Effects of neuronal nitric oxide synthase inhibition on susceptibility to the development of anorexia nervosa-related behaviors in animals exposed to maternal deprivation.

• Grant number: 23/01686-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2023
• End date: December 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Sabrina Francesca de Souza Lisboa
• Grantee: Isabela Pavan Silva
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/19731-6 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD), AP.JP

Abstract

Anorexia nervosa (AN) is an eating disorder that predominantly affects women in adolescence, characterized by extreme weight loss, body image distortion, and caloric restriction. Although its etiology is still not well established, stressful events and childhood trauma can increase the susceptibility to eating disorders. A promising animal model for studying this aspect is neonatal maternal deprivation, which directly impacts the hypothalamic-pituitary-adrenal (HPA) axis, altering the adult animal's response to stressors, and predisposing an onset to psychiatric disorders, such as anxiety, depression, and eating disorders. The maternal deprivation in CD1 animals on postnatal day 9 (PND9) has shown relevant results, such as lower body weight in adulthood, less exploration in the center in the open field test, an increase in baseline plasma ACTH levels, and serotonergic turnover. In addition, there is negative regulation of mRNA transcription of corticotrophin-releasing hormone (CRH) in the paraventricular nucleus, and pro-opiomelanocortin (POMC) in the pituitary. There was also a significant increase in nitric oxide (NO) levels in the prefrontal cortex and hippocampus in male and female Wistar rats. Within this context, the nitric oxide pathway stands out because nitric oxide is a metabolite involved in the regulation of food intake and appetite, in addition to being a relevant neuromodulator and mediator of immunological processes. It can be synthesized from three isoforms of the nitric oxide synthase enzyme: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Studies revealed an exacerbated NO synthesis in patients with AN and an increased nNOS expression in animals that have undergone maternal separation. Based on this assumption, the present project aims to evaluate whether exposure of CD1 mice to neonatal maternal deprivation stress increases the susceptibility to the development of behaviors related to AN by an increase of nNOS activity and whether this panel will be reversed in animals treated with 7-Nitroindazole, a drug that inhibits this enzyme. Therefore, the analysis of these mechanisms would corroborate elucidating one of the facets involved in the etiopathogenesis of Anorexia Nervosa, highlighting the role of neonatal programming in the development of psychiatric disorders throughout the individual's growth.