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The role of aldehyde dehydrogenase 2 and 4-hydroxynonenal in neuropathic pain

Grant number: 13/05937-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2013
Effective date (End): September 03, 2014
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Vanessa Olzon Zambelli
Grantee:Beatriz Stein Neto
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Aldehyde-dehydrogenase 2 (ALDH-2) is a mitochondrial enzyme responsible for the metabolism of toxic aldehydes, including the removal of 4-hydroxynonenal (4-HNE), an aldehyde generated during mitochondrial lipid peroxidation. 4-HNE accumulation has been recently related to increased pain. Recent data from our group has been shown that activation of ALDH2, using a small molecule (Alda-1), displays a potent antinoceptive effect in a model of carrageenan-induced hyperalgesia (intraplantar, i.pl) in rats. Biochemical analysis show that carrageenan increases 4-HNE-protein adducts (high affinity chemical bindings) in the paw of carrageenan-treated animals, and Alda-1 decreases the adduct formation. These data show for the first time that ALDH-2 activation induces analgesia by reducing aldehydic load. However, the role of ALDH-2 and 4-HNE in neuropathic pain control as well as the mechanisms involved in this effect are still unknown. Pilot studies indicated Alda-1 blocks neuropathic pain in a model of chronic constriction injury (CCI) of the sciatic nerve. Therefore, we propose to investigate the involvement of ALDH2 in neurophatic pain development and to characterize the involvement of toxic aldehydes, such as 4-HNE, in this process. To address this question we will investigate whether (a) the endogenous ALDH2 is involved in CCI-induced chronic pain in wild type and dominant negative transgenic mice for the ALDH2, or using selective ALDH2 inhibitor and Alda-1; (b) ALDH2 enzymatic activity is changed in CCI-induced neuropathic pain in mice; using enzymatic assays and Alda-1 as control; (c) whether CCI induces formation of 4-HNE adducts in both spinal cord (L4-L6)and dorsal root ganglia (DRG) using western blotting (results will be validated by using Alda-1). Taken together, our proposal will contribute to the identification of a new molecular process involved in neuropathic pain as well as the development of new pharmacological tools in pain control. (AU)