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

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...

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Published in:Naunyn-Schmiedeberg's archives of pharmacology 2023-10, Vol.396 (10), p.2627-2636
Main Authors: Harby, Sahar A., Khalil, Nehal A., El-Sayed, Norhan S., Thabet, Eman H., Saleh, Samar R., Fathelbab, Mona Hassan
Format: Article
Language:English
Subjects:
Adjuvants
Antidiabetics
Antiepileptic agents
Bioavailability
Biomedical and Life Sciences
Biomedicine
Blood-brain barrier
Breast cancer
Convulsions & seizures
Drug resistance
Epilepsy
Lamotrigine
Metformin
Neurosciences
Pentylenetetrazole
Pharmacology/Toxicology
Seizures
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Summary: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.
ISSN:0028-1298
1432-1912
1432-1912
DOI:10.1007/s00210-023-02485-7