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Dual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy
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SYSNO ASEP 0556128 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Dual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy Author(s) Adámek, Pavel (FGU-C) RID, ORCID, SAI
Heleš, Mário (FGU-C) ORCID, RID, SAI
Bhattacharyya, Anirban (FGU-C) RID, SAI, ORCID
Pontearso, Monica (FGU-C) ORCID
Slepička, Jakub (FGU-C) ORCID
Paleček, Jiří (FGU-C) RID, ORCIDSource Title Journal of Neuroscience. - : Society for Neuroscience - ISSN 0270-6474
Roč. 42, č. 9 (2022), s. 1864-1881Number of pages 18 s. Language eng - English Country US - United States Keywords spinal-cord ; dorsal horn ; glycine ; neuropathy ; pain ; pi3k ; trpv1 OECD category Neurosciences (including psychophysiology R&D Projects GA20-19136S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 000766775600005 EID SCOPUS 85125680816 DOI 10.1523/JNEUROSCI.1324-21.2021 Annotation 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. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2023 Electronic address https://doi.org/10.1523/JNEUROSCI.1324-21.2021
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