Assessment of the Role of Aldehyde Dehydrogenase-2 in Nociception in a Mice Model of Complex Regional Pain Syndrome Type I
Julia Frare1, Patrícia Rodrigues1, Fernanda Viero1, Diulle Peres1, Náthaly Ruviaro1, Vanessa Zambelli2, Gabriela Trevisan1
1Federal University of Santa Maria, 2Federal University of São Paulo
Objective:
This study aims to investigate the role of ALDH-2 in a CRPS-I model in mice following treatment with Alda-1.
Background:
Complex regional pain syndrome type I (CRPS-I) is a disabling condition triggered by ischemia and reperfusion after physical injury. Tissue damage releases reactive substances such as 4-hydroxy-2-nonenal (4-HNE), linked to pain in CRPS-I through TRPA1 activation. The enzyme aldehyde dehydrogenase-2 (ALDH-2) metabolizes 4-HNE, but its role in CRPS-I remains unclear. Alda-1, an ALDH-2 activator, has shown analgesic effects in ischemia models.
Design/Methods:
C57BL/6 mice (UFSM; 4736260620) were evaluated for baseline mechanical and cold allodynia, rotarod performance, and body weight prior to osmotic minipump implantation. Chronic post-ischemia pain (CPIP) was induced by applying an elastic tourniquet to the right hind paw for two hours to promote ischemia followed by reperfusion. Mice were then treated with Alda-1 or vehicle (16 mg/kg) for 15 days via osmotic minipump. Behavioral assessments were performed daily, and nest building was analyzed between the 15th and 16th days. The 4-HNE protein adducts and NADPH oxidase enzyme in the dorsal horn of the spinal cord (DHSC; L3-L5), spinal cord, and nerve sciatic were assessed.
Results:
Mice receiving vehicle exhibited marked mechanical, cold allodynia compared to controls, whereas Alda-1 treatment significantly reduced both pain responses throughout the experiment. No alterations in body weight or locomotor activity were observed. Additionally, Alda-1 preserved nest building behavior, which was reduced in CPIP-vehicle animals, indicating potential antinociceptive and neuroprotective effects. Alda-1 treatment significantly reduced 4-HNE protein adduct levels, whereas NADPH oxidase (NOX) expression remained unchanged.
Conclusions:
The results of our study indicate a promising approach for CRPS-I. ALDH-2 activation by Alda-1 significantly attenuated nociception, associated with reduced 4-HNE levels. Our findings suggest that ALDH-2 activation may be an alternative for pain management in CRPS-I and other ischemic diseases.
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