TY - JOUR

T1 - Distinct effects on cAMP signaling of carbamazepine and its structural derivatives do not correlate with their clinical efficacy in epilepsy

AU - Krarup, Sara

AU - Mertz, Christoffer

AU - Jakobsen, Emil

AU - Lindholm, Sandy E. H.

AU - Pinborg, Lars H.

AU - Bak, Lasse K.

PY - 2020

Y1 - 2020

N2 - The antiepileptic sodium channel blocker, carbamazepine, has long been known to be able to attenuate cAMP signals. This could be of clinical importance since cAMP signaling has been shown to be involved in epileptogenesis and seizures. However, no information on the ability to affect cAMP signaling is available for the marketed structural derivatives, oxcarbazepine and eslicarbazepine acetate or their dominating metabolite, licarbazepine. Thus, we employed a HEK293 cell line stably expressing a cAMP biosensor to assess the effect of these two drugs on cAMP accumulation. We find that oxcarbazepine does not affect cAMP accumulation whereas eslicarbazepine acetate, surprisingly, is able to enhance cAMP accumulation. Since the transcription of ADCY8 (adenylyl cyclase isoform 8; AC8) has been found to be elevated in epileptic tissue from patients, we subsequently expressed AC8 in the HEK293 cells. In the AC8-expressing cells, oxcarbazepine was now able to attenuate whereas eslicarbazepine maintained its ability to increase cAMP accumulation. However, at all concentrations tested, licarbazepine demonstrated no effect on cAMP accumulation. Thus, we conclude that the effects exerted by carbamazepine and its derivatives on cAMP accumulation do not correlate with their clinical efficacy in epilepsy. However, this does not disqualify cAMP signaling per se as a potential disease-modifying drug target for epilepsy since more potent and selective inhibitors may be of therapeutic value.

AB - The antiepileptic sodium channel blocker, carbamazepine, has long been known to be able to attenuate cAMP signals. This could be of clinical importance since cAMP signaling has been shown to be involved in epileptogenesis and seizures. However, no information on the ability to affect cAMP signaling is available for the marketed structural derivatives, oxcarbazepine and eslicarbazepine acetate or their dominating metabolite, licarbazepine. Thus, we employed a HEK293 cell line stably expressing a cAMP biosensor to assess the effect of these two drugs on cAMP accumulation. We find that oxcarbazepine does not affect cAMP accumulation whereas eslicarbazepine acetate, surprisingly, is able to enhance cAMP accumulation. Since the transcription of ADCY8 (adenylyl cyclase isoform 8; AC8) has been found to be elevated in epileptic tissue from patients, we subsequently expressed AC8 in the HEK293 cells. In the AC8-expressing cells, oxcarbazepine was now able to attenuate whereas eslicarbazepine maintained its ability to increase cAMP accumulation. However, at all concentrations tested, licarbazepine demonstrated no effect on cAMP accumulation. Thus, we conclude that the effects exerted by carbamazepine and its derivatives on cAMP accumulation do not correlate with their clinical efficacy in epilepsy. However, this does not disqualify cAMP signaling per se as a potential disease-modifying drug target for epilepsy since more potent and selective inhibitors may be of therapeutic value.

KW - Epilepsy

KW - cAMP

KW - AC8

KW - Carbamazepine

KW - Oxcarbazepine

KW - Eslicarbazepine

KW - CYCLIC-AMP

KW - ANTIEPILEPTIC DRUGS

KW - OXCARBAZEPINE

KW - INHIBITION

KW - KEY

U2 - 10.1016/j.ejphar.2020.173413

DO - 10.1016/j.ejphar.2020.173413

M3 - Journal article

C2 - 32758572

VL - 886

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

M1 - 173413

ER -