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Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice
1Health Care Discovery, Novo Nordisk A/S, Måløv, Denmark.
Abstract:
This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice. Omega-Conotoxin MVIIC (0.1, 0.3 micrograms ICV/mouse) and omega-agatoxin IVA (0.1, 0.3, 1 micrograms ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED50 values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04-0.36) micrograms ICV and 0.09 (0.05-0.15) micrograms ICV respectively and against tonic seizures 0.07 (0.03-0.16) micrograms ICV and 0.08 (0.04-0.13) micrograms ICV, respectively). The N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA were also tested in this model. Omega-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 micrograms ICV prevented tonic seizures in 60% of the animals; 10 micrograms ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas omega-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 micrograms ICV. Both omega-conotoxin GVIA and omega-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 microgram ICV, whereas omega-conotoxin MVIIC and omega-agatoxin IVA did not produce shaking at any of the doses examined. Finally, omega-conotoxin GI (0.01-1 microgram ICV) and alpha-conotoxin SI (0.3-30 micrograms ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of omega-conotoxin MVIIC and omega-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.
Insights
Voltage-sensitive calcium channel blockers, omega-conotoxin MVIIC and omega-agatoxin IVA, effectively prevented seizures in DBA/2 mice. These P-/Q-type calcium channel blockers offer potential for further exploration in epilepsy treatment.
Area of Science:
- Neuropharmacology
- Epilepsy Research
- Calcium Channel Modulation
Background:
- Voltage-sensitive calcium channels (VSCCs) play critical roles in neuronal excitability and neurotransmitter release.
- DBA/2 mice exhibit sound-induced seizures, serving as a valuable model for studying epilepsy.
- Different subtypes of VSCCs are implicated in various neurological functions and disorders.
Purpose of the Study:
- To investigate the anticonvulsant and behavioral effects of specific voltage-sensitive calcium channel blockers in DBA/2 mice.
- To differentiate the effects of blockers targeting N-type versus P-/Q-type calcium channels.
- To explore the potential of P-/Q-type calcium channel blockers in managing reflex epilepsy.
Main Methods:
- Administration of various conotoxins (omega-conotoxin MVIIC, omega-agatoxin IVA, omega-conotoxin GVIA, omega-conotoxin MVIIA) and alpha-conotoxin SI via intracerebroventricular (ICV) injection in DBA/2 mice.
- Assessment of anticonvulsant activity against sound-induced clonic and tonic seizures.
- Observation and documentation of behavioral side effects, such as shaking syndrome.
- Calculation of ED50 values for seizure prevention.
Main Results:
- Omega-conotoxin MVIIC and omega-agatoxin IVA (P-/Q-type blockers) demonstrated significant anticonvulsant effects against sound-induced seizures.
- Omega-conotoxin GVIA (N-type blocker) showed anticonvulsant activity only at high doses and induced a shaking syndrome.
- Omega-conotoxin MVIIA (N-type blocker) was ineffective as an anticonvulsant and also induced shaking.
- Omega-conotoxin GI and alpha-conotoxin SI (nicotinic acetylcholine receptor blockers) had no anticonvulsant effects and did not induce shaking.
Conclusions:
- Blockers of P-/Q-type calcium channels (omega-conotoxin MVIIC, omega-agatoxin IVA) possess anticonvulsant properties in DBA/2 mice, potentially by inhibiting excitatory amino acid release.
- N-type calcium channel blockers (omega-conotoxin GVIA, omega-conotoxin MVIIA) exhibit different efficacy and behavioral side effect profiles.
- The distinct effects of different VSCC subtype blockers highlight their specific roles and therapeutic potential in epilepsy.
- P-/Q-type calcium channel blockers warrant further investigation for their anti-epileptic potential.