Oxcarbazepine does not suppress cortical spreading depression

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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Spreading Depression: From Serendipity to Targeted Therapy in Migraine Prophylaxis

Cephalalgia ◽

10.1111/j.1468-2982.2009.01982.x ◽

2009 ◽

Vol 29 (10) ◽

pp. 1095-1114 ◽

Cited By ~ 57

Author(s):

C Ayata

Keyword(s):

Targeted Therapy ◽

Drug Discovery ◽

Drug Screening ◽

Spreading Depression ◽

Migraine Prophylaxis ◽

Rational Approach ◽

Predictive Utility ◽

Mechanistic Insight ◽

Prophylactic Drugs ◽

Prophylactic Drug

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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Does Metoprolol Inhibit the Cortical Spreading Depression? Acute Effects of Systematic Metropol on CSD in Rats

Cephalalgia ◽

10.1111/j.1468-2982.2007.01390.x ◽

2007 ◽

Vol 27 (9) ◽

pp. 1010-1013 ◽

Cited By ~ 7

Author(s):

M Alemdar ◽

Ö Akman ◽

HM Selekler ◽

SŞ Komsuoğlu ◽

N Ateş

Keyword(s):

Dura Mater ◽

Cortical Spreading Depression ◽

Wistar Rats ◽

Spreading Depression ◽

Migraine Prophylaxis ◽

Migraine Aura ◽

Direct Effects ◽

Acute Effects ◽

Before And After ◽

Induction Model

Cortical spreading depression (CSD) is supposed to be the underlying biological basis of the migraine aura. Metoprolol was proven to be effective in migraine prophylaxis in clinical trials, but its mechanism of action has not been clarified yet. We studied direct effects of metoprolol on a continuous CSD induction model in rats. Six adult Wistar rats were anaesthetized with intraperitoneal thiopental (50 mg/kg). CSD was induced with application of 1 M KCL through a burr hole into the left frontal dura-mater, and recorded by an Ag/AgCl DC electrode on the left parietal dura-mater. After a basal recording of CSD induction during the first 40-min period, metoprolol (5 mg/kg) was infused within 4 min. Then DC recordings were maintained for a further 120 min. Any significant differences in total number and duration of CSDs before and after metoprolol administration were not detected. This study suggests that the mode of action of metoprolol in prophylaxis is not via direct CSD inhibition.

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Faculty Opinions recommendation of Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1161355.621864 ◽

2009 ◽

Author(s):

David Dodick ◽

Todd Schwedt

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Migraine Prophylaxis ◽

Proof Of Concept ◽

Double Blind ◽

Double Blind Placebo ◽

Concept Study

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Migraine

Oxford Textbook of Neurologic and Neuropsychiatric Epidemiology ◽

10.1093/med/9780198749493.003.0022 ◽

2020 ◽

pp. 213-224

Author(s):

Julio R Vieira ◽

Richard B Lipton

Keyword(s):

Chronic Migraine ◽

Migraine With Aura ◽

Cortical Spreading Depression ◽

Migraine Without Aura ◽

Spreading Depression ◽

Headache Frequency ◽

Motor Symptoms ◽

Migraine Aura ◽

Younger Age ◽

Psychiatric Conditions

This chapter examines migraine. The incidence of migraine varies depending on multiple aspects, including age, sex, and the presence of aura. At an earlier age (younger than age ten), migraine initially affects more boys than girls, with migraine with aura (MA) occurring at a younger age than migraine without aura (MO). Later in life, when puberty starts, this relationship changes and it becomes more common in women than men. Migraine aura are focal neurological symptoms that typically occur prior to the onset of a headache due to a phenomenon called cortical spreading depression. The prevalence of migraine with aura vary between visual, sensory, or motor symptoms. It can also present as diplopia, slurred speech, aphasia, dizziness, vertigo, and hemiparesis. Moreover, the prevalence of migraine varies according to headache frequency. The chapter then looks at chronic migraine and menstrual migraine. It also explores several comorbidities associated with migraine, including many neurologic, medical, and psychiatric conditions.

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Translational imaging studies of cortical spreading depression in experimental models for migraine aura

Expert Review of Neurotherapeutics ◽

10.1586/14737175.8.5.759 ◽

2008 ◽

Vol 8 (5) ◽

pp. 759-768 ◽

Cited By ~ 2

Author(s):

Justin M Smith ◽

Michael F James ◽

James A Fraser ◽

Christopher L-H Huang

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Experimental Models ◽

Migraine Aura ◽

Imaging Studies ◽

Translational Imaging

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Cortical spreading depression and the migraine aura

Internal Medicine Journal ◽

10.1111/j.1445-5994.2010.02309.x ◽

2010 ◽

Vol 40 (11) ◽

pp. 798-798

Author(s):

A. S. Zagami

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Migraine Aura

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High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16647398 ◽

2016 ◽

Vol 37 (3) ◽

pp. 890-901 ◽

Cited By ~ 24

Author(s):

Tsubasa Takizawa ◽

Mamoru Shibata ◽

Yohei Kayama ◽

Toshihiko Shimizu ◽

Haruki Toriumi ◽

...

Keyword(s):

Cortical Neurons ◽

Cortical Spreading Depression ◽

Microglial Activation ◽

Spreading Depression ◽

High Mobility ◽

High Mobility Group ◽

Migraine Aura ◽

Double Knockout ◽

Activated Microglia ◽

Important Mediator

Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1–TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

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