Modulation of P-Glycoprotein in the Blood Brain Barrier for the Enhancement of Drug Delivery
Many types of research are going on for the development of novel drugs to treat neurodegenerative diseases like epilepsy, Parkinson’s disease, Alzheimer’s disease, but the major problem during the drug development is that the pharmacotherapy of such drugs is restricted by the actions of drug transporters in the blood-brain barrier. P glycoprotein is also one of the drug transporters in the blood-brain barrier which is there to restrict the entry of many substances like xenobiotics, toxicants into the brain cells. It also effluxes drug content from the cells which is the main reason for the reduced pharmacotherapy. To obtain the maximum therapeutic effect drug have to enter into the cell which is difficult when P glycoprotein is in action that’s why we have to modulate or inhibit the P glycoprotein action in the blood-brain barrier.
The drugs that are using to treat neurodegenerative diseases encounter an issue at the blood-brain barrier which is their inability to enter the brain cells because the blood-brain barrier contains many drug transporters. Those transporters act as gatekeepers and prevent the entry of many drugs. P glycoprotein is one of the drug transporters which have a wide range of substrates that play a key role in drug transportation. P glycoprotein is an ATP binding cassette transporter. It acts as an efflux transporter in the brain which transports substances like xenobiotics, toxicants out of the cells [1,2]. It exhibits a defensive mechanism by inhibiting the entry of inappropriate particles into the cell. It pumps out drug content from the cell which shows the effect on drug plasma concentration then automatically reduces the pharmacological effect of the drug. At that time we have to increase the dose to achieve therapeutic plasma concentration. On frequent usage of higher doses of a specific drug, there may be chances of the development of drug resistance. Like this P glycoprotein is responsible for the development of multidrug resistance. So we have to modulate the action of P glycoprotein. We can modulate P-gp by influencing the hMDR1 gene which is encoded for the expression of P glycoprotein by DNA methylation and histone acetylation. We can also modulate the P-gp without influencing the gene modulation which includes the post-translational mechanisms like degradation of protein, protein Phosphorylation.
Plants from this family contain lipophilic substances called acetogenins, from which annonacin is the most well-known. Annonacin provokes apoptosis of dopaminergic and GABAergic neurons by inhibition of mitochondrial complex I and has a stronger neurotoxic effect than MPTP or rotenone. Acetogenins were studied for their capacity to reverse multidrug resistance by efflux transporters on human tumoral cells. For example Roemerine, leaf extract of Annona senegalensis, enhanced vinblastine toxicity in tumal cells by inhibition of P-gp. Thus, it is hypothesized that the protective role of P-gp at the BBB could be inhibited by acetogenin, leading to accumulation of neurotoxins and enhancing neuro-degeneration.