Evaluation of the effect of caffeine on the transcriptional control of genes in the Nrf2/Txn1/Nlrp3 axis

Abstract

Caffeine is an alkaloid molecule derived from the most popular and consumed xanthine in the world, has a molecular formula C8H10N4O2, and is mainly used as a stimulant of the Central Nervous System (CNS). Its short-term effects are mainly characterized by the reduction of deficits associated with sleep loss. As a neurological agent, caffeine decreases adenosine-activated transmission by blocking subunits of A1 and A2A type receptors. However, there are studies that indicate that caffeine is capable of triggering neuroprotective mechanisms, not only related to receptors but also has anti-inflammatory actions. There is a growing body of evidence showing that psychostimulant drugs induce neuroadaptive changes through epigenetic mechanisms. Studies have demonstrated the action of caffeine both in the transcriptional control of enzymes involved in DNA methylation, as well as in the dynamics of post-translational modifications that occur in histones. In this sense, this project aims to evaluate the neuroprotective effect of caffeine pretreatment on epigenetic transcriptional control of the Nrf2/Txn1/Nlrp3 axis in a lipopolysaccharide-induced neuroinflammation model. For this purpose, adult male Swiss mice (3 to 5 months) kept in the Laboratory of Oxidative Stress Laboratory (LABOX) were used. Neuroinflammation was induced by administering a single injection of lipopolysaccharide (LPS) (0.33mg/kg) 15 minutes after acute caffeine treatment (6mg/kg) (CEUA protocol number PP00760). Brain structures were collected 24 h after neuroinflammation induction and total RNA and genomic DNA were extracted by TRIzol/Chloroform and Phenol/Chloroform/Isoamyl alcohol methods, respectively. Analysis of gene expression and methylation of the promoter region of Nrf2/Txn1/NLRP3 genes will be performed by qPCR after extraction and processing of genomic material. With the results obtained, we hope to contribute to the elucidation of the neuroprotective effects of caffeine.(AU)