Involvement of Aldehyde Dehydrogenase-2 in Central and Peripheral Neuroinflammation Induced by Alcoholic Neuropathy.

• Grant number: 24/22482-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2025
• End date: September 30, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Danielly Flores de Souza
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Chronic and excessive alcohol consumption is a public health issue that affects 76.3 million individuals worldwide and is directly associated with various pathologies, including alcoholic neuropathy. Alcoholic neuropathy is a chronic condition characterized by axonal degeneration of sensory and motor nerve fibers, resulting in motor deficits, sensory changes, including chronic hyperalgesia. The mechanisms involved in the development and maintenance of this type of neuropathy are not yet fully understood. Literature data show that there is a correlation between the prevalence of this disease and a mutation that leads to the loss of function of the enzyme aldehyde dehydrogenase-2 (ALDH2), also known as ALDH22, found in about 40% of the East Asian population. ALDH2 is the primary enzyme responsible for the clearance of toxic aldehydes that accumulate after ethanol consumption (i.e., acetaldehyde). Additionally, this enzyme metabolizes aldehydes resulting from oxidative stress, such as 4-hydroxy-2-nonenal (4-HNE). Studies conducted by our group have shown that impairment of ALDH2 activity, associated with chronic alcohol intake, accelerates the development of neurotoxicity and chronic hyperalgesia due to elevated levels of 4-HNE in nociceptive pathways. However, it is not yet known whether ALDH2 is correlated with neuroinflammation in this model. We hypothesize that the impairment of ALDH2 activity, associated with chronic alcohol intake, accelerates central and peripheral neuroinflammation, contributing to neurotoxicity and chronic hyperalgesia due to elevated levels of 4-HNE in nociceptive pathways. Thus, the aim of this study is to investigate the role of ALDH2 in ethanol-induced neuroinflammation. To this end, wild-type and transgenic animals with ALDH2 loss-of-function (ALDH21*2), with or without AD6626 (a molecule derived from Alda-1, with oral activity), will be subjected to chronic ethanol treatment. Mechanical and thermal nociceptive thresholds will be evaluated using von Frey filaments and tail immersion tests, respectively. Finally, levels of 4-HNE and glial cell activation (astrocytes and microglia) in the spinal cord and macrophage migration in the sciatic nerve will be assessed by western blot and immunofluorescence, respectively. With this project, we aim to advance knowledge of the mechanisms involved in alcoholic neuropathy, as well as identify a new therapeutic class with potential antinociceptive properties, such as ALDH2 activators. (AU)