Background & Aims
Chronic and abusive alcohol consumption is a public health problem affecting 76.3 million individuals worldwide. This is directly related to several pathologies, including alcoholic neuropathy. Alcoholic neuropathy is a chronic condition characterized by axonal degeneration of sensory and motor nerve fibers, which results in motor deficit and sensory changes, including chronic hypernociception. The mechanisms involved in the development of this neuropathy are not yet fully elucidated. A promising target is the enzyme aldehyde dehydrogenase-2 (ALDH2) wich is the main enzyme responsible for the clearance of toxic aldehydes that accumulate after consumption of ethanol (ie, acetaldehyde). Additionally, this enzyme metabolizes painful aldehydes resulting from oxidative stress, such as 4-hydroxy-2-nonenal, (4-HNE). Thus, our aim was to investigate the participation of ALDH2 in the development and maintenance of alcoholic neuropathy.
Methods
We employed both wild-type and transgenic animals with reduced ALDH2 function (ALDH2*2). To induce alcoholic neuropathy, we administered ethanol daily (1g/kg, orally) for six weeks. For the activation of ALDH2, we administered AD6626 (40 mg/kg/day, orally). The mechanical and thermal nociceptive threshold were evaluated using von Frey filaments and tail flick test, respectively. Motor coordination and locomotor activity were evaluated using the rotarod and open field tests, respectively. ALDH2 expression and activity were evaluated in the spinal cord and liver, respectively. The 4-HNE levels were assessed in the spinal cord by immunoblot.
Results
Animals with reduced ALDH2 activity (ALDH2*2) exhibited mechanical hypernociception earlier than wild-type animals (second week 2 vs third, respectively). Notably, this hypernociception was more pronounced in the ALDH2*2 group in comparison to WT animals (44.73% vs. 8.72% in the second week; 90.39% vs. 79.05% in the fourth week; and 90.71% vs. 75.21% in the sixth week). Similar trends were observed for thermal hypernociception. AD6626 administration effectively reduced hypernociception in both WT and ALDH2*2 animals throughout the observation period. No motor differences were detected. As expected, the ALDH2 expression is decreased (71.02%) in ALDH2*2 when compared to WT mice, however, ethanol further reduced the ALDH2 activity in WT and ALDH2*2. AD6626 treatment restored the ALDH2 activity. Additionally, ethanol increases the 4-HNE protein adducts in WT and ALDH2*2 in the ventral horn and dorsal horn of the spinal cord.AD6626 completely blocks the aldehydic load in the spinal cord.
Conclusions
Our findings indicate that decreased ALDH2 activity accelerates and intensifies neuropathic hypernociception. The present work reveals the pivotal role of the ALDH2 enzyme in modulating the ethanol-induced aldehydic load and the onset of alcoholic neuropathy, as well as identifying a new therapeutic class to treat this condition.
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Presenting Author
Johann Ciotti Back Silva
Poster Authors
Johann Silva
Bachelor in Neuroscience
Federal University of ABC
Lead Author
Danielly Flores De Souza
Butantan Institute
Lead Author
Queren Alcantara Msc
Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, Brazil.
Lead Author
Natalia Gabriele Hösch
Butantan Institute
Lead Author
Bárbara Martins Msc
Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, Brazil.
Lead Author
Topics
- Mechanisms: Biological-Molecular and Cell Biology