Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice

Translated title
A ativação do eixo PKCε-ALDH2 previne a dor induzida por 4-HNE em camundongos

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Article
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English
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Open access
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CC BY
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Abstract
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.
Reference
Martins BB, Hösch NG, Alcantara QA, Budas GR., Chen C-H, Mochly-Rosen D, et al. Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice. Toxins. 2021 Nov; 11(12):1798. doi:10.3390/biom11121798.
Link to cite this reference
https://repositorio.butantan.gov.br/handle/butantan/4081
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Issue Date
2021


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