Voltage-gated calcium channels are not affected by the novel anti-epileptic drug lacosamide

Wang, Yuying; Khanna, Rajesh

doi:10.2478/s13380-011-0002-9

Cited by 18 publications

(18 citation statements)

References 55 publications

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“…We have previously shown that (R)-LCM does not inhibit Ca 2+ currents in hippocampal neurons [70] but whether ( S )-LCM inhibits Ca 2+ currents in sensory neurons is unknown. For these voltage-clamp experiments we chose a concentration of 10µM ( S )-LCM, a value ~8 times the IC 50 value calculated from Ca 2+ imaging experiments, to assess potential off-target effects.…”

Section: Resultsmentioning

confidence: 99%

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(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Moutal

Chew

Yang

et al. 2016

Pain

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Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2–CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration–approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca2+ influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca2+ currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

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Section: Resultsmentioning

confidence: 99%

“…Vimpat modulates slow inactivation of Na + channels [22; 56] with an IC 50 of 80 µM [71]. Critically, we and others have demonstrated that at doses active in vivo for inhibition of seizures, ( R )-LCM does not modulate Ca 2+ activity [70]. …”

Section: Introductionmentioning

confidence: 99%

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Moutal

Chew

Yang

et al. 2016

Pain

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“…Primary cultured hippocampal neurons were treated with 300 μM lacosamide for 0.5–24 hours. Whole cell patch clamp recordings revealed that neither acute nor chronic treatment altered current density or kinetics of activation or inactivation [46]. As the L-type calcium channel currents were inhibited by the presence of nifedipine, currents predominantly represented calcium carried through N-type channels, with a small percentage attributed to P/Q-type channels at this age in culture [47].…”

Section: Does Lacosamide Have a Dual Mode Of Action?mentioning

confidence: 99%

Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide

Wilson

Khanna

2014

Mol Neurobiol

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The novel anti-epileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide’s ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e. seizures). While the role of CRMP2 in epilepsy has not been well-studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease-modifying. Recently, however, the validity of lacosamide’s interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2, as well as, the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of anti-epileptic drugs influence only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome.

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“…Catecholamine A-differentiated (CAD) Cell Culture-CAD cells were cultured exactly as described (20,21).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

Wilson

Schmutzler

Brittain

et al. 2012

Journal of Biological Chemistry

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Background: N-type Ca 2ϩ channels (CaV2.2) are clinically validated targets for chronic pain. Results: Two peptides from CaV2.2 and CaV1.2 perturb binding to a regulatory protein, CRMP2, inhibit calcium influx, and attenuate mechanical hyperalgesia in a rodent model of drug-induced chronic pain. Conclusion: Ca 2ϩ channel peptides block drug-and nerve injury-induced chronic pain. Significance: Ca 2ϩ channel peptide therapeutics can be useful in mitigating chronic pain.

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Voltage-gated calcium channels are not affected by the novel anti-epileptic drug lacosamide

Cited by 18 publications

References 55 publications

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

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