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

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.

Aspects of cAMP Signaling in Epileptogenesis and Seizures and Its Potential as Drug Target.

Epilepsy is one of the most common chronic neurological conditions. Today, close to 30 different medications to prevent epileptic seizures are in use; yet, far from all patients become seizure free upon medical treatment. Thus, there is a need for new pharmacological approaches including novel drug targets for the management of epilepsy. Despite the fact that a role for cAMP signaling in epileptogenesis and seizures was first suggested some four decades ago, none of the current medications target the cAMP signaling system. The reasons for this are probably many including limited knowledge of the underlying biology and pathology as well as difficulties in designing selective drugs for the different components of the cAMP signaling system. This review explores selected aspects of cAMP signaling in the context of epileptogenesis and seizures including cAMP response element binding (CREB)-mediated transcriptional regulation. We discuss the therapeutic potential of targeting cAMP signaling in epilepsy and point to an increased knowledge of the A-kinase anchoring protein-based signaling hubs as being of seminal importance for future drug discovery within the field. Further, in terms of targeting CREB, we argue that targeting upstream cAMP signals might be more fruitful than targeting CREB itself. Finally, we point to astrocytes as cellular targets in epilepsy since cAMP signals may regulate astrocytic K+ clearance affecting neuronal excitability.

Aspects of astrocytic cAMP signaling with an emphasis on the putative power of compartmentalized signals in health and disease.

This review discusses aspects of known and putative compartmentalized 3',5'-cyclic adenosine monophosphate (cAMP) signaling in astrocytes, a cell type that has turned out to be a key player in brain physiology and pathology. cAMP has attracted less attention than Ca2+ in recent years, but could turn out to rival Ca2+ in its potential to drive cellular functions and responses to intra- and extracellular cues. Further, Ca2+ and cAMP are known to engage in extensive crosstalk and cAMP signals often take place within subcellular compartments revolving around multi-protein signaling complexes; however, we know surprisingly little about this in astrocytes. Here, we review aspects of astrocytic cAMP signaling, provide arguments for an increased interest in this subject, suggest possible future research directions within the field, and discuss putative drug targets.