Diniz, C. R. A. F. | Search bioRxiv

bioRxiv2017

Elastase-2 knockout mice display anxiogenic- and antidepressant-like phenotype: putative role for BDNF metabolism in prefrontal cortex

Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANG II). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the later. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.

animal behavior and cognition↗

bioRxiv2016

Antidepressant-like effects of P2 purinergic antagonist PPADS is dependent on serotonergic and noradrenergic integrity

Depression is a common mental disorder affecting around 350 million of individuals globally. The available antidepressant drug monotherapy is far from ideal since it has an efficiency of approximately 60% and takes around 3-4 week to achieve clinical improvement. Attention has been paid to the purinergic signaling regarding neuropathological mechanisms, since it might be involved in psychiatric disorders, such as depression. In fact, blockade of purinergic P2X receptors induces antidepressant-like effects in preclinical models. However, the mechanisms involved in this effect are not yet completely understood. The present work investigated the interplay between a P2X receptor antagonist (PPADS) and clinically used antidepressant drugs on the forced swimming test, an animal model predictive of antidepressant effect. We observed significant synergistic effect of PPADS combined with sub-effective doses of fluoxetine or reboxetine in the FST. Moreover, depletion of serotonergic or noradrenergic systems, with PCPA and DSP-4 treatment, respectively, blocked the antidepressant-like effect of PPADS. No increase in locomotion, a possible source of confusion on FST data, was detected in any of the treated groups. Our results indicate the antidepressant-like effect of PPADS depends on the integrity of serotonergic and noradrenergic transmission.

pharmacology and toxicology↗