Dibué-Adjei Maxine, Kamp Marcel A, Alpdogan Serdar, Tevoufouet Etienne E, Neiss Wolfram F, Hescheler Jürgen, Schneider Toni
Institute for Neurophysiology, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Cell Physiol Biochem. 2017;44(3):935-947. doi: 10.1159/000485361. Epub 2017 Nov 24.
BACKGROUND/AIMS: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Cav2.3-deficient mice and controls on KA-induced seizures.
Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM).
Ablation of Cav2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Cav2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice.
These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice.
背景/目的：拉莫三嗪（LTG）是一种常用的现代抗癫痫药物（AED），然而，其作用机制尚未完全明确，因为已知它可调节多个离子通道家族的许多成员。在异源系统中，LTG可抑制Cav2.3（R型）钙电流，而该电流在体内可导致 kainic 酸（KA）诱发的癫痫。为深入了解R型电流在LTG体内药物作用中的作用，我们比较了LTG与托吡酯和拉科酰胺对Cav2.3基因敲除小鼠和对照小鼠KA诱发癫痫的影响。
注射20mg/kg[和30mg/kg]KA后进行行为性癫痫评分和定量脑电图检查。在注射KA前1小时，小鼠分别用30mg/kg LTG、50mg/kg托吡酯（TPM）或30mg/kg拉科酰胺（LSM）进行预处理。
Cav2.3基因敲除使癫痫总评分降低28.6%（p = 0.0012），LTG预处理使对照小鼠的癫痫活动降低23.2%（p = 0.02）。在Cav2.3基因敲除小鼠中，LTG预处理使癫痫活动增加22.1%（p = 0.018），并增加了CA1锥体神经元变性的百分比（p = 0.02）。所有三种受试的AED均降低了对照小鼠的癫痫活动，但只有非钙通道调节的AED拉科酰胺在Cav2.3基因敲除小鼠中有抗惊厥作用。此外，LTG在两种基因型中对脑电图参数的影响不同，与Cav2.3基因敲除小鼠相比，它降低了对照小鼠发作期棘波的相对功率。
这些发现首次在体内证明了Cav2.3在LTG药理学中的重要作用，并揭示了在其缺失时LTG的矛盾效应。此外，LTG似乎在Cav2.3基因敲除小鼠中促进发作期活动，导致CA1区域神经毒性增加。这种矛盾机制可能反映了在增强抑制后锥体CA1神经元的反弹性过度兴奋，可能是理解临床实践中观察到的LTG诱发癫痫加重的关键。
