Name: Rafael Moraes AguiarType: MSc dissertationPublication date: 08/05/2019Advisor:

Name	Role
Adair Roberto Soares dos Santos	Advisor *

Examining board:

Name	Role
Adair Roberto Soares dos Santos	Advisor *
Cristina Martins e Silva	Co advisor *
Lívia Carla de Melo Rodrigues	External Examiner *
Fabiana Vasconcelos Campos	Internal Examiner *

Summary: Indroduction: Post-traumatic stress disorder (PTSD) is one of the most prevalent and disabling psychiatric disorders developed by exposure to traumatic events such as wars, accidents, assaults, kidnackers, violations, assaults, abductions, traffic accidents, fires, wars, sexual and/or physical violence among others. Although most patients recover from this disorder, through psychotherapy and/or pharmacotherapy, most patients experience relapses, resistance or response refractory to treatment, in addition to deregulation of the hypothalamic-pituitary adrenal (HPA) axis associated with alterations in cortisol secretion and prognosis of severe neuronal degeneration in amygdala hippocampus and prefrontal cortex. Among the alternative therapies, the use of medicinal plants or their derivatives had shown to be highly attractive for the treatment of several neuropathologies. In this context, rosmarinic acid (RA) treatment has previously exhibited antioxidant, neuroprotective, and antidepressant-like effects. RA is a polyphenol derived from caffeic acid and 3.4- dihydroxyphenylacetic acid found in several plants, mainly in Rosemary (Rosmarinus officinalis). Objective: In the present study, we tested whether RA has a therapeutic potential to alleviate the symptoms and biochemical alterations in a pre-clinical murine model of PTSD. Material and methods: Male Swiss mice were traumatic to a PTSD induction model through a strategy of inescapable foot shock (ISF). Behavioral evaluation at the level of locomotor activity and emotional evaluation in a dose-response curve paradigm was also performed. Influences on learning and memory were evaluated through the inhibitory avoidance test. The expressed amounts of the proteins neurotrophic factors derived from the brain (BDNF) and from the glial cells (GDNF) via Western Blot were taken. Results and conclusion: The behavioral analysis showed a U-shaped result in the dose-response curve paradigm of the animals treated with RA, pointing the dose of 30 mg/kg as the most efficient in reversing the freezing behavior (F(5, 78) = 18.36, p ≤ 0.0001], considered the main behavior in the etological analysis of trauma models. The dose of AR 30 mg/kg also maintained the levels of corticosterone 24h after the traumatic event [F(3, 22) = 5.93, p = 0.0040], maintaining at levels similar to that of healthy animals up to 48h after the traumatic event [F(3, 24) = 5.235, p = 0.0064], suggesting a protective effect of RA over the HPA axis. The inhibitory avoidance test showed no negative or nonspecific action on memory or learning in the treatment with RA at a dose of 30 mg/kg [F(1, 31) = 167.1, p ≤ 0.0001]. The AR 30 mg/kg, despite the non-statistical difference, maintained the tendency to regulate the expression profile of BDNF and GDNF at the level of healthy animals. Through these results, it is possible to assign RA as an alternative and safe tool for the treatment and development of PTSD. In conclusion, we strongly suggest that the treatment with RA in the 30mg/kg dose regimen may be a potential drug to relieve debilitating behavioral symptoms and to regulate the expressive biochemical alterations triggered in PTSD patients.

Key words: Posttraumatic stress disorder (PTSD), rosmarinic acid (RA), hypothalamic-pituitary-adrenal (HPA) axis, inhibitory avoidance (IA), neurotrofic factors, neuroinflammation.Access to document