Sex-Related and Brain Regional Differences of URB597 Effects on Modulation of MAPK/PI3K Signaling in Chronically Stressed Rats.

Gender differences exist in depression incidence and antidepressant efficacy. In addition to the neurotransmission theory of depression, inflammation and disrupted signaling pathways play crucial roles in the pathophysiology of depression. Endocannabinoids offer a novel approach to treat inflammatory and emotional disorders like depression. URB597, a FAAH inhibitor, reduces endocannabinoids breakdown. In this study, URB597 effects were investigated on the pro-inflammatory cytokine interleukin-1ß (IL-1ß), nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3), and mitogen-activated protein kinase (MAPK)/ phosphatidylinositol 3-hydroxy kinase/ protein kinase B (PI3K) signaling in the hippocampus and the medial prefrontal cortex (mPFC) of male and female rats subjected to chronic unpredictable stress (CUS). The results show that CUS induces depression-like behaviors, and the URB597 exhibited antidepressant-like effects inboth sexes. URB597 reduced the CUS-induced NLRP3 and IL-1ß increase in the hippocampus and mPFC of both sexes. URB597 increased the reduced pERK1/2 levels in the mPFC of both sexes and hippocampus of CUS males. URB597 also prevented the increase in p38 phosphorylation after chronic stress in the mPFC of both sexes and in the hippocampus of the females. The CUS suppressed the downstream Akt phosphorylation in the mPFC and hippocampi of both sexes. URB597 produced an up-regulation of the pAkt in the hippocampus of the CUS animals but did not affect the pAkt in the mPFC. These data demonstrated a sexual dimorphism in the neural cell signaling, and in the effects of endocannabinoids, and indicated these dimorphisms are region-specific.

Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats.

Wistar-Kyoto (WKY) rats subjected to chronic mild stress (CMS) represent a valid model of treatment-resistant depression (TRD). Considering that depression is more prevalent in women than in men, in the present study, female rats were used. We investigated the effect of CMS on behavior and different factors involved in neuroinflammatory processes and neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC) of WKY female rats. The results show that unstressed WKY females exhibited hypolocomotion, decreased exploratory behavior, and an increase in the total grooming time. After exposure to CMS, WKY females displayed intensified grooming. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed signaling and inflammatory pathways in the hippocampus and mPFC. The findings indicate reduced BDNF and elevated levels levels of IL-1ß in both brain structures and NLRP3 in the mPFC of unstressed WKY female rats. WKY rats subjected to CMS showed a further decrease in BDNF levels and increased IL-1ß and NLRP3 in these brain structures. WKY showed reduced pERK1/2 and increased pp38 levels in both brain structures, while CMS revealed a further increase of pp38 in WKY in these brain structures. Expressions of p110ß and pAKT were decreased in the hippocampus and mPFC of WKY rats. The CMS further suppressed p110 and the downstream AKT phosphorylation in the hippocampus, but did not affect the p110 and pAKT in the mPFC. Our findings indicate behavioral and molecular differences in genetically vulnerable WKY female rats and in their response to CMS that may be involved in TRD.

Homozygous-Recessive Characteristics as a Biomarker of Predisposition for COVID-19.

Coronavirus disease (COVID-19), a new form of severe acute respiratory syndrome, has caused a global pandemic. The aim of this study was to analyze homozygous-recessive characteristics (HRC) in the group of COVID-19 patients, considering their gender, forms of the disease (mild and severe symptoms), risk factors: hypertension, diabetes mellitus type 2, hyperlipidemia, smoking habits, and the distribution of ABO blood group. Using the HRC test, we analyzed 20 HRCs in a sample of 321 individuals: 205 patients and 116 controls. The average HRC in patients was significantly higher than controls, as well as in patients with severe symptoms compared to patients with mild symptoms. The patients with higher HRC (cut-off ≤5.5) experienced a significantly increased risk of disease of 2.3 times (OR = 2.315, p < .0005). Our results indicate that the HRC test could be used as a screening in recognizing predisposition for COVID-19.