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Contribution of the Mitocondrial Aldehyde dehydrogenase-2 Enzime on Neuropathic Pain.

Grant number: 17/16071-5
Support type:Regular Research Grants
Duration: December 01, 2017 - December 31, 2020
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Vanessa Olzon Zambelli
Grantee:Vanessa Olzon Zambelli
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Julio Cesar Batista Ferreira

Abstract

Adequate control of neuropathic pain is still a challenge and an unmet clinical need. In addition, adverse effects and rapid development of tolerance have been associated to some of the drugs currently used for the treatment of pain, evidencing the need for new analgesic substances. Aldehyde-dehydrogenase 2 (ALDH-2) is a mitochondrial enzyme responsible for the metabolism of toxic aldehydes, including the removal of 4-hydroxynonenal (4-HNE). This aldehyde is generated by the lipidic peroxidation of the mitochondrial membrane and induces covalent modification of important biomolecules including proteins (Michaelis adducts). The results of this modification are protein inactivation and cellular dysfunction. We demonstrated recently that besides 4-HNE, malondialdehyde and acetaldehyde are involved in inflammatory nociception and that ALDH2 is a key enzyme for the pain control. However, to our knowledge, there is no study investigating the role of this enzyme in neuropathic pain. Then, our hypothesis is that the mitochondrial dysfunction induced by ALDH2 inactivation and redox disbalance observed in peripheral neuropathy, increases the aldehydic load leading to cellular collapse and neuropathic pain aggravation. Using gain and loss of function strategies we aim to investigate the involvement of this mitochondrial enzyme on the development and progression of an experimental neuropathic pain model. Therefore, a small molecule that activates ALDH-2, Alda-1 and an ALDH2*2 inactivating mutation in mice will be used. Taken together, the results obtained may allow us to identify the cellular and molecular mechanisms involved in the genesis and progression of neuropathic pain, contributing for the characterization of a new molecular target in neuropathic pain control. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BOZI, LUIZ H. M.; CAMPOS, JULIANE C.; ZAMBELLI, VANESSA O.; FERREIRA, NIKOLAS D.; FERREIRA, JULIO C. B. Mitochondrially-targeted treatment strategies. MOLECULAR ASPECTS OF MEDICINE, v. 71, FEB 2020. Web of Science Citations: 0.

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