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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 ASEP0556128
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevDual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy
    Tvůrce(i) Adámek, Pavel (FGU-C) RID, ORCID, SAI
    Heleš, Mário (FGU-C) ORCID, RID
    Bhattacharyya, Anirban (FGU-C) RID, SAI, ORCID
    Pontearso, Monica (FGU-C)
    Slepička, Jakub (FGU-C)
    Paleček, Jiří (FGU-C) RID, ORCID
    Zdroj.dok.Journal of Neuroscience - ISSN 0270-6474
    Roč. 42, č. 9 (2022), s. 1864-1881
    Poč.str.18 s.
    Jazyk dok.eng - angličtina
    Země vyd.US - Spojené státy americké
    Klíč. slovaspinal-cord ; dorsal horn ; glycine ; neuropathy ; pain ; pi3k ; trpv1
    Obor OECDNeurosciences (including psychophysiology
    CEPGA20-19136S GA ČR - Grantová agentura ČR
    Institucionální podporaFGU-C - RVO:67985823
    UT WOS000766775600005
    EID SCOPUS85125680816
    DOI10.1523/JNEUROSCI.1324-21.2021
    AnotaceThe 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.
    PracovištěFyziologický ústav
    KontaktLucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
    Rok sběru2023
    Elektronická adresahttps://doi.org/10.1523/JNEUROSCI.1324-21.2021
Počet záznamů: 1