The Pharmacology of Calcium Channel Antagonists: a Novel Class of Anti‐migraine Agents?

Peroutka, Stephen J.

doi:10.1111/j.1526-4610.1983.hed2306278.x

Cited by 54 publications

(23 citation statements)

References 24 publications

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“…Given that Flunarizine’s effect as an anti-migraine drug is attributed to its properties as a CC blocker17 we hypothesized that cytosolic calcium concentration ([Ca 2+ ]) might play a critical role in Angpt-2 synthesis and the interplay with Flunarizine. To test this, we analysed the Angpt-2 lowering capacity of other CC blockers.…”

Section: Resultsmentioning

confidence: 99%

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

Retzlaff

Thamm

Ghosh

et al. 2017

Sci Rep

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Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection leading to systemic inflammation and endothelial barrier breakdown. The vascular-destabilizing factor Angiopoietin-2 (Angpt-2) has been implicated in these processes in humans. Here we screened in an unbiased approach FDA-approved compounds with respect to Angpt-2 suppression in endothelial cells (ECs) in vitro. We identified Flunarizine – a well-known anti-migraine calcium channel (CC) blocker – being able to diminish intracellular Angpt-2 protein in a time- and dose-dependent fashion thereby indirectly reducing the released protein. Moreover, Flunarizine protected ECs from TNFα-induced increase in Angpt-2 transcription and vascular barrier breakdown. Mechanistically, we could exclude canonical Tie2 signalling being responsible but found that three structurally distinct T-type - but not L-type - CC blockers can suppress Angpt-2. Most importantly, experimental increase in intracellular calcium abolished Flunarizine’s effect. Flunarizine was also able to block the injurious increase of Angpt-2 in murine endotoxemia in vivo. This resulted in reduced pulmonary adhesion molecule expression (intercellular adhesion molecule-1) and tissue infiltration of inflammatory cells (Gr-1). Our finding could have therapeutic implications as side effects of Flunarizine are low and specific sepsis therapeutics that target the dysregulated host response are highly desirable.

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Section: Resultsmentioning

confidence: 99%

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

Retzlaff

Thamm

Ghosh

et al. 2017

Sci Rep

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“…However, the mechanism of action of these drugs is thought to target the vascular aetiology of migraine, e.g. lower cerebral vasoconstriction by reducing Ca 2+ cellular influx (31,32). A recent meta-analysis of clinical trials data from a range of CCBs found no difference in reduction of migraine headaches relative to placebo (33), though clearly more data on specific drugs are required.…”

Section: Discussionmentioning

confidence: 99%

Serum calcium and risk of migraine: a Mendelian randomization study

et al. 2016

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Migraine affects ∼14% of the world’s population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising >1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 × 10−13), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 × 10−3). Second, we observed co-heritability (rg = 0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31–2.46, P = 2.5 × 10−4), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biological mechanism, pathways, and clinical implication for risk management.

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“…Painful, cold, "heavy," or "bursting" paresthesias of the face, mouth, and limbs have occurred during treatment with verapamil [ [147,149) have pointed out that, if intracranial vasoconstriction is important in the genesis of the migraine attack, Ca2 + channel antagonists might be ideal therapeutic agents, since they inhibit Ca2+-dependent vascular smooth muscle contraction evoked by a wide variety of vasoactive substances. Alternatively or in addition, these drugs could counteract central serotonergic abnormalities by inhibiting the release of serotonin from neurons [121).…”

Section: Clinical Pharmacologymentioning

confidence: 99%

Calcium channels and calcium channel antagonists

Greenberg

1987

Annals of Neurology

135

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Changes in free intracellular Ca2+ levels provide signals that allow nerve and muscle cells to respond to a host of external stimuli. A major mechanism for elevating the level of intracellular Ca2+ is the influx of extracellular Ca2+ through voltage-dependent channels in the cell membrane. Recent research has yielded new insights into the physiological properties, molecular structure, biochemical regulation, and functional heterogeneity of voltage-dependent Ca2+ channels. In addition, Ca2+ channel antagonist drugs have been developed that are valuable both as probes of channel structure and function and as therapeutic agents. Preliminary evidence suggests that these drugs may be useful in the treatment of diverse neurological disorders, including headache, subarachnoid hemorrhage, stroke, and epilepsy.

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The Pharmacology of Calcium Channel Antagonists: a Novel Class of Anti‐migraine Agents?

Cited by 54 publications

References 24 publications

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

Serum calcium and risk of migraine: a Mendelian randomization study

Calcium channels and calcium channel antagonists

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