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Published on: December 18, 2016
Expressional Study of Permeability Glycoprotein and Multidrug Resistance Protein 1 in Drug-resistant Mesial Temporal
Mandeep Kaur1, Tulika Gupta1, Mili Gupta2
1Department of Anatomy, Institute of Medical Education and Research, Chandigarh, India.
Introduction:
About 30% of patients with epilepsy do not respond to anti-epileptic drugs, leading to refractory seizures. The pathogenesis of drug-resistance in mesial temporal lobe epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue.
Methods:
We have studied P-gp and MRP-1 drug-efflux transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery patients (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15).
Results:
Statistically significant over expression of both P-gp (P<0.0001) and MRP-1 (P=0.01) at gene and protein levels were found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of the patient group showed increased immunoreactivity of P-gp at blood-brain barrier and increased reactivity of MRP-1 in the parenchyma. The results were confirmed by confocal immunofluorescence microscopy.
Conclusion:
Our results suggested that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy. P-gp and MRP-1 could be important determinants of bio availability and tissue distribution of anti-epileptic drugs in the brain which can pharmacologically inhibited to achieve optimal drug penetration to target site.
Insights
Drug-efflux transporters, permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1), are overexpressed in drug-resistant epilepsy. This suggests P-gp and MRP-1 contribute to treatment resistance in epilepsy patients.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Approximately 30% of epilepsy patients exhibit drug resistance, leading to refractory seizures.
- The underlying mechanisms of drug resistance in mesial temporal lobe epilepsy (MTLE) remain incompletely understood.
- Increased activity of drug-efflux transporters, such as P-gp and MRP-1, may reduce anti-epileptic drug concentrations at the target site.
Purpose of the Study:
- To investigate the expression of P-gp and MRP-1 in drug-resistant epilepsy.
- To compare transporter expression in epileptic tissues versus non-epileptic tissues.
Main Methods:
- Studied P-gp and MRP-1 drug-efflux transporters in sclerotic hippocampal tissues from 15 epilepsy surgery patients.
- Compared transporter expression profiles with 15 age-matched non-epileptic autopsy cases.
- Utilized gene and protein expression analysis, immunohistochemistry, and confocal immunofluorescence microscopy.
Main Results:
- Statistically significant overexpression of both P-gp (P<0.0001) and MRP-1 (P=0.01) at gene and protein levels was observed in MTLE cases.
- P-gp showed a more pronounced fold change in expression compared to MRP-1.
- Immunohistochemistry revealed increased P-gp immunoreactivity at the blood-brain barrier and increased MRP-1 reactivity in the parenchyma.
Conclusions:
- P-gp and MRP-1 are suggested to be responsible for multi-drug resistance in epilepsy.
- These transporters may significantly influence the bioavailability and brain distribution of anti-epileptic drugs.
- Pharmacological inhibition of P-gp and MRP-1 could enhance anti-epileptic drug penetration to target sites.
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