Role of aldehyde dehydrogenase 2 in neuroinflammation induced by chronic constriction of the sciatic nerve

Abstract

Aldehyde dehydrogenase-2 (ALDH-2) is a mitochondrial enzyme responsible for eliminating toxic aldehydes from the peroxidation of unsaturated lipids present in the mitochondrial membrane. Initial studies carried out by our group, using a small activating molecule of ALDH-2, Alda-1, demonstrated that this molecule has a potent antinociceptive effect in an acute model of inflammatory hypernociception, induced by carrageenan and in a model of chronic neuropathy, induced by sciatic nerve constriction (SNC) in mice. This effect is due to the decrease in reactive aldehydes, such as 4-HNE in the injured tissues that are involved with nociceptive pathways such as paw, sciatic nerve and spinal cord. It is known that the activation of glial cells and macrophages present in the nociceptive pathways constitute a key mechanism in the installation, chronification and sensitization of both central and peripheral neuropathic pain. It is possible that the release of reactive aldehydes by these cells contributes to the induced neuroinflammation by the SNC. Thus, this project aims to investigate the role of ALDH2 in the production of 4-HNE in peripheral and central neuroinflammation. For that, we will use strategies of gain and loss of function of ALDH2 in animals submitted to SNC. For the gain of function, the animals will be treated with the activator of ALDH2, Alda-1 and for the loss of function, we will use transgenic mice with a mutation in this enzyme, which confers a loss of up to 100% in their enzymatic activity (ALDH2*2). Our specific objectives are: to characterize the formation of adducts (high affinity covalent bond) of 4-HNE with neuronal proteins and glial cells (astrocytes and microglia) in the spinal cord and nerve fiber proteins, macrophages and Schwann cells in the nerve sciatic of mice submitted to SNC, using techniques of immunofluorescence and cell co-localization. (AU)