Anti-Inflammatory and Antioxidant Effects of Diosmetin-3-O-ß-d-Glucuronide, the Main Metabolite of Diosmin: Evidence from Ex Vivo Human Skin Models.

Diosmin is used to relieve chronic venous disease (CVD) symptoms. This study aimed to investigate the anti-inflammatory and antioxidant effects of diosmetin-3-O-ß-d-glucuronide, the major metabolite of diosmin, using human skin explants. The explants were exposed to substance P (inflammation model) or UVB irradiation (oxidative model) and to five diosmetin-3-O-ß-d-glucuronide concentrations. Inflammation was evaluated through interleukin-8 (IL-8) secretion measurements and capillary dilation observation, and oxidation was evaluated by measuring the hydrogen peroxide levels and observing cyclobutane pyrimidine dimers (CPDs). In substance-P-exposed explants, diosmetin-3-O-ß-d-glucuronide induced a significant decrease in IL-8 secretions, with a maximal effect at 2700 pg/mL (-49.6%), and it reduced the proportion of dilated capillaries and the mean luminal cross-sectional area (p < 0.0001 at all tested concentrations), indicating a vasoconstrictive effect. In UVB-irradiated fragments, diosmetin-3-O-ß-d-glucuronide induced a significant decrease in hydrogen peroxide production and in the number of CPD-positive cells, reaching a maximal effect at the concentration of 2700 pg/mL (-48.6% and -52.0%, respectively). Diosmetin-3-O-ß-d-glucuronide induced anti-inflammatory and antioxidant responses, with the maximal effect being reached at 2700 pg/mL and corresponding to the peak plasma concentration estimated after the oral intake of 600 mg of diosmin, the daily dose usually recommended for the treatment of CVD. These ex vivo findings suggest a protective role of diosmetin-3-O-ß-d-glucuronide against inflammatory and oxidative stress affecting the vascular system in CVD pathophysiology.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25-6981, increases glutamate neurotransmission and induces antidepressant-like effects.

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N-methyl-D-aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult-born GCs for antidepressant-like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B-containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)-(4-hydroxyphenyl)-(ßS)-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 µg each side) following a chronic fluoxetine (18 mg/kg/day) treatment-known to increase adult hippocampal neurogenesis-in a mouse model of anxiety/depression. Responses in a neurogenesis-dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma-aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid-acting antidepressant-like effect of local Ro25-6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine-independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.

Role of adult-born granule cells in the hippocampal functions: Focus on the GluN2B-containing NMDA receptors.

Adult-born granule cells constitute a small subpopulation of the dentate gyrus (DG) in the hippocampus. However, they greatly influence several hippocampus-dependent behaviors, suggesting that adult-born granule cells have specific roles that influence behavior. In order to understand how exactly these adult-born granule cells contribute to behavior, it is critical to understand the underlying electrophysiology and neurochemistry of these cells. Here, this review simultaneously focuses on the specific electrophysiological properties of adult-born granule cells, relying on the GluN2B subunit of NMDA glutamate receptors, and how it influences neurochemistry throughout the brain. Especially in a critical age from 4 to 6 weeks post-division during which they modulate hippocampal functions, adult-born granule cells exhibit a higher intrinsic excitability and an enhanced long-term potentiation. Their stimulation decreases the overall excitation/inhibition balance of the DG via recruitment of local interneurons, and in the CA3 region of the hippocampus. However, the link between neurochemical effects of adult-born granule cells and behavior remain to be further examined.

Optogenetic activation of granule cells in the dorsal dentate gyrus enhances dopaminergic neurotransmission in the Nucleus Accumbens.

The dentate gyrus (DG) has distinct roles along its dorso-ventral axis. In the mouse, we recently demonstrated that dorsal DG (dDG) stimulation enhances exploratory behavior (Kheirbek et al., 2013). Dopamine (DA) release in the Nucleus Accumbens (NAcc), which belongs to the reward system, could be a key target of dDG mediating this motivation-related behavior. Here, an optogenetic stimulation of either ventral (vDG) or dDG granule cells was coupled with NAcc DA release monitoring using in vivo microdialysis. Only dDG stimulation enhanced NAcc DA release, indicating differential interconnections between dDG and vDG to the reward system.

Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy.

BACKGROUND: As rates of polypharmacy rise and medication regimens become more complex, the risk of potential cytochrome P450 (CYP)-mediated drug-drug interactions (DDIs) is a growing clinical concern for older adults. OBJECTIVE: To determine the prevalence of potential CYP-mediated DDIs in older hospitalized adults with polypharmacy and analyze the relationship between the number of drugs dispensed and the probability of these interactions in this high-risk population. METHODS: A prospective 16-week cohort study was conducted among consecutive new patients aged 65 years and older with polypharmacy (>5 drugs) admitted to a community hospital. The medication profiles of these patients were analyzed with a new multidrug cytochrome-specific software program. The prevalence of potential CYP-mediated DDIs was determined, with the probability calculated as a function of the number of medications dispensed using multivariate Poisson regression adjusted for age and sex. Comparative performance of the software program and a standard 2-drug alert program for detecting these DDIs was evaluated using the Wilcoxon-Mann-Whitney rank-sum test. Pharmacists' decisions to recommend medication adjustment based on the probability of CYP-mediated DDIs were recorded. RESULTS: The prevalence of potential CYP-mediated DDIs detected among 275 older adults with polypharmacy was 80%. The probability of at least 1 CYP-mediated DDI was 50% for persons taking 5-9 drugs, 81% with 10-14 drugs, 92% with 15-19 drugs, and 100% with 20 or more drugs. Addition of each medication to a 5-drug regimen conferred a 12% increased risk of a potential CYP-mediated DDI after adjustment for age and sex (OR 1.12; 95% CI 1.09-1.14). The multidrug software identified a median increase of 3 (95% CI 2.5-3.5) potential CYP-mediated DDIs per patient, compared to use of the standard 2-drug alert software. Pharmacists targeted patients for medication adjustment or close clinical monitoring in 23% of cases. CONCLUSIONS: The prevalence of potential CYP-mediated DDIs is high in geriatric patients with polypharmacy. The risk of DDIs increases as a function of the number of medications dispensed. Pharmacists' decision to intervene for potential CYP-mediated DDIs depends on clinical judgment in addition to the output from drug alert software programs, but may be facilitated by a single multicomponent, multidrug potential CYP-mediated DDI assessment.

Detection and prevention of drug-drug interactions in the hospitalized elderly: utility of new cytochrome p450-based software.

BACKGROUND: Polypharmacy increases the risk of cytochrome P450-based drug-drug interactions (CYP450-DDIs), leading to decreased therapeutic efficacy or increased drug toxicity. OBJECTIVE: The aims of this study were to investigate the utility of a new CYP450-DDI software, InterMED-Rx, in aiding pharmacists in detecting CYP450-DDIs in hospitalized elderly patients and to ascertain pharmacists' agreement on how to intervene for each CYP450-DDI. METHODS: A consensus panel of geriatric pharmacists first established guidelines for managing clinically relevant pharmacokinetic CYP450-DDIs. A prospective study was then conducted of patients newly admitted to a geriatric hospital whose pharmaceutical profile underwent analysis with InterMED-Rx. Rates and types of interventions were recorded. RESULTS: Pharmacists' interrater agreement on how to manage CYP450-DDIs was initially only moderate (Cohen's κ, 0.51; 95% CI, 0.39-0.62), but improved subsequent to deliberation (Cohen's κ, 0.79; 95% CI, 0.70-0.88). Persistent disagreement involved interactions between 2 drugs with similar affinities for the same cytochrome. One hundred patients with polypharmacy (≥5 medications) aged 82.3 years (range, 65-96), with a mean (SD) of 12.2 (4.1) drugs (range, 5-27) were recruited for the prospective study. Eighty percent of patients had at least 1 CYP450 DDI detected with InterMED-Rx. A total of 238 CYP450-DDIs were identified involving CYP3A4 (70.2%), CYP2D6 (22.7%), and CYP2C9 (3.4%) substrates or inhibitors. Nineteen percent of patients received immediate medication adjustment, and 39% required follow-up of clinical signs, symptoms, and laboratory tests to determine whether future modification was needed. More than one half (56%) of all patients who required clinical follow-up had further medication adjustment prior to discharge. CONCLUSIONS: Use of the InterMED-Rx software identified elderly patients at risk for pharmacokinetic interactions and facilitated interventions aimed at reducing adverse drug events. Although consensus can be reached among pharmacists on how to intervene for many CYP450-DDI scenarios, certain situations allow for multiple intervention strategies.