The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug‐resistant epilepsy

Vázquez, Marta; Fagiolino, Pietro

doi:10.1002/epi4.12542

Cited by 12 publications

(3 citation statements)

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“…Besides the role of seizures in inducing BCRP transporter expression, it should be emphasized that the transporter hypothesis of DRE does not only include seizures as a trigger. A growing body of literature suggests that in addition to seizures, AEDs may themselves induce efflux transporters expression (Vázquez and Fagiolino 2022 ). This evidence appears in the present study through the increased brain BCRP level in LTG group compared to the normal control group.…”

Section: Discussionmentioning

confidence: 99%

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine

Harby

Khalil

El-Sayed

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Blood–brain barrier (BBB) efflux transporters' overexpression hinders antiepileptic drug brain entry. Breast cancer resistance protein (BCRP) is a major BBB efflux transporter. In the present work, BCRP's role as a mechanism that might contribute to drug-resistant epilepsy (DRE) in a mouse model of acute seizures was studied with further assessment of the effect of its inhibition by ko143 and metformin (MET) on lamotrigine (LTG) bioavailability and efficacy. 42 male mice divided into 6 groups: G1: Normal control, G2: LTG-injected healthy mice: LTG 20 mg/kg i.p., G3: Acute seizures (A.S) mice: Pentylenetetrazole (PTZ) 50 mg/kg i.p., G4: LTG-treated A.S mice: LTG 20 mg/kg + PTZ 50 mg/kg i.p., G5: Ko143 + LTG treated A.S mice: Ko143 15 mg/kg i.p. before LTG + PTZ, G6: MET + LTG treated A.S mice: MET 200 mg/kg i.p. before LTG + PTZ. Seizures severity, serum, brain LTG, and brain BCRP were assessed. PTZ group experienced the highest seizure frequency and brain BCRP expression. Ko143 and MET groups showed a significant decrease in brain BCRP with subsequent improvement in brain LTG level and better seizure control. BCRP has a significant role in epilepsy resistance and its inhibition with ko143 or MET adds value to DRE management.

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Section: Discussionmentioning

confidence: 99%

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine

Harby

Khalil

El-Sayed

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The blood–brain barrier is the most extensive “firewall”, which includes various defense mechanisms. In addition to the physical blockade, which is constituted by biological membranes connected by the tight and adherens junctions (TJs and AJs), there are also mechanisms for the active removal of xenobiotics (efflux transporters; P-glycoprotein) [ 2 ] or an enzymatic activity [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Chromatographic Data in Statistical Analysis of BBB Permeability Indices

Wanat

Brzezińska

2023

Membranes

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Blood–brain barrier (BBB) permeability is an essential phenomena when considering the treatment of neurological disorders as well as in the case of central nervous system (CNS) adverse effects caused by peripherally acting drugs. The presented work contains statistical analyses and the correlation assessment of the analyzed group of active pharmaceutical ingredients (APIs) with their BBB-permeability data collected from the literature (such as computational log BB; Kp,uu,brain, and CNS+/− groups). A number of regression models were constructed in order to observe the connections between the APIs’ physicochemical properties in combination with their retention data from the chromatographic experiments (TLC and HPLC) and the indices of bioavailability in the CNS. Conducted analyses confirm that descriptors significant in BBB permeability modeling are hydrogen bond acceptors and donors, physiological charge, or energy of the lowest unoccupied molecular orbital. These molecular descriptors were the basis, along with the chromatographic data from the TLC in log BB regression analyses. Normal-phase TLC data showed a significant contribution to the creation of the log BB regression model using the multiple linear regression method. The model using them showed a good predictive value at the level of R2 = 0.87. Models for Kp,uu,brain resulted in lower statistics: R2 = 0.56 for the group of 23 APIs with the participation of k IAM.

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“…A novel notion is that the drug resistance phenotype is associated with changes in the central and peripheral expression of multidrug transporters proteins 7 . On the other hand, overexpression of multidrug transporter proteins can result from the administration of antiseizure medications 8 . Indeed, it is suggested that this situation can be avoided changing the regimen of administration of the antiseizure medications or using adjuvant drugs that downregulate the expression of transporters.…”

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confidence: 99%

Introduction to the special issue “Redesigning the hypotheses for drug‐resistant epilepsy”

Rocha¹

2022

Epilepsia Open

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Drug-resistant epilepsy represents an important neurological condition. Its prevalence is not modified in spite of the different hypotheses established to understand the mechanisms involved. The special issue "Redesigning the hypotheses for drug-resistant epilepsy" represents an effort of different investigators to discuss the limitations of the hypotheses that explain the drug resistance in epilepsy. In addition, new paradigms and novel strategies to control drug-resistant epilepsy are pointed out to understand this condition. K E Y W O R D S drug-resistant seizures, epilepsyHow to cite this article: Rocha L. Introduction to the special issue "Redesigning the hypotheses for drug-resistant epilepsy".

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The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug‐resistant epilepsy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 115 publications

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine

Chromatographic Data in Statistical Analysis of BBB Permeability Indices

Introduction to the special issue “Redesigning the hypotheses for drug‐resistant epilepsy”

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