Pharmacological Treatment of Alzheimer's Disease: Insights from Drosophila melanogaster.

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer's disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular ß-amyloid (Aß) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

The role of stochastic gene switching in determining the pharmacodynamics of certain drugs: basic mechanisms.

In this paper we analyze the impact of the stochastic fluctuation of genes between their ON and OFF states on the pharmacodynamics of a potentially large class of drugs. We focus on basic mechanisms underlying the onset of in vitro experimental dose-response curves, by investigating two elementary molecular circuits. Both circuits consist in the transcription of a gene and in the successive translation into the corresponding protein. Whereas in the first the activation/deactivation rates of the single gene copy are constant, in the second the protein, now a transcription factor, amplifies the deactivation rate, so introducing a negative feedback. The drug is assumed to enhance the elimination of the protein, and in both cases the success of therapy is assured by keeping the level of the given protein under a threshold for a fixed time. Our numerical simulations suggests that the gene switching plays a primary role in determining the sigmoidal shape of dose-response curves. Moreover, the simulations show interesting phenomena related to the magnitude of the average gene switching time and to the drug concentration. In particular, for slow gene switching a significant fraction of cells can respond also in the absence of drug or with drug concentrations insufficient for the response in a deterministic setting. For higher drug concentrations, the non-responding fraction exhibits a maximum at intermediate values of the gene switching rates. For fast gene switching, instead, the stochastic prediction follows the prediction of the deterministic approximation, with all the cells responding or non-responding according to the drug dose.

Increased agonist affinity at the µ-opioid receptor induced by prolonged agonist exposure.

Prolonged exposure to high-efficacy agonists results in desensitization of the µ-opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling; however, the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased after prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa594, was unaffected by similar agonist pretreatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise, the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knock-out animals increased after treatment of the cells with the desensitization protocol. Thus, opioid receptors were "imprinted" with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long-lasting but reversible conformational change in the receptor.

Effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by efonidipine.

The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 µM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-∞)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-∞) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect-time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions.