The brain is wide open
A new strategy for drug delivery to the brain is being developed
Nanonewsnet based on the materials of NIEHS: Strategy developed to improve delivery of medicines to the brainIn an article published in the Proceedings of the National Academy of Sciences (Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain), scientists from the National Institute of Environmental Health Sciences (NIEHS), USA, propose a new strategy for the treatment of diseases of the central nervous system systems such as brain and spinal cord injuries, brain cancer, epilepsy and neurological complications of HIV infection.
The experimental treatment method, tested so far on laboratory rats, allows low-molecular therapeutic compounds to safely overcome the blood–brain barrier by "turning off" P-glycoprotein, one of the main "gatekeepers" that prevent drugs from reaching targets in the brain.
"Many promising drugs fail because they are unable to deliver a therapeutic dose to the brain, since they cannot effectively overcome the blood–brain barrier," explains David Miller, PhD, head of the Laboratory of Toxicology and Pharmacology at NIEHS.
Scientists have found that the treatment of rat brain capillaries with the drug Gilenia (fingolimod) – a means for the treatment of multiple sclerosis – stimulates a specific biochemical pathway in the blood-brain barrier, which quickly and reversibly "turns off" the membrane protein P-glycoprotein. P-glycoprotein, a molecular pump that removes drugs from the brain, is one of the main obstacles on the way of low–molecular compounds to the central nervous system through the blood–brain barrier.
Preliminary administration of fingolimod to rats, and then three other drugs, which, unfortunately, P-glycoprotein usually quickly and effectively removes from the brain, leads to a significant decrease in the transport activity of P-glycoprotein and, as a consequence, to a 3-5-fold increase in the absorption of each of these three drugs by the brain.
The transmembrane molecule of P-glycoprotein, penetrating the bilayer of the cytoplasmic membrane, provides resistance to a number of drugs, including anticancer agents, "carrying" them out of the cell. This process is energy-consuming and requires the mandatory presence of ATP molecules. The mechanism of xeno compounds removal is still unknown for sure. (Fig. nature.com )
The next task that the researchers intend to solve is to understand how this signaling system suppresses the function of P–glycoprotein. A researcher in Dr. Miller's laboratory, Ronald Cannon, PhD, the first author of the article, compares this mechanism to what happens when we turn off the light. "If you physically turn off the light with a button on the wall, the light goes out because the electric current going to the bulb is interrupted. But what happens when this signaling pathway turns off the P-glycoprotein? Does it bind any other protein to this pump? Or deprives him of an energy source? [P-glycoprotein needs the presence of ATP to perform its function.] Does it change the structure of the protein or something else?", – determines the direction of further research by Dr. Cannon.
The delivery of drugs to the central nervous system is one of the most advanced frontiers in pharmacotherapy. "We hope that in the future our new strategy will be useful for people with brain diseases," concludes Dr. Miller.
Portal "Eternal youth" http://vechnayamolodost.ru10.09.2012