Mechanisms of T-type calcium channel blockade by zonisamide

Abstract

We investigated the effects of zonisamide, a new antiepileptic drug, on voltage-dependent T-type calcium current (ICa) in cultured neuroblastoma cells of human origin (NB-I). Zonisamide reduced T-type ICa in a concentration-dependent manner without evoking any change in its inactivation kinetics or voltage dependence of action. The mean percent reduction was 38.3 +/- 5.8% at 50 microM. Further, zonisamide shifted the inactivation curve approximately 20 mV negative compared to the control. These resting blocking actions suggest that zonisamide shifts the channel population toward the inactivation state, allowing fewer channels to open during membrane depolarization. The blockade of T-type calcium channels by zonisamide could suppress an important component of inward current that underlies epileptiform cellular bursting, thereby inhibiting the spread of seizure activity.

Different Mechanisms Underlying the Antiepileptic and Antiparkinsonian Effects of Zonisamide

“…However, subsequent pharmacological studies have demonstrated that the target molecules of ZNS include T-type voltage-sensitive Ca 2+ channel (Kito et al, 1996;Suzuki et al, 1992), Ca 2+ induced Ca 2+ releasing system (CICR) (Yamamura et al, 2009b;Yoshida et al, 2005), carbonic anhydrase (Yamamura et al, 2009a), redox (Tokumaru et al, 2000;Ueda et al, 2005;Ueda et al, 2003), neuronal depolarization-induced glutamate release (Okada et al, 1998;, enhancement of release of inhibitory neurotransmitters, e.g., GABA , dopamine and serotonin (Murakami et al, 2001;Okada et al, 1999;Okada et al, 1992;Okada et al, 1995) and lack of affinity to GABA A receptor (Rock et al, 1989). With regard to its antiparkinsonian action, ZNS enhances both the turnover and release of dopamine, and inhibits MAO-B activity and dopaminergic oxidative stress (Asanuma et al, 2008;Komatsu et al, 2000;Leppik, 2004;Mori et al, 1998;Murata, 2004;Okada et al, 1992;Okada et al, 1995;Ueda et al, 2005).…”

“…ZNS inhibits high-threshold voltage-sensitive Ca 2+ channel (L-type Ca 2+ channel) (Kito et al, 1996;Rossier et al, 1996 ). ZNS also inhibits low-threshold voltage-sensitive Ca 2+ channel (T-type Ca 2+ channel) in a concentration-dependent manner (Kito et al, 1996;Rossier et al, 1996;Suzuki et al, 1992).…”

“…ZNS inhibits high-threshold voltage-sensitive Ca 2+ channel (L-type Ca 2+ channel) (Kito et al, 1996;Rossier et al, 1996 ). ZNS also inhibits low-threshold voltage-sensitive Ca 2+ channel (T-type Ca 2+ channel) in a concentration-dependent manner (Kito et al, 1996;Rossier et al, 1996;Suzuki et al, 1992). The T-type Ca 2+ channel is activated by small depolarization of the neuronal plasma membrane; and the resulting Ca 2+ influx generates low threshold spikes that can trigger a burst of action potentials mediated by Na + channels (Perez-Reyes, 2003).…”

Treatment of epilepsy: existing therapies and future developments

“…The mechanism of action of zonisamide has not been elucidated, but it is known to block sodium channels (429) and T-type calcium channels (430). Block of T-type channels would be expected to shift the channel population toward the inactivation state, thus allowing fewer channels to open upon depolarization.…”

Cav3 T-Type Channels As Drug Targets For Treating Epilepsy

“…No medicines clinically available today are specific for blocking T-type calcium channels alone, but many of the current therapeutics for treating epilepsy do reduce T-type channel activity as one of its many drugs targets. Standard childhood absence epilepsy drugs that block T-type channels include Zarontin ® (ethosuximide; Parke-Davis, Pfizer, NY, USA) [13] and Depakote ® (valproate; Abbott Laboratories, IL, USA) [14], and newer generation, antiepileptic drug, Zonegran ® (zonisamide; Élan, Dublin, Ireland) [15] introduced this century and old formulation (1938), Dilantin ® (Phenytoin; Parke-Davis) [16]. Posicor ® (mibefradil; Roche Laboratories, NJ, USA) originally marketed as a selective antihypertensive agent, will block T-type channels and prevent seizure activity in animal models [14], but is no longer in clinical use because of its side effects on drug metabolism.…”