+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy

, : Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Current Drug Targets 4(4): 297-304

Long term treatment with antiepileptic drugs (AEDs) is the standard therapeutic approach to eradicate seizures. However, a small but significant number of patients fail AED treatment. Intrinsic drug resistance may depend on two main and not necessarily mutually exclusive mechanisms: 1) Loss of pharmacological target (e.g., GABAA receptors); 2) poor penetration of the drug into the central nervous system (CNS). The latter is due to the action of multiple drug resistance proteins capable of active CNS extrusion of drugs. These include MDR1 (P-glycoprotein, PgP), the multidrug resistance related proteins MRP1-5, and lung-resistance protein (LRP). Overexpression of MDR1 occurs in human epileptic brain. It has therefore been proposed that MDR1/PgP may contribute to multiple drug resistance in epilepsy. In addition to MDR1/PgP, other genes such as MRP2, MRP5, and human cisplatin resistance-associated protein are also overexpressed in drug-resistant epilepsy. In normal brain tissue MDR1/PgP is expressed almost exclusively by endothelial cells (EC), while in epileptic cortex both EC and perivascular astrocytes express MDR1/PgP. The underlying causes for tissue differences may be genomic (i.e., at the DNA level), or MDR1/PgP could be induced by seizures, previous drug treatment, or a combination of the above. We will present evidence showing that expression of multiple drug resistance genes in epilepsy is a complex phenomenon and that glial cells are involved. This second line of defense for xenobiotics may have profound implications for the pharmacokinetic properties of antiepileptic drugs and their capacity to reach neuronal targets.


PMID: 12699350

DOI: 10.2174/1389450033491109

Other references

van Bergen, E.; Osbaldeston, D.; Kodandaramaiah, U.; Brattström, O.; Aduse-Poku, K.; Brakefield, P.M., 2017: Conserved patterns of integrated developmental plasticity in a group of polyphenic tropical butterflies. Developmental plasticity is thought to have profound macro-evolutionary effects, for example, by increasing the probability of establishment in new environments and subsequent divergence into independently evolving lineages. In contrast to plastic...

Milazzo, L.; Foschi, A.; Antinori, S., 2012: Rapid virological response: is it four or eight weeks?. Hepatology 55(3): 979; Author Reply 980-1

Lowenberger, CA.; Smartt, CT.; Bulet, P.; Ferdig, MT.; Severson, DW.; Hoffmann, JA.; Christensen, BM., 1999: Insect immunity: molecular cloning, expression, and characterization of cDNAs and genomic DNA encoding three isoforms of insect defensin in Aedes aegypti. Aedes aegypti were immune activated by injection with bacteria, and the expression of insect defensins was measured over time. Northern analyses indicated that defensin transcriptional activity continued for at least 21 days after bacterial inject...

Zimmer, A.; Miller, G.; Mallal, S.; Thomas, L., 2015: Human leukocyte antigen and risk of disseminated histoplasmosis in solid organ transplant recipients. Transplant Infectious Disease 18(1): 160-161

Anonymous, 1889: Mental Science. Science 14(349): 252-254

Ruscak, M., 1959: Relationship between adrenalin hypertension and serum potassium level. Acta Physiologica Polonica 10(2): 261-264

Kucera, M., 1966: Occurrence and importance of the venous thromboembolic disease in patients with heart diseases. Vnitrni Lekarstvi 12(3): 209-217

Stevens P.; Waldeck J.M.; Strohl J.; Nakon R., 1978: Generation of stable acidic solutions of copper iii chelates from basic copper ii solutions. Journal of the American Chemical Society 100(11): 3632-3634

Kozlinskii, Vm, 1984: Planning the development of social infrastructure of a rural settlement. Vestis Latvijas PSR zinatnu akademijas = Izvestiia Akademii nauk Latviiskoi SSR: 1) 37-44

Wright, J.D.; Reuter, C.W.M.; Weber, M.J., 1996: Identification of sites on epidermal growth factor receptors which are phosphorylated by pp60-src in vitro. The Epidermal Growth Factor Receptor (EGF-R) becomes constitutively tyrosine phosphorylated on two novel sites in v-Src transformed cells, and these phosphorylations are associated with enhanced signaling activity (1). To determine whether Src cou...