Sunday, 9 September 2012

Research: Spingosine 1 phosphate and brain transporters

Epub: Cannon et al. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci U S A. 2012 Sep 4.

P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling.

Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, (3)H-verapamil (threefold increase), (3)H-loperamide (fivefold increase), and (3)H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain (14)C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.

The brain is shielded from things in the blood by the blood brain barrier. This works because the cellular barrier is immpermeable to many thing. Due to the fact that cell membranes contain a fatty acid structutres they will repell water just like oil floats on water. However fatty substances can easily get through the membranes because likes attract. To deal with this the blood brain barrier has a number of pumps that can pump things into the brain to maintain its health or it can pump things out to mentain its health. On molecule called Permeability glyprotein or p-glycoprotein which is a member of a group of about 50-60 energy dependent pumps. P-glycoprotein is ABCB1. P glycoprotein is expressed in the intestine but also at high levels in the brain. This keeps certain fatty substances including many drugs out of the brain. This one of the reasons that drugs against tumours do not work because they put such pumps on their surface and keep drugs out. The levels of drug pumps at the blood brain barrier can in part influnece how well a drug may work [click].

This study reports that the sphingosine-1-phosphate and the spingocine-1-phosphate receptor can down regulated the action of p-glycoprotein. They reported that stimulation of the S1PR can lead to accumulation of drugs into the brain that who be pumped out by p-glycoprotein. There are examples above but another could be tetrahydrocannabinol in cannabis which is weakly affected by p-glycoprotien. They therefore think that gilenya which stimulates and down regulates S1P1R could be used to get other drugs into the CNS. It is very clear that the active agent from Gilenya has no problem in getting into the brain, and a lack of activity by p glycoprotein may be why it accumulates in the brain. However this is a warning about using gilenya in combination with other drugs because of drug interactions. This could cause the dose of drugs receaching the brain to be increased and increase side effects. Is this important?

p-glycoprotein which looks like a peg floating in the cell membrane binds drug in the spring region because drug goes through th cell membrane of the cells blood vessel. Then using energy the end of the molecule moves together and the end of the molecule opens and the drug is pumped out abit like opening a peg.

There are a group of drugs that kill worms and skin parasites that have been used in ovver 40 million people to treat river blindness and 5 billion animals to get rid of parasites. However in CF-1 mice or Collie Dogs, which lack p-glycoprotein, this drug either kills them or causes severe neurological problems because the the drug kills nerves. Does this happen in people? I once went to a conference were a worker had very serve neurological problems working in a medical cannabis. The cannabis was sprayed because they had mites (skin parasite) so maybe they were p-glycoprotein deficient.

All drugs are checked to determine whether they are affected by p-glycoprotein, and the example above is an extreme example where drug-drug interaction could be bad.

However before thinking about using drugs to down regulate p-glycoprotein maybe you just look at MS and then you will find that p-glycoprotein goes down in MS lesions so this could be used as a way of targeting drugs to lesions, if fact we have been doing this.

No comments:

Post a Comment

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.