Investigação dos mecanismos envolvidos no efeito tipo-ansiolítico do 7- cloro-4-(fenilselanil) quinolina em camundongos

Abstract

Anxiety is the most commonly diagnosed and treated psychiatric disease in the world. Faced with this situation, research to elucidate the mechanisms involved in anxiety and the search for new therapeutic agents has attracted the interest of researchers. Recently, we demonstrated the promising anxiolytic action of 7-chloro-4-(phenylselanyl) quinolone (4-PSQ) in mice. For this reason, the first objective of this study was to expand our previous findings by investigating the contribution of serotoninergic and GABAergic systems in the anxiolytic action of this compound in male adult Swiss mice. Initially, the involvement of the serotonergic system was evaluated, so the mice received pretreatment with pindolol (1 mg/kg, intraperitoneal (i.p.), a non-selective 5-HT1A/1B receptor antagonist) or WAY100635 (0.7 mg/kg, i.p., a non-selective 5-HT1A receptor antagonist) or ketanserin (0.3 mg/kg, i.p., a selective 5-HT2A/2C receptor antagonist), and after 15 min received treatment with 4-PSQ (50 mg/kg, per oral (p.o.)). Pretreatment with the antagonists blocked the anxiolytic effect caused by 4-PSQ in the elevated plus-maze (EPM) test. The contribution of the GABAergic system in animals was investigated by pretreatment with pentylenetetrazole (35 mg/kg, i.p., a GABAA receptor antagonist) (PTZ). Twenty four hours after the animals received the treatment with 4-PSQ (50 mg/kg, p.o.). The administration of the compound reduced PTZ-induced anxiety in the EPM test. Later, this group of animals was euthanized and blood was collected to determine the levels of corticosterone and the cerebral cortex and hippocampus were removed to determine the mRNA expression levels of cAMP response element-binding protein (CREB), brain derived neurotrophic factor (BDNF) and nuclear factor kappa B (NF-κB), as well as the Na+, K+ ATPase activity and reactive species levels (RS). A single dose of 4-PSQ was able to significantly reverse the increase in RS and corticosterone levels, as well as the decrease of CREB and BDNF expression in the cerebral structures and increase of NF-κB expression in the hippocampus. Additionally, 4-PSQ was also able to restore Na+, K+ ATPase activity in the evaluated brain structures. Here, we showed that the modulation of serotonergic and GABAergic systems and factors related to neurogenesis, oxidative status, and Na+ , K+ ATPase activity contributes to the anxiolytic effect of 4-PSQ and reinforces the therapeutical potential of this compound for the treatment of anxiety.