- Queen Square authors prominent in Brain collection of classic articles
- Toxic proteins implicated in frontotemporal dementia and motor neurone disease
- Double mutation linked to frontotemporal dementia
- Equation to predict happiness
- Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia
- Researchers test whether diabetes drug can help Parkinson’s patients
- Acute optic neuritis: a review and proposed protocol
- Hippocampal subfield size predicts the precision of memory recall
- Immune system implicated in dementia development
- UCL and Chiesi Group announce partnership to develop a novel therapeutic for birth asphyxia
- Professor Golay made a Fellow of the ISMRM
- The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials
- Professor Rees wins UCLU Student Choice Teaching Award
- New epilepsy treatment offers ‘on demand’ seizure suppression
- Professor Tabrizi and Professor Price elected to Fellowship of the Academy of Medical Sciences.
- Professor Dolan and Professor Friston elected to EMBO membership
- Vitamin B3 treatment for ataxia shows promise in first human trial
- Teaching Awards 2014
- Light-activated neurons from stem cells restore function to paralysed muscles
- UCL and Max Planck Society invest €5m to open world’s first computational psychiatry centre
- Successful launch of new annual leading edge neurology course
- Statins could help control MS
- Professor Hardy awarded Thudichum Medal by Biochemical Society
- Population Screening for vCJD Using a Novel Blood Test
- Chief Medical Officer appoints Professor Rossor as NIHR National Director for Dementia Research
- New partnership between UCLP brain tumour scientists and Brain Tumour Research
- Professor Hardy awarded Dan David Prize for work on the amyloid gene encoding APP
- NIHR award £650,000 for research into rare neurodegenerative and neuromuscular diseases
- Lowering levels of toxic protein reverses abnormalities in cells from patients with Huntington's disease
- Major initiative in understanding synaptic basis of neuropsychiatric disease
- Visit to the Berlin School of Mind and Brain
- Institute of Neurology ranked as the world’s top institution for epilepsy research.
- Predicting age at onset in SCA1 : does size matter?
- UCL takes the lead with £8.5m funding for dementia research
- Secretary of State visits leading dementia research projects
- Riboflavin Treatment for Childhood onset Motor Neuron Disease
- Dreading pain can be worse than pain itself
- Different gene expression in male and female brains helps explain differences in brain disorders
- New £20m centre pioneers first-in-man trials for neurodegenerative diseases
- RNA build-up linked to dementia and motor neuron disease
- Researchers estimate one in 2,000 people in the UK carry variant CJD proteins
- Professor Alan Thompson discusses Atlas of MS on Lancet News
- Wellcome Trust Principal Fellowship award to explore neural coding with the tripartite synapse
- Marsden's Book of Movement Disorders wins Neurology first prize at the 2013 BMA Book Awards
- Scientists develop refined diagnostic tool for inherited dementias
- Genetic mutations linked to Parkinson's Disease
- P-glycoprotein over-activity and drug resistance in temporal lobe epilepsy
- New Yale-UCL collaboration in brain aneurysm genetics
- ‘Risky’ stroke prevention procedure may be safe in some patients
- The Michael J. Fox Foundation awards grant for Exenatide research
- Institute Professor leads cross-disciplinary study on use of glucose in detecting cancer.
- Irreversible tissue loss seen within 40 days of spinal cord injury
- From Bedside to Bench in the Institute’s MRC Centre for Neuromuscular Diseases
- Centralising acute stroke services has saved more than 400 lives since 2010
- Rapid Response Innovation Award from The Michael J. Fox Foundation
- Predicting Language Outcome and Recovery After Stroke (PLORAS) project launches new website
- BRC awards over £500k to neuroscience projects
- ABTA Winners
- Diabetes drug could help treat Parkinson's Disease
- Clinical trials are vital tools in stroke research
- New gene identified for Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraparesis
- Teaching Awards 2013
- 14th Annual Queen Square Symposium
- TRACK-HD study identifies early predictors of disease progression in Huntington’s disease
- The Great Brain Experiment: crowdsourcing data on how we think and act
- Psychogenic diseases linked to abnormal brain activity
- Human Brain Project wins major EU funding
- Gene mutation causes familial form of cranio-cervical dystonia
- Professor Ray Dolan awarded prestigious Klaus Joachim Zülch Prize
- Professor Dimitri Kullmann elected Editor of Brain
- IoN News Archive (2012)
- IoN News Archive (2011)
- IoN News Archive (2010)
- IoN News Archive (2009)
- GCH1 gene and Parkinson’s risk
Published: Jan 16, 2014 12:32:49 PM
Published: May 11, 2013 3:39:00 PM
Published: Aug 12, 2014 1:23:13 PM
Published: Sep 16, 2013 1:37:21 PM
Published: Dec 10, 2013 2:49:43 PM
Published: Jul 30, 2014 4:41:41 PM
P-glycoprotein over-activity and drug resistance in temporal lobe epilepsy
1 August 2013
A major study published in this month's issue of Lancet Neurology, led by researchers at UCL's Institute of Neurology and funded by the EU-Framework 7 programme, provides the first in-vivo human evidence of an association between over-activity of P-glycoprotein (a drug transporter) at the blood-brain barrier and drug resistance in temporal lobe epilepsy (TLE).
Drug resistance is an important clinical problem. Globally, 50,000,000 people have epilepsy: current treatments are ineffective in 30% of patients due to drug resistance. One generic mechanism for drug resistance, relevant for epilepsy and other brain disorders (e.g. depression, cancer, HIV) is over-activity of drug transporter(s) at the blood-brain-barrier, such as P-glycoprotein.
There is compelling evidence from animal models that P-glycoprotein over-activity prevents drugs from reaching therapeutic concentrations at their targets.
The research, which was part of EURIPIDES, a large consortium of basic scientists and clinical epileptologists co-oordinated by UCL, revealed that brain uptake of a P-glycoprotein biomarker ( [11C]verapamil PET) in drug-sensitive patients was higher than those in drug-resistant patients, suggesting that P-glycoprotein over-activity at the blood-brain barrier in drug-resistant patients results in lower drug concentrations in the brain.
The study looked for a change in biomarker
before and after
administering a P-glycoprotein inhibitor (tariquidar) and showed that
tariquidar-induced increases in brain uptake were attenuated in the sclerotic hippocampus (the brain area involved in TLE).
The findings correlate with those found in surgical temporal lobe specimens of patients who had undergone surgery, and are in keeping with the hypothesis that there is localized P-glycoprotein over-activity in drug-resistant TLE.
Professor Matthias Koepp, the Chief Investigator of EURIPIDES comments:
“Our study supports the hypothesis of multidrug transporter over-activity as an important mechanism for drug resistance in epilepsy. The availability of imaging biomarkers, such as [11C]verapamil PET, will support the development of new treatment strategies targeted at multidrug transporters and aimed at reversing drug resistance with selection of optimal patients and assessment of molecular targets.
Until now there has not been any conclusive way to detect the underlying mechanisms of drug-resistance, such as P-glycoprotein over-activity, and treat patients rationally. The stage is now set for direct translation to clinical trials. We have a tool to identify patients in whom P-glycoprotein over-activity could conceivably contribute to drug resistant epilepsy, and drugs, which can modulate or inhibit P-glycoprotein function.”
EURIPIDES was run from University College London and included 14 European research and hospital centres from UK, Netherlands, France, Germany, Denmark, Austria, Denmark and Greece. Drug-resistant and drug-sensitive patients with temporal lobe epilepsy and unilateral hippocampal sclerosis were recruited for this study from the National Hospital for Neurology & Neurosurgery and PET scans were performed at the Wolfson Molecular Imaging Centre in Manchester.
Feldmann et al. (2013) P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurology, Volume 12, Issue 8, Pages 777–785. DOI: 10.1016/S1474-4422(13)70109-1
EU Framework 7 programme : http://www.ucl.ac.uk/research/europe/funding
Page last modified on 31 jul 13 12:55