IL6 and TNFα upregulation in both acute and chronic manners. In vitro experiments further revealed that paclitaxel directly interacts with epithelial cells of the choroid plexus, leading to increased levels of TLR9, FPR2, IL6, and TNFα. Additionally, treatment of cells with CpG ODN, an agonist of TLR9, elicited upregulation of IL6 and TNFα. Our findings determined that paclitaxel influences the choroid plexus through both direct and indirect mechanisms, resulting in inflammatory profile alterations. Given the pivotal role of the choroid plexus in brain homeostasis, a compromised choroid plexus following chemotherapy may facilitate the spread of peripheral inflammation into the brain, consequently exacerbating the development of neuropathic pain.

• Keywords
• DAMPs, PINP, blood-CSF barrier, choroid plexus, neuroinflammation, paclitaxel,
• Publication type
• Journal Article MeSH

The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra), a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behavior and pronociceptive signaling in DRGs and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, and increased PI3K/Akt signaling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA-approved drug with known side effects.SIGNIFICANCE STATEMENT We show that duvelisib, a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behavior in males and females and prevents pronociceptive signaling in DRGs and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.

• Keywords
• PI3K, TRPV1, dorsal horn, glycine, neuropathy, pain,
• MeSH
• Pain MeSH
• Phosphatidylinositol 3-Kinases MeSH
• Antineoplastic Agents, Phytogenic * pharmacology   MeSH
• Hyperalgesia chemically induced   drug therapy   prevention & control   MeSH
• Isoquinolines MeSH
• Rats MeSH
• Mice MeSH
• Peripheral Nervous System Diseases MeSH
• Neuralgia * chemically induced   drug therapy   prevention & control   MeSH
• Paclitaxel adverse effects   MeSH
• Purines MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• duvelisib MeSH Browser
• Antineoplastic Agents, Phytogenic * MeSH
• Isoquinolines MeSH
• Paclitaxel MeSH
• Purines MeSH