piperidines and ropinirole

Parkinson's disease (PD) is a neurodegenerative disorder caused by selective dopaminergic neuronal loss. Rotenone is a neurotoxin that selectively destroys dopaminergic neurons, leading to PD-like symptoms. Quercetin possesses antioxidant, anti-inflammatory, and neuroprotective properties but a major drawback is its low bioavailability. Therefore, the present study was designed to evaluate the neuroprotective effect of quercetin in combination with piperine against rotenone- and iron supplement-induced model of PD. Rotenone was administered at a dose of 1.5 mg/kg through an intraperitoneal route with iron supplement at a dose of 120 μg/g in diet from day 1 to day 28. Pre-treatment with quercetin (25 and 50 mg/kg, p.o.), piperine (2.5 mg/kg, p.o.) alone, quercetin (25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg), and ropinirole (0.5 mg/kg, i.p.) was administered for 28 days 1 h prior to rotenone and iron supplement administration. All behavioral parameters were assessed on weekly basis. On the 29th day, all animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite, GSH, mitochondrial complexes I and IV), neuroinflammatory (TNF-α, IL-1β, and IL-6), and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) estimation. Quercetin treatment attenuated rotenone- and iron supplement-induced motor deficits and biochemical and neurotransmitter alterations in experimental rats. However, combination of quercetin (25 mg/kg) with piperine (2.5 mg/kg) significantly enhanced its neuroprotective effect as compared with treatment with quercetin alone. The study concluded that combination of quercetin with piperine contributed to superior antioxidant, anti-inflammatory, and neuroprotective effect against rotenone- and iron supplement-induced PD in experimental rats.

Topics: Alkaloids; Benzodioxoles; Corpus Striatum; Dietary Supplements; Drug Synergism; Electron Transport Complex I; Electron Transport Complex IV; Glutathione; Indoles; Interleukin-1beta; Interleukin-6; Iron; Lipid Peroxidation; Neuroprotective Agents; Neurotransmitter Agents; Nitrites; Parkinson Disease, Secondary; Piperidines; Polyunsaturated Alkamides; Quercetin; Rotenone; Tumor Necrosis Factor-alpha

Topics: Animals; Benzodiazepines; Carbamates; Carbazoles; Cephapirin; Humans; Indoles; Labetalol; Nevirapine; Olanzapine; Pharmaceutical Preparations; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Species Specificity; Voriconazole

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that 'kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.

Topics: Animals; Aripiprazole; CHO Cells; Cricetulus; Dopamine; Dopamine Agonists; Indoles; Kinetics; Ligands; Piperazines; Piperidines; Principal Component Analysis; Protein Stability; Receptors, Dopamine D2