Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine.
OBJECTIVE
Alterations in neuronal calcium (Ca2+) homeostasis are believed to play an essential role in the generation and propagation of epileptiform events. Levetiracetam (LEV) and lamotrigine (LTG), novel antiepileptic drugs (AEDs), were tested on epileptiform events and the corresponding elevations in intracellular Ca2+ concentration ([Ca2+]i) recorded from rat neocortical slices.


METHODS
Electrophysiological recordings were performed from single pyramidal neurons from a slice preparation. Spontaneous epileptiform events consisting of long-lasting, repetitive paroxysmal depolarization shifts (PDSs) and interictal spike activity were induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. Simultaneously, microfluorimetric measurements of [Ca2+]i were performed. Optical imaging with Ca2+ indicators revealed a close correlation between Ca2+ transients and epileptiform events.


RESULTS
Both LEV and LTG were able to reduce both amplitude and duration of PDSs, as well as the concomitant elevation in [Ca2+]i, in a dose-dependent fashion. Whole-cell patch-clamp recordings from isolated neocortical neurons revealed that LEV significantly reduced N-, and partially P/Q-type high-voltage-activated (HVA) Ca2+ currents, whereas sodium currents were unaffected. Interestingly, the inhibitory effects of LEV were mimicked and occluded by LTG or by a combination of omega-conotoxin GVIA and omega-agatoxin IVA, selective blockers of N- and P/Q-type HVA channels, respectively, suggesting a common site of action for these AEDs.


CONCLUSIONS
These results demonstrate that large, transient elevations in neuronal [Ca2+]i correlate to epileptiform discharges. The antagonistic effects of LEV and LTG on [Ca2+]i overload might represent the basis for their anticonvulsant efficacy and could preserve neuronal viability.
Pisani
Antonio
A
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma "Tor Vergata,", Rome, Italy. pisani@uniroma2.it
Bonsi
Paola
P
Martella
Giuseppina
G
De Persis
Cristiano
C
Costa
Cinzia
C
Pisani
Francesco
F
Bernardi
Giorgio
G
Calabresi
Paolo
P
D015761:4-Aminopyridine; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014227:Triazines / Q000494:pharmacology*
D015761:4-Aminopyridine; D000927:Anticonvulsants; D001640:Bicuculline; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D000077213:Lamotrigine; D000077287:Levetiracetam; D010889:Piracetam; D014227:Triazines