Pharmacological study of spreading depression. The effect of antiepileptic drugs used in migraine prophylaxis

Despite the relatively well-characterized headache mechanisms in migraine, upstream events triggering individual attacks are poorly understood. This lack of mechanistic insight has hampered a rational approach to prophylactic drug discovery. Unlike targeted abortive and analgesic interventions, mainstream migraine prophylaxis has been largely based on serendipitous observations (e.g. propranolol) and presumed class effects (e.g. anticonvulsants). Recent studies suggest that spreading depression is the final common pathophysiological target for several established or investigational migraine prophylactic drugs. Building on these observations, spreading depression can now be explored for its predictive utility as a preclinical drug screening paradigm in migraine prophylaxis.

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Oxcarbazepine does not suppress cortical spreading depression

Cephalalgia ◽

10.1177/0333102410388433 ◽

2010 ◽

Vol 31 (5) ◽

pp. 537-542 ◽

Cited By ~ 12

Author(s):

Ulrike Hoffmann ◽

Ergin Dileköz ◽

Chiho Kudo ◽

Cenk Ayata

Keyword(s):

Single Dose ◽

Cortical Spreading Depression ◽

Chronic Treatment ◽

Spreading Depression ◽

Screening Tool ◽

Positive Control ◽

Migraine Prophylaxis ◽

Migraine Aura ◽

Predictive Utility ◽

Prophylactic Drugs

Background: Cortical spreading depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress cortical spreading depression, implicating spreading depression as a common therapeutic target in migraine prophylaxis. Materials and methods: In order to assess the negative predictive value of spreading depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical spreading depression susceptibility was measured in rats using topical KCl or electrical stimulation. Results: Oxcarbazepine did not suppress spreading depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed spreading depression susceptibility after chronic dosing, while a single dose was ineffective. Conclusions: These data provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models.

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Nα -Methyl Histamine Safety and Efficacy in Migraine Prophylaxis: Phase III Study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100004960 ◽

2006 ◽

Vol 33 (2) ◽

pp. 195-199 ◽

Cited By ~ 22

Author(s):

Rebeca O. Millán-Guerrero ◽

Rebeca Isais-Millán ◽

Trujillo-Hernández Benjamín ◽

Carlos E. Tene

Keyword(s):

Therapeutic Potential ◽

International Headache Society ◽

Pharmacological Study ◽

Subcutaneous Administration ◽

Migraine Prophylaxis ◽

Phase Iii ◽

Controlled Clinical Trial ◽

Double Blind ◽

Adverse Experiences ◽

Phase Iii Study

ABSTRACT:Background:The histamine catabolite, Nα-methylhistamine, possesses a selective affinity for H3 receptors. For this reason, we considered evaluating the efficacy of this histaminergic H3 agonist in migraine prophylactic treatment.Objective:To study the therapeutic potential of the subcutaneous administration of Nα-methylhistamine in migraine prophylaxis, in a Phase III clinical pharmacological study.Methods:Using a controlled double-blind, placebo controlled clinical trial for 12 weeks, 60 patients with migraine, who fit the criteria established by the International Headache Society, were selected. The efficacy of subcutaneous administration of Nα-methylhistamine 1 to 3 ng twice a week against placebo was studied, evaluating the outcome of headache intensity, frequency, duration, and analgesic intake.Results:Comparison between the groups treated with placebo (n=30) and Nα-methylhistamine (n=30), on data collected for the 4th, 8th and 12th weeks of treatment, revealed that Nα-methylhistamine exerted a significant (p<0.0001) reduction (compared to placebo) in intensity, frequency, and duration of migraine attacks, as well as on the use of analgesic intake. No significant (p>0.05) adverse experiences or side effects developed in either group.Conclusions:The present study provides evidence of the efficacy of Nα-methylhistamine, given subcutaneously at doses of 1 to 3 ng twice a week, offering a new therapeutic alternative and laying the clinical and pharmacological groundwork for the use of histaminergic H3-agonists in migraine prophylaxis, which may specifically inhibit the neurogenic edema response involved in migraine pathophysiology.

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