Sunday 20 May 2012

P-glycoprotein: lock on transporters

During a post a while back, I did promise that I would discuss an interesting compound called P-glycoprotein in relation to the blood-brain barrier and its helping, transporting hand. Well here is it is. A recent article titled "P-glycoprotein: Why this drug transporter may be clinically important" attracted my attention in timely fashion discussing drug interactions which, as coincidence would have it, is something that I have also been reading about recently.

This paper by van Assema and colleagues* cropped up on my Twitter radar recently. In it, the authors describe how problems with a pretty important transporter system, P-glycoprotein (otherwise known as ATP-binding cassette sub-family B member 1, ABCB1) might put some fundamental observations in Alzheimer's disease (AD) into perspective.

I don't want to rehash the whole AD story because it has been summarised in other posts. The watchwords are: beta-amyloid peptide fragment, reactivity, and plaques. Dr/Prof. van Assema and team carried out some investigations on P-glycoprotein function in a small number of patients with AD compared with controls. They reported lower P-glycoprotein functioning and concluding that the ability to transport things out of the brain through the blood-brain barrier might be problematic at least in some cases of AD. 

This is not the first time that P-glycoprotein has been implicated in AD. This paper and its accompanying commentary hinted at similar things in a mouse model looking at transporting those pesky beta-amyloid peptides away and reducing the accumulation. I note that there is some growing interest in this and related areas following the news that AD might have some interesting spreading capability

As per my previous post on amyloid precursor protein, AD is not autism. Indeed, the evidence seems quite the contrary when it comes to looking at both the precursor protein and plasma levels of the nasty peptide fragment/s in relation to autism.

Having said that P-glycoprotein has been looked at in cases of autism; specifically to account for the variable effectiveness of some medications given to manage peripheral issues such as hyperactivity. This paper by McCracken and colleagues** suggested that individual responses to the drug guanfacine might be influenced quite strongly by certain genetic differences in the p-glycoprotein gene. So the presence of a certain mutation (SNP) might account for lower levels of P-glycoprotein, which in turn means less 'hold my hand' transport of the drug across the blood-brain barrier to exert an effect. 

Acknowledging that the blood-brain barrier is a highly complex barrier and that we need to tread cautiously in terms of what we allow in and out across this barrier, there is a whole new world to be explored here perhaps rivaling that other barrier of great interest in relation to autism and a few other things. 

* van Assema et al. Blood–brain barrier P-glycoprotein function in Alzheimer's disease. Brain. November 2011.

** McCracken JT. et al. Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. Journal of Child & Adolescent Psychopharmacology. February 2010.

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