Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice
| العنوان: | Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice |
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| المؤلفون: | Grant R. Budas, Che-Hong Chen, Julio Cear Batista Ferreira, Natalia Gabriele Hosch, Vanessa Zambelli, Barbara Behr Martins, Queren A. Alcantara, Daria Mochly-Rosen |
| المصدر: | Biomolecules; Volume 11; Issue 12; Pages: 1798 Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Biomolecules Biomolecules, Vol 11, Iss 1798, p 1798 (2021) |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Pain, Protein Kinase C-epsilon, Mitochondrion, Carrageenan, Biochemistry, Neuroprotection, Microbiology, Article, Gene Knockout Techniques, Mice, oxidative stress, neuroprotection, protein kinase, neurodegeneration, hyperalgesia, medicine, Animals, Gene Knock-In Techniques, Protein kinase A, Molecular Biology, ALDH2, Aldehydes, Chemistry, Activator (genetics), Aldehyde Dehydrogenase, Mitochondrial, QR1-502, Cell biology, Mitochondria, Disease Models, Animal, Protein Transport, Hyperalgesia, Knockout mouse, MITOCÔNDRIAS, Nociceptor, medicine.symptom |
| الوصف: | Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2218-273X |
| DOI: | 10.3390/biom11121798 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e90d5b37b8989faaccd807a11ea10427 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e90d5b37b8989faaccd807a11ea10427 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2218273X |
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| DOI: | 10.3390/biom11121798 |