Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: Pre-Clinical Evaluation of Novel Pharmacological Targets for the Treatment of Alcohol Use Disorders: Focus on Endocannabinoid and Inflammatory System

Alcohol is the most prevalent recreational substance, with increasing consumption among youth and adolescents. Adolescents subjected to intermittent alcohol use are likely to take part in heavy episodic drinking subsequently. The coexistence of alcohol use disorders with concurrent mental illnesses, such as anxiety and depression, together with comorbid organic problems such as alcoholic liver disease, typically detrimentally affects cognition and memory. mediators of a homeostatic mechanism that reduces alcohol neurotoxicity. Synaptische Neurotransmission und Kunststoffität erfordern bioaktive Phospholipiden als Schutzmechanismen. Lysophosphatid acid (LPA; 1-acyl-2-hydroxy-sn-glycero-3-phosphate) is a lipid mediator found in plasma and biological fluids, including cerebrospinal fluid, in various LPA species. It is synthesized in cell membranes or via enzymatic lipid cleavage in the bloodstream. Mostly present in the central nervous system, LPA1 affects several developmental processes. The LPA/LPA1 signaling pathway is important in alcoholism, according to many studies. In mice with extreme alcohol intoxication, LPA receptor deletion or pharmacological suppression decreased ethanol sensitivity and increased anxiety-like behavior. Other research shows that LPA affects liver tissue regeneration, fibrosis, inflammation, and injury responses in addition to neurological development.In the first project, we investigated whether LPA promotes liver and fat tissue inflammation. In rats, elevated LPA levels caused hepatic inflammation. Thus, we used a reliable preclinical model of continuous voluntary ethanol exposure in a two-bottle choice paradigm. This study examined the effects of extended alcohol exposure on locomotion, anxiety-like behaviors (measured by open field and elevated-plus maze), and cognitive deficits (evaluated by new recognition object test) in wild type (WT) and maLPA knockout (KO) mice. The behavioral modulation is linked to "genotype" and "sex" but not "ethanol exposure", possibly due to the ethanol exposure model used. A significant modulation of endocannbinoid signaling system biomarkers and an increase in inflammatory signaling system biomarkers in liver tissue of both genders may be due to continuous ethanol exposure, LPA receptor deletion, and hepatic damage. For the second project, we studied binge drinking and its effects on heart and liver tissue, along with the effects of treatments (NF10-360 and NOS). Binge drinking (BD) involves consuming a lot of alcohol quickly, followed by abstention. Although the criteria are disputed, several definitions of BD have been presented. Alcohol consumption is a typical statistic, although gender, consumption rate, frequency, and others are also included. Heavy drinking promotes hepatocellular apoptosis, which can progress to alcoholic liver disease, steatosis, fibrosis, cirrhosis, and cancer. Chronic alcohol use, especially binge drinking, disrupts lysosomal function, causing hepatocytes to accumulate damaged proteins and organelles. Chronic and binge alcohol consumption enhance cardiomyocyte apoptosis and autophagy injury in cardiac tissue, causing alcoholic cardiomyopathy (ACM), heart failure, and arrhythmias. Dual PPARα/γ agonists aim to improve lipid and glucose metabolism by activating both receptors simultaneously.We investigated the impact of dual PPARα/γ agonists and ligands on alcohol consumption. We used an intensive binge drinking program, a viable preclinical model. This study investigated the preventive effects of NAE-modeled drugs NF 10-360 (Dual PPARα/γ ligands) and NOS (Dual PPARα/VR1 ligand) on cardiac and hepatic damage in Wistar rats. We measured endocannabinoid, inflammatory, and lipid metabolism indicators such as lipogenesis and lipo-oxidation pathway mRNA and protein levels. Apoptosis and necrosis markers were also evaluated. we employed an aggressive binge alcohol consumption regimen, a preclinical model of considerable validity. This study sought to delineate the protective effects of NAE-modeled compounds NF 10-360 (Dual PPARα/γ ligands) and NOS (Dual PPARα/VR1 ligand) against cardiac and hepatic damage in Wistar rats. We examined the mRNA levels and protein expression of the endocannabinoid signaling system, inflammatory signaling system, and indicators of lipid metabolism, including lipogenesis and the lipo-oxidation pathway. In addition, we examined the indicators of apoptosis and necrosis.