Voltage-activated calcium channels: targets of antiepileptic drug therapy?
Voltage-gated calcium currents play important roles in controlling neuronal excitability. They also contribute to the epileptogenic discharge, including seizure maintenance and propagation. In the past decade, selective calcium channel blockers have been synthesized, aiding in the analysis of calcium channel subtypes by patch-clamp recordings. It is still a matter of debate whether whether any of the currently available antiepileptic drugs (AEDs) inhibit these conductances as part of their mechanism of action. We tested oxcarbazepine, lamotrigine, and felbamate and found that they consistently inhibited voltage-activated calcium currents in cortical and striatal neurons at clinically relevant concentrations. Low micromolar concentrations of GP 47779 (the active metabolite of oxcarbazepine) and lamotrigine reduced calcium conductances involved in the regulation of transmitter release. In contrast, felbamate blocked nifedipine-sensitive conductances at concentrations significantly lower than those required to modify N-methyl-D-aspartate (NMDA) responses or sodium currents. Aside from contributing to AED efficacy, this mechanism of action may have profound implications for preventing fast-developing cellular damage related to ischemic and traumatic brain injuries. Moreover, the effects of AEDs on voltage-gated calcium signals may lead to new therapeutic strategies for the treatment of neurodegenerative disorders.
Stefani
A
A
IRCCS Ospedale S. Lucia and Clinica Neurologica, Università di Tor Vergata, Rome, Italy.
Spadoni
F
F
Bernardi
G
G
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D000078328:Felbamate; D006801:Humans; D000077213:Lamotrigine; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D000078330:Oxcarbazepine; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D015220:Calcium Channels; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D002220:Carbamazepine; D000077213:Lamotrigine; D000078330:Oxcarbazepine; D000078328:Felbamate