The role of aldehyde dehydrogenase-2 enzyme and reactive aldehydes in neuropathic pain

• Grant number: 16/14385-0
• Support type: Scholarships in Brazil - Master
• Effective date (Start): March 01, 2017
• Effective date (End): February 28, 2019
• Field of knowledge: Biological Sciences - 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 dehydrogenese-2 (ALDH-2) is a mithocondrial enzyme which metabolizes reactive aldehydes. Aldehydes accumulation such as 4-hidroxinonenal (4-HNE) has been related to increased pain. 4-HNE is an aldehyde formed by the oxidation of unsatured lipids in the mitochondrial membrane. Recently, our group showed that activation of ALDH2, using a small molecule called Alda-1, displays antinoceptive effect in inflammatory pain models induced by carrageenan in rats. However, the role of ALDH2 in neuropathic pain control is unknown. Biochemical analysis have showed that carrageenan increased 4-HNE adducts formation with tissue proteins. Alda-1 reduces the levels of these adducts. This data showed, for the first time, that the activation of ALDH2 induces analgesia associated with a decrease of toxic aldehydes. However, the role of ALDH-2 in neuropathic pain, as well in the mechanisms involved in this phenomenon is unknown. Previous experiments, performed during the Scientific Initiation of the student, indicate that Alda-1 exhibit antinociceptive effect in the neuropathic pain model in mice. Therefore, we propose to characterize the involvement of ALDH2 enzyme in chronic nociception, evaluating the contribution of the endogenous aldehydes, such a 4-HNE, in this process. To address this question we will investigate (a) the involvement of endogenous ALDH2 in the pain induced by chronic constriction injury (CCI) using pharmacological treatments (inhibitor of ALDH2 and Alda-1); (b) whether the CCI interferes with ALDH2 activity, by using enzymatic assays, using Alda-1 as control; (c) whether the CCI contributes to 4-HNE adducts in spinal cord, dorsal root ganglia (DRG) and sciatic nerve proteins; (d) the development of neuropathic pain in transgenic mice carriers of Asian allele ALDH2*2 carrying the E487K mutation in the enzyme ALDH2. Together, the data will allow us to identify the cellular and molecular mechanisms involved in the antinociceptive the effect of Alda-1 in neuropathic pain and contribute to the caracterization of a new cell target to control chronic pain.