Interaction between Ca²⁺, K⁺, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with a microdialysis electrode

Abstract

Multiple components of hippocampal glutamate release were examined by study of Ca2+‐ and K+‐evoked hippocampal extracellular glutamate release using an in vivo microdialysis glutamate biosensor in urethane‐anaesthetized rats. In addition, the effects of the antiepileptic drugs, carbamazepine (CBZ) and zonisamide (ZNS) perfused through the probe on glutamate release were assessed. Basal glutamate levels were below detection limits (∼0.1 μm). An increase in extracellular KCl (from 2.7 to 50 and 100 mm) increased extracellular hippocampal glutamate levels to 9.2±1.4 and 20.0±2.6 μm, respectively, calculated from the area under curve (AUC) for 60 min. This KCl‐evoked glutamate release consisted of three components: an initial transient rise, a late gentle rise, and late multiple phasic transient rises. An increase in or removal of extracellular CaCl2 levels respectively enhanced and reduced the 50 mm KCl‐evoked hippocampal glutamate release (AUC for 60 min) from 9.2±1.4 to 12.4±2.1 and 5.8±0.9 μm. Perfusion with 100 μm CBZ or 1 mm ZNS inhibited both the 50 mm KCl‐evoked hippocampal glutamate release (AUC for 60 min) from 9.2±1.4 to 5.5±1.1 and to 5.8±1.3 μm, respectively, as well as the stimulatory effects of Ca2+ on KCl‐evoked hippocampal glutamate release. These results suggest that both CBZ and ZNS may reduce epileptiform events by inhibiting excitatory glutamatergic transmission. British Journal of Pharmacology (1998) 124, 1277–1285; doi:

Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists

“…However, the mechanisms underlying the effects of this AED have not been completely identified, and are still a matter of debate. It has been shown that CBZ can inhibit Ca 2 + channels (Elliott, 1990;Schirrmacher et al, 1993;Schumacher et al, 1998), enhance 4-aminopyridine-sensitive potassium currents in cortical neurons (Olpe et al, 1991), acts as an antagonist of adenosine A 1 receptors (Biber et al, 1996), attenuates cAMP production (Chen et al, 1996), induces the release of serotonin (Dailey et al, 1997a,b), and inhibits the release of glutamate (Waldmeier et al, 1996;Okada et al, 1998). Preischemic treatment with CBZ also tends to reduce the cerebral damage and neurological deficit (Minato et al, 1997).…”

Different Mechanisms Underlying the Antiepileptic and Antiparkinsonian Effects of Zonisamide

“…However, subsequent studies demonstrated that different affinities to carbonic anhydrase subtypes (Casini et al, 2003;Supuran, 2008). The Ki values for ZNS on cytosolic hCAII (35 nM), mitochondrial hCAV (20 nM) and plasma membrane binding hCAIX (5.1 nM) (Casini et al, 2003;Supuran, 2008) are lower than the therapeutic-relevant plasma concentrations of ZNS Okada et al, 1995;Yamamura et al, 2009a). Activation of GABA A receptor opens its Cl − channel, which is permeable to both HCO 3 − efflux and Cl − influx (Staley et al, 1995).…”

“…Both systemic administration of therapeutically-relevant dose and local perfusion of therapeutically-relevant concentration of ZNS reduced depolarization induced glutamate release in the hippocampus and frontal cortex (Okada et al, 1998;Yamamura et al, 2009a;Yamamura et al, 2009b;Yamamura et al, 2009c;Yoshida et al, 2005). It has been demonstrated that continuous stimulation induced by glutamate release has several components: (1) a Ca 2+ -dependent initial rise, which is neuronal activity-independent, (2) this initial rise s followed by a series of Ca 2+ -dependent phasic rises associated with neuronal activity, and (3) a small overflow of glutamate that persists in a Ca 2+ -independent manner (Obrenovitch et al, 1993;Obrenovitch et al, 1996;Okada et al, 1998;Zilkha et al, 1995).…”

“…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). While the typical dose of ZNS is 300 to 600 mg/day for patients with epilepsy (Seino et al, 1988), a significant improvement in motor symptoms is reported in patients of Parkinson's disease treated with only 25 to 100 mg/day of ZNS (Murata, 2004;Murata et al, 2007).…”

Moderate toxic effects following acute zonisamide overdose

“…Zonisamide (ZNS), a sulfonamide derivative, is an anti-epileptic drug (AED) that acts on voltage-sensitive sodium and T-type calcium channels [1,2], blocking potassiumevoked glutamate response [3]. ZNS modulates GABA-mediated neuronal inhibition [4] and weakly inhibits carbonic anhydrase (CA) activity [5].…”