ROLE OF ALDEHYDE DEHYDROGENASE-2 IN THE DEVELOPMENT OF ALCOHOL NEUROPATHY IN MICE

• Grant number: 22/15640-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Johann Ciotti Back Silva
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Chronic and abusive alcohol consumption is a public health problem that affects 76.3 million individuals worldwide and 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, sensory changes, including chronic hypernociception. The mechanisms involved in the development and maintenance of this type of neuropathy are not yet fully elucidated. Data from the literature show a strong correlation between the prevalence of this disease and the mutation that leads to the loss of function of the enzyme aldehyde dehydrogenase-2 (ALDH2), also known as ALDH2*2, found in approximately 40% of the East Asian population. ALDH2 is the main enzyme responsible for the clearance of toxic aldehydes that accumulate after consumption of ethanol (ie, acetaldehyde). Additionally, this enzyme metabolizes aldehydes resulting from oxidative stress, such as 4-hydroxy-2-nonenal, (4-HNE). Studies carried out by our group showed that both acetaldehyde and 4-HNE are endogenously produced in inflammatory processes and the activation of ALDH2, by a small molecule called Alda-1, induces antinociception by reducing the levels of these aldehydes. Despite this evidence, we still do not know the role of this enzyme in the development and progression of alcoholic neuropathic pain. We hypothesized that impaired ALDH2 activity associated with chronic alcohol intake anticipates the development of neurotoxicity and chronic hypernociception due to elevated levels of acetaldehyde and 4-HNE in nociceptive pathways.Thus, the objective of this work is to investigate the participation of ALDH2 in the development and maintenance of alcoholic neuropathy. For this purpose, wild and transgenic animals with loss of ALDH2 function (ALDH2*1*2) will be used, in the presence or absence of AD6626 (a molecule derived from Alda-1, with oral activity) that will be submitted to chronic treatment with ethanol (1g/Kg/day for 6 days). The mechanical and thermal nociceptive threshold will be evaluated using von Frey filaments and tail dipping test, respectively. Motor coordination, locomotor activity and anxiety-like behavior will be evaluated using the rotarod and open field test, respectively. Finally, the participation of ALDH2 on ethanol-induced neurotoxicity will be evaluated. Therefore, we will investigate the levels of lipid peroxidation, 4-HNE, neuronal activation (ATF-3 and c-FOS) and cell death (Bax, Bcl-2, Caspase 3) in the cell bodies of nociceptive neurons (DRG) and spinal cord , by T-bars and western blot. With this project, we hope to advance knowledge about the mechanisms involved in alcoholic neuropathy, as well as identify a new therapeutic class with antinociceptive potential, such as ALDH2 activators.