Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

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.

Hydrogen Sulfide Increases the Analgesic Effects of µ- and δ-Opioid Receptors during Neuropathic Pain: Pathways Implicated

“…Indeed, elevated levels of 4-HNE, an endogenous α,β-unsaturated aldehyde generated during oxidative stress [ 40 ], were found in animals with carrageenan-induced inflammation [ 41 ] and with spinal cord injury-induced neuropathic pain [ 42 ]. Other studies have further revealed that the injection of 4-HNE incites mechanical allodynia [ 43 ], and that an accumulation of 4-HNE may disrupt many cell signaling pathways, including the regulation of apoptosis [ 40 , 44 ]. Moreover, increased levels of 4-HNE and/or BAX have been detected in the AMG and PAG of nerve-injured animals, and in the AMG of animals with osteoarthritis pain [ 23 , 24 ].…”

Plasma Concentration of the Lipid Peroxidation (LP) Biomarker 4-Ηydroxynonenal (4-HNE) in Benign and Cancer Patients

“…Kärkkäinen et al (15) reported earlier that RSB-analgesia does significantly increase the SOD-1 concentrations immediately after operation, but SOD-1 concentration drops back 24 h postoperatively. Martins et al (21) have previously demonstrated that accumulation of 4-HNE plays a major role in the establishment and progression of pain showing that the 4-HNE is an endogenous aldehyde generated during oxidative stress, mainly through the LP process in the mitochondria. Therefore, increased 4-HNE adducts in the injured tissue positively correlates with pain (21).…”

“…Martins et al (21) have previously demonstrated that accumulation of 4-HNE plays a major role in the establishment and progression of pain showing that the 4-HNE is an endogenous aldehyde generated during oxidative stress, mainly through the LP process in the mitochondria. Therefore, increased 4-HNE adducts in the injured tissue positively correlates with pain (21). Sauer et al (22) showed that the Delphinidin (DEL), a plant-derived antioxidant with potential to treat inflammatory pain, prevented 4-HNE-induced mechanical hyperalgesia, cold allodynia, and an increase in the intracellular calcium concentration into transient receptor potential ankyrin 1 expressing cells.…”

Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium

“…Endogenous aldehydes can also trigger pain [ 24 , 25 ]. Martins et al reported that ALDH2 is an important PKCε substrate in reducing aldehyde-induced hyperalgesia in rodents [ 26 ]. The clearance of 4-HNE by ALDH2 mitigated the aldehyde-mediated mechanical hypersensitivity in rodents and mice carrying the ALDH2*2 variant displayed persistent hypersensitivity due to the accumulation of 4-HNE adducts.…”