Premium
Retracted : Ca v 2.3 ( R ‐type) calcium channels are critical for mediating anticonvulsive and neuroprotective properties of lamotrigine in vivo
Author(s) -
Dibué Maxine,
Kamp Marcel A.,
Alpdogan Serdar,
Tevoufouet Etienne E.,
Neiss Wolfram F.,
Hescheler Jürgen,
Schneider Toni
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12250
Subject(s) - lamotrigine , pharmacology , anticonvulsant , lacosamide , epilepsy , topiramate , in vivo , ictal , kainic acid , chemistry , calcium channel , anesthesia , medicine , calcium , neuroscience , receptor , psychology , glutamate receptor , biology , biochemistry , microbiology and biotechnology
Summary Purpose 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 Ca v 2.3 ( 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 two other AED s in Ca v 2.3‐deficient mice and controls on KA ‐induced seizures. Methods 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 30 mg/kg LTG , 50 mg/kg topiramate ( TPM ), or 30 mg/kg lacosamide ( LSM ). Key Findings Ablation of Ca v 2.3 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 Ca v 2.3‐deficient mice, LTG pretreatment increased seizure activity by 22.1% (p = 0.018) and increased the percentage of degenerated CA 1 pyramidal neurons (p = 0.02). All three AED s reduced seizure activity in control mice; however, only the non–calcium channel modulating AED , LSM , had an anticonvulsive effect in Ca v 2.3‐deficient mice. Furthermore, LTG altered electrocorticographic parameters differently in the two genotypes: decreasing relative power of ictal spikes in control mice but increasing relative power of high frequency fast ripple discharges during seizures in Ca v 2.3‐deficient mice. Significance These findings provided the first in vivo evidence for an essential role for Ca v 2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Ca v 2.3‐deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA 1. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA 1 neurons after increased inhibition, may be key in understanding LTG ‐induced seizure aggravation observed in clinical practice.