Signaling to P-glycoprotein - A new therapeutic target to treat drug-resistant epilepsy

2009 ◽  
Vol 22 (7) ◽  
pp. 393 ◽  
Author(s):  
A.M.S. Hartz ◽  
S. Notenbom ◽  
B. Bauer
2017 ◽  
Vol 136 (6) ◽  
pp. 639-644 ◽  
Author(s):  
H. A. Elkhayat ◽  
R. H. Aly ◽  
I. A. Elagouza ◽  
R. H. El-Kabarity ◽  
Y. I. Galal

Author(s):  
Urvashi Langeh ◽  
Pooja Chawla ◽  
Ghanshyam Das Gupta ◽  
Shamsher Singh

Abstract:: Refractory epilepsy is a type of epilepsy involving seizures uncontrolled by first or second-line anticonvulsant drugs at a regular therapeutic dose. Despite considerable growth in epileptic pharmacotherapy, one-third of the patients are resistant to current therapies. In this, the mechanisms responsible for resistant epilepsy are either increased expulsion of an-tiepileptic drugs (AEDs) by multidrug resistance (MDR) transporters from the epileptogenic tissue or reduced sensitivity of drug in epileptogenic brain tissue. The difficulty to treat refractory epilepsy is because of drug resistance due to cellular drug efflux, use of drug monotherapy, and subtherapeutic dose administration. Increased expression of Pgp is also responsible for resistance epilepsy or refractory epilepsy. Increase glutamate expression via inhibition of cyclooxygenase-II (COX-II) en-zyme also upregulate P-glycoprotein (Pgp) expression and augment instance of recurrent seizures. Peripheral and central in-hibition of Pgp is a powerful tool to control this drug resistance epilepsy. Drug resistance primarily involves multidrug re-sistance (MDR1) gene which is responsible for encoding P-glycoprotein (PgP1 or MDR1). Currently, there is no drug under clinical practice which inhibits MDR1. The present review cites some drugs like calcium channel blockers, COX-II inhibi-tors, and glutamate receptors antagonists that inhibit P-gp. The exploitation of these targets may emerge as a beneficial ap-proach for patients with drug-resistant epilepsy. The present review further highlights the mechanistic role of Pgp in drug-resistant epilepsy, glutamate role in drug efflux, and management approach.


2019 ◽  
Author(s):  
John Eaton ◽  
Richard A. Ruberto ◽  
Anneke Kramm ◽  
Vasanthi S. Viswanathan ◽  
Stuart Schreiber

<div><div><div><p>GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. While most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently the protein’s catalytic selenocysteine residue, the discovery and mechanistic elucidation of structurally diverse GPX4-inhibiting molecules has uncovered novel electrophilic warheads that bind and inhibit GPX4. Here we report our discovery that diacylfuroxans can act as masked nitrile oxides that inhibit GPX4 covalently. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also suggest that nitrile oxides may be uniquely suited to targeting GPX4.</p></div></div></div>


2018 ◽  
Vol 26 (2) ◽  
pp. 13-18
Author(s):  
Yu.M. Zabrodskaya ◽  
◽  
D.A. Sitovskaya ◽  
S.M. Malyshev ◽  
T.V. Sokolova ◽  
...  

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