Computational study of the therapeutic potentials of a new series of imidazole derivatives against SARS-CoV-2.

Owing to the urgent need for therapeutic interventions against the SARS-coronavirus 2 (SARS-CoV-2) pandemic, we employed an in silico approach to evaluate the SARS-CoV-2 inhibitory potential of newly synthesized imidazoles. The inhibitory potentials of the compounds against SARS-CoV-2 drug targets - main protease (Mpro), spike protein (Spro) and RNA-dependent RNA polymerase (RdRp) were investigated through molecular docking analysis. The binding free energy of the protein-ligand complexes were estimated, pharmacophore models were generated and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the compounds were determined. The compounds displayed various levels of binding affinities for the SARS-CoV-2 drug targets. Bisimidazole C2 scored highest against all the targets, with its aromatic rings including the two imidazole groups contributing to the binding. Among the phenyl-substituted 1H-imidazoles, C9 scored highest against all targets. C11 scored highest against Spro and C12 against Mpro and RdRp among the thiophene-imidazoles. The compounds interacted with HIS 41 - CYS 145 and GLU 288 - ASP 289 - GLU 290 of Mpro, ASN 501 of Spro receptor binding motif and some active site amino acids of RdRp. These novel imidazole compounds could be further developed as drug candidates against SARS-CoV-2 following lead optimization and experimental studies.

Postpartum State, but Not Maternal Caregiving or Level of Anxiety, Increases Medial Prefrontal Cortex GAD65 and vGAT in Female Rats.

Upregulation of the inhibitory neurotransmitter, GABA, is involved in many of the behavioral differences between postpartum and nulliparous female rodents. This is evidenced by studies showing that pharmacological blockade of GABAergic activity impairs maternal caregiving and postpartum affective behaviors. However, the influence of motherhood on the capacity for GABA synthesis or release in the medial prefrontal cortex (mPFC; brain region involved in many social and affective behaviors) is not well-understood. Western blotting was used to compare postpartum and nulliparous rats in protein levels of the 65-kD isoform of glutamic acid decarboxylase (GAD65; synthesizes most GABA released from terminals) and vesicular GABA transporter (vGAT; accumulates GABA into synaptic vesicles for release) in the mPFC. We found that postpartum mothers had higher GAD65 and vGAT compared to virgins, but such differences were not found between maternally sensitized and non-sensitized virgins, indicating that reproduction rather than just the display of maternal caregiving is required. To test whether GAD65 and vGAT levels in the mPFC were more specifically related to anxiety-related behavior within postpartum mothers, we selected 8 low-anxiety and 8 high-anxiety dams based on their time spent in the open arms of an elevated plus maze on postpartum day 7. There were no significant differences between the anxiety groups in either GAD65 or vGAT levels. These data further indicate that frontal cortical GABA is affected by female reproduction and more likely contributes to differences in the display of socioemotional behaviors across, but not within, female reproductive state.

Study of Adverse Drug Effects of Direct-Acting Antivirals for Chronic HCV Infection at Fayoum Governorate, Egypt - A Pharmacovigilance Study.

BACKGROUND: Different combinations of Direct Antiviral Agents (DAAs) have been used against different Hepatitis C Virus (HCV) genotypes and in different types of patients. Despite being effective and characterized by a very low rate of adverse effects in clinical trials, few data are available on adverse events in real life studies. OBJECTIVES: The aim of this study was to identify the incidence and pattern of Adverse Drug Reactions (ADRs) caused by DAAs; daclatasvir and sofosbuvir and their combination with ribavirin and to assess the causality and the severity of the reported ADRs. METHODS: A prospective observational study was conducted over six months at treatment HCV center of Health Insurance Hospital in Fayoum Governorate, Egypt. A pre-tested, interviewed structured questionnaire was used by authors to gather required data from 345 enrolled patients regarding demographics, co-morbidity and ADRs. Causality and severity of ADRs were assessed. RESULTS: According to our data. we have found that 75.7% (261out of 345) patients reported 36 different ADRs involving different systems, of these 1.2% experienced Serious Adverse Events (SAEs), including three deaths (0.9%). A majority of ADRs were more significantly reported with ribavirin-containing regimen. Out of 345 patients, 23.5% have comorbidities. Among them, 92.6% reported ADRs. Causality assessment of ADRs by WHO-UMC criteria revealed that 38.89% were probable while 61.11% were possible. CONCLUSION: New antiviral drugs require careful follow-up of any significant adverse event that may occur and can affect adherence. Special population as the elderly and those with comorbidities should always be managed with caution to avoid development of serious side effects.

L-amino acid decarboxylase- and tyrosine hydroxylase-immunoreactive cells in the extended olfactory amygdala and elsewhere in the adult prairie vole brain.

Neurons synthesizing dopamine (DA) are widely distributed in the brain and implicated in a tremendous number of physiological and behavioral functions, including socioreproductive behaviors in rodents. We have recently been investigating the possible involvement of sex- and species-specific TH-immunoreactive (TH-ir) cells in the male prairie vole (Microtus ochrogaster) principal bed nucleus of the stria terminalis (pBST) and posterodorsal medial amygdala (MeApd) in the chemosensory control of their monogamous pairbonding and parenting behaviors. These TH-ir cells are not immunoreactive for dopamine-beta-hydroxylase (DBH), suggesting they are not noradrenergic but possibly DAergic. A DAergic phenotype would require them to contain aromatic L-amino acid decarboxylase (AADC) and here we examined the existence of cells immunoreactive for both TH and AADC in the pBST and MeApd of adult virgin male and female prairie voles. We also investigated the presence of TH/AADC cells in the anteroventral periventricular nucleus (AVPV), medial preoptic area (MPO), arcuate nucleus (ARH), zona incerta (ZI), substantia nigra (SN) and ventral tegmental area (VTA). Among our findings were: (1) the pBST and MeApd each contained completely non-overlapping distributions of TH-ir and AADC-ir cells, (2) the AVPV contained surprisingly few AADC-ir cells and almost no TH-ir cells contained AADC-ir, (3) approximately 60% of the TH-ir cells in the MPO, ARH, and ZI also contained AADC-ir, (4) unexpectedly, only about half of TH-ir cells in the SN and VTA contained AADC-ir, and (5) notable populations of AADC-ir cells were found outside traditional monoamine-synthesizing regions, including some sites that do not contain AADC-ir cells in adult laboratory rats or cats (medial septum and cerebral cortex). In the absence of the chemical requirements to produce DA, monoenzymatic TH-ir cells in the virgin adult prairie vole pBST, MeApd, and elsewhere in their brain may instead produce L-DOPA as an end product and use it as a neurotransmitter or neuromodulator, similar to what has been observed for monoenzymatic TH-synthesizing cells in the laboratory rat brain.

Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions.

New cells, including neurons, arise in several brain regions during puberty in rats. Sex differences in pubertal addition of cells coincide with adult sexual dimorphisms: for each region, the sex that gains more cells during puberty has a larger volume in adulthood. Removing gonadal hormones before puberty eliminates these sex differences, indicating that gonadal steroids direct the addition of new cells during puberty to maintain and accentuate sexual dimorphisms in the adult brain.

Female pheromones stimulate release of luteinizing hormone and testosterone without altering GnRH mRNA in adult male Syrian hamsters (Mesocricetus auratus).

In many species chemosensory stimuli function as important signals that influence reproductive status. Neurons synthesizing the peptide gonadotropin-releasing hormone (GnRH) are critical mediators of reproductive function via their regulation of the hypothalamic-pituitary-gonadal (HPG) axis, and they are thought to be responsive to chemosensory information. In the present study, we sought to elucidate the effects of female chemosensory stimuli on the HPG axis in sexually naive adult male Syrian hamsters. In Experiment 1, serial blood samples were collected from catheterized male hamsters following exposure to female pheromones in order to characterize the luteinizing hormone (LH) response to this chemosensory stimulus. In Experiment 2, brains and terminal blood samples were collected from animals 0, 60, and 120 min following pheromone exposure. GnRH mRNA was measured in brain tissue sections using in situ hybridization, and plasma concentrations of LH and testosterone were measured using radioimmunoassay. Data from Experiment 1 indicated that female pheromones elicited a rapid rise in plasma LH that peaked at 15 min and returned to baseline 45 min after exposure. In Experiment 2, testosterone was elevated in terminal blood samples obtained 60 min, but not 120 min, after exposure to pheromones. LH levels were unaffected at both of these time points. The chemosensory-induced increases in LH and testosterone release were not accompanied by subsequent changes in GnRH mRNA over the time course studied. These data suggest that while activation of the male HPG axis by female pheromones involves release of GnRH, it does not involve increases in GnRH mRNA 1-2 h after pheromonal stimulation as a mechanism for replenishment of released peptide.