P-gp transporter and its role in neurodegenerative diseases.
ABSTRACT This paper describes an overview of recent insights concerning some socially relevant neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and Creutzfeldt-Jakob's (CJD) diseases, amyotrophic lateral sclerosis (ALS) and epilepsy. For each pathological state, the direct and/or indirect involvement of P-glycoprotein (P-gp) efflux transport is underlined. On this basis, P-gp still represents an innovative target which can offer new tools for the development of more effective and preventive therapeutic strategies for neurodegenerative disorders. For each of them, therefore, a possible use of drugs affecting P-gp transport activity has been suggested.
Article: Substrates, inhibitors and activators of P-glycoprotein: candidates for radiolabeling and imaging perspectives[show abstract] [hide abstract]
ABSTRACT: In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [ 11 C]verapamil and [ 11 C]loperamide can be employed to visualize P-gp activity, but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as [ 11 C]elacridar, [ 11 C]laniquidar and [ 11 C]tariquidar have been tested to investigate P-gp expression and the results need further investigation. Recently, we developed MC18, MC266 and MC80, that have been characterized as an inhibitor, substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with 11 C and been evaluated in vivo. In the present review, we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors [ 11 C]MC18 and [ 11 C]elacridar, the P-gp substrates [ 11 C]MC266 and [ 11 C]verapamil, the P-gp inducer [ 11 C]MC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings, the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimer's and Parkinson's disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.Current Topics in Medicinal Chemistry. 01/2010; 10.
Article: Development of Classification Models for Identifying "True" P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays.[show abstract] [hide abstract]
ABSTRACT: P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as "true" P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function.International Journal of Molecular Sciences 01/2012; 13(6):6924-43. · 2.60 Impact Factor