Involvement of monoaminergic targets in the antidepressant- and anxiolytic-like effects of the synthetic alkamide riparin IV: Elucidation of further mechanisms through pharmacological, neurochemistry and computational approaches.

Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

Virulence characteristics of genetically related isolates of group B streptococci from bovines and humans.

The present study had the objective of evaluating the pathogenic potential of the genetically related strains of Streptococcus agalactiae no. 80427 (human origin) and no. 87159 (bovine origin), and comparing the results with two other strains isolated from bovine mastitis (no. 87244) and invasive human infection (no. 90356), with no genetic or epidemiologic relationship between them or with the first 2 isolates. Virulence genes hylB (hyaluronidase) and lmb (laminin-binding protein) were detected in the 4 strains, and genes bac (beta protein) and bca (alpha protein) were only detected in human strains. The protein profile obtained using SDS-PAGE did not indicate any differences between the 4 strains. No significant difference was detected between human and bovine strains in the assays of adherence to and invasion of 16HBe cells, as well as in the resistance assay for intracellular bacterial survival in macrophages. However, the strain 87159 exhibited a greater survival in the killing test with whole human blood and was more virulent in newborn mice than the 80427 strain. The strain 87244 was not virulent in mice. These data suggest that isolates of human and bovine origins may express similar virulence attributes, leading to a possible, however limited, dissemination.