Levetiracetam Selectively Blocks N-Type Calcium Channels in Rat Isolated CA1 Hippocampal Neurons
Abstract number :
A.07
Submission category :
Year :
2001
Submission ID :
3119
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
E.A. Lukyanetz, PhD, Assoc. Prof., General Physiology of Nervous System, Bogomoletz Institute of Physiology, Kiev, Ukraine; V.M. Shkryl, PhD Student, General Physiology of Nervous System, Bogomoletz Institute of Physiology, Kiev, Ukraine; P.G. Kostyuk, Ph
RATIONALE: The anti-seizure mechanisms of the antiepileptic drug levetiracetam (LEV) are not yet fully understood. However, it was previously reported that LEV inhibits high-voltage-activated (HVA) Ca2+ current in CA1 pyramidal neurons from rat hippocampal slices (Niespodziany [italic]et al., Epilepsia[/italic] 41, Suppl. 7, 37, 2000). We studied, therefore, the sensitivity of LEV for the different HVA Ca2+ channel subtypes in rat isolated CA1 pyramidal neurons, aiming to discriminate their selectivity to LEV.
METHODS: Whole-cell patch clamp recordings of HVA Ca2+ channel activity of isolated hippocampal CA1 neurons were used. Drugs were applied using a system, which delivers the solutions by gravity flow from a pipette placed above the preparation and changes the solutions by microvalves. For the separation of Ca2+ channel subtypes, their selective blockers were used: 20 [mu]M nifedipine, 1 [mu]M [omega]-Conotoxin-GVIA, 50 nM [omega]-Agatoxin and 200 nM [omega]-Conotoxin MVIIC for L-, N-, P- and Q-types respectively.
RESULTS: Ca2+ currents were elicited by shifting a holding potential from -70 mV to depolarizing test potentials (ranging from -60 to +50 mV) for 50 ms. In control cells L-type channels accounted for 25.0 [plusminus] 2.5 % (n=8), N-type for 45.5 [plusminus] 3.6 % (n=8), P-type for 16.8 [plusminus] 2.7 % (n=7) and Q-type for 9.4 [plusminus] 1.4 % (n=9), (mean [plusminus] SEM). Application of 5 [ndash] 200 [mu]M LEV irreversibly inhibited the evoked I[sub]Ca[/sub]in all tested cells (n=122). IC[sub]50[/sub] for the inhibition by LEV of voltage-dependent Ca2+ channels was 14.7 [plusminus] 1.6 [mu]M (n=62). The maximum inhibition was observed at 200 [mu]M and was about 18 %. Application of 200 [mu]M LEV in the presence of the corresponding selective blockers further reduced the calcium current amplitude by 17.0 [plusminus] 4.6 % (n=8), 15.6 [plusminus] 5.6 % (n=4) and 17.4 [plusminus] 2.1 % (n=8) for L-, P- and Q-types respectively. However, LEV was ineffective in the presence of the selective blocker of N-type channels.
CONCLUSIONS: The present study indicates that LEV selectively influences the activity of N-type Ca2+ channels of CA1 pyramidal hippocampal neurons with 37% maximal inhibitory efficacy.
Support: A grant from UCB SA
Disclosure: Grant - UCB SA