Universität zu Köln

Dibue-Adjei, Maxine, Kannp, Marcel A., Alpdogan, Serdar, Tevoufouet, Etienne E., Neiss, Wolfram F., Hescheler, Juergen and Schneider, Toni (2017). Ca(v)2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo. Cell. Physiol. Biochem., 44 (3). S. 935 - 948. BASEL: KARGER. ISSN 1421-9778

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Abstract

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 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 either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). Results: 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 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 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 compared to Ca(v)2.3-deficient mice. Conclusion: These findings give 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 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. (C) 2017 The Author(s) Published by S.Karger AG, Basel

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dibue-Adjei, Maxine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kannp, Marcel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alpdogan, Serdar UNSPECIFIED UNSPECIFIED UNSPECIFIED Tevoufouet, Etienne E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neiss, Wolfram F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Toni UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-244702
DOI:	10.1159/000485361
Journal or Publication Title:	Cell. Physiol. Biochem.
Volume:	44
Number:	3
Page Range:	S. 935 - 948
Date:	2017
Publisher:	KARGER
Place of Publication:	BASEL
ISSN:	1421-9778
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CA2+ CHANNEL; MICE LACKING; CA1 NEURONS; H-CHANNELS; EPILEPSY; SEIZURES; LACOSAMIDE; EEG; OSCILLATIONS; DEATH Multiple languages Cell Biology; Physiology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24470