Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo
| Autor: | Toni Schneider, Wolfram F. Neiss, Maxine Dibué-Adjei, Marcel A. Kamp, Jürgen Hescheler, Etienne E. Tevoufouet, Serdar Alpdogan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Topiramate Lacosamide Genotype Physiology Antiepileptic drugs Calcium Channels R-Type Fructose Lamotrigine Pharmacology lcsh:Physiology lcsh:Biochemistry 03 medical and health sciences Epilepsy Mice 0302 clinical medicine Acetamides medicine Animals lcsh:QD415-436 Ictal Mice Knockout Kainic Acid Toxicity lcsh:QP1-981 Voltage-dependent calcium channel Behavior Animal Chemistry Triazines Pyramidal Cells Neurotoxicity R-type medicine.disease Immunohistochemistry Mice Inbred C57BL Cav2.3 030104 developmental biology Neuroprotective Agents Quantitative electroencephalography Mechanism of action Anticonvulsants Electrocorticography medicine.symptom 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 44, Iss 3, Pp 935-947 (2017) |
| ISSN: | 1421-9778 |
| Popis: | 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. 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 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. Conclusion: 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. |
| Databáze: | OpenAIRE |
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