The impact of triptan and doxycycline on neuroinflammatory biomarkers in acute migraine: study protocol of a randomized controlled trial

Authors

DOI:

https://doi.org/10.3823/1612

Keywords:

headache, migraine, biomarkers, inflammation

Abstract

Background

Increased inflammatory cytokines and matrix metalloproteinases (MMPs) have been recently implicated in migraine. Inflammation may be a key player in the pathophysiology of migraine by altering blood-brain barrier (BBB) function. As an inflammation induced MMP, MMP-9 is involved in both BBB disruption and neuropathic pain, and is largely derived by neutrophil degranulation during neutrophil-BBB interaction. The tetracycline group of antibiotics may suppress MMP production and neutrophil degranulation.

Methods/Design

We hypothesize that migraine is a primary neuroinflammatory disorder. We will address this theory by measuring serum biomarkers in healthy controls and after one of three abortive therapy strategies for acute migraine attacks and inter-ictally. We intend to investigate known neuroinflammatory biomarkers with a focus on BBB breakdown during acute migraine attacks and assess marker responses to conventional treatment (triptans), novel MMP targeted therapy (doxycycline), or a combination of triptan and doxycycline. We will measure the effects of the interventions on neuroinflammatory markers for acute migraine attacks, clinical outcomes (headache relief and recurrence) for acute migraine attacks, inter-ictal neuroinflammatory load per serum biomarkers in migraineurs versus healthy controls, and neuroinflammatory markers correlation with headache duration and peak headache intensity during acute migraine attacks.

Discussion                                 

To our knowledge, this trial will be the first systematic study on the use of a MMP inhibitor in episodic migraine. Our pilot project data will supplement future projects investigating novel therapeutic strategies such as MMP inhibitors in both migraine acute treatment and prevention.

Trial Registration

ClinicalTrials.gov NCT01653522, registered 07/23/2012.

References

Burton WN, Landy SH, Downs KE, et al. The Impact of Migraine and the Effect of Migraine Treatment on Workplace Productivity in the United States and Suggestions for Future Research. Mayo Clin Proc 2009; 84(5): 436-445.

Longoni M, Ferrarese C. Inflammation and excitotoxicity: role in migraine pathogenesis. Neurol Sci 2006; 27 Suppl 2:S107-10.

Sánchez-del-Rio M, Reuter U. Migraine aura: new information on underlying mechanisms. Curr Opin Neurol 2004; 17(3):289-93.

Bolay H, Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in migraine model. Nat Med 2002; 8(2):136-42.

Waeber C, Moskowitz MA. Migraine as an inflammatory disorder. Neurology 2005; 64(10 Suppl 2):S9-15.

Moskowitz MA, Macfarlane R. Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 1993, 5(3):159-77.

Welch KM, Brandes AW, Salerno L, et al. C-reactive protein may be increased in migraine patients who present with complex clinical features. Headache 2006; 46(2):197-9.

Welch KM. Stroke and migraine—the spectrum of cause and effect. Func Neurol 2003; 18(3):121-6.

Koçer A, Memişoğullari R, Domaç FM, et al. IL-6 levels in migraine patients receiving topiramate. Pain Pract 2009; 9(5):375-9.

Kaciński M, Gergont A, Kubik A, et al. Proinflammatory cytokines in children with migraine with or without aura. Przegl Lek 2005;62(11):1276-80.

Gergont A, Kaciński M. Blood interleukin-6 level in children with idiopathic headaches. Neurol Neurochir Pol 2005; 39(4 Suppl 1):S1-8.

Perini F, D'Andrea G, Galloni E, et al. Plasma cytokine levels in migraineurs and controls. Headache 2005; 45(7):926-31.

Fidan I, Yüksel S, Ymir T, et al. The importance of cytokines, chemokines and nitric oxide in pathophysiology of migraine. J Neuroimmunol 2006;171(1-2):184-8.

Gupta VK. CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev Neurother 2009;9(11):1595-614.

Matrisian LM. Metalloproteinases and their inhibitors in matrix remodelling. Trends Genet 1990;121-125.

Chandler S, Miller KM, Clements JM, et al. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: An overview. J Neuroimmunol 1997; 72:155-161.

Leppert D, Waubant E, Galardy R, et al. T cell gelatinases mediate basement membrane transmigration in vitro. J Immunol 1995; 154:4397-4389.

Aoki T, Sumii T, Mori T, et al. Blood-brain barrier disruption and matrix-metalloproteinase-9 expression during reperfusion injury: Mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke 2002; 33:2711-2777.

Leira R, Sobrino T, Rodríguez-Yáñez M, et al. MMP-9 Immunoreactivity in Acute Migraine. Headache 2007; 47(5): 698-702.

Imamura K, Takeshima T, Fusayasu E, et al. Increased Plasma Matrix Metalloproteinase-9 Levels in Migraineurs. Headache 2008; 48(1): 135-139.

Ashina M, Tvedskov JF, Lipka K, et al. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia 2010; 30(3):303-310.

Berneckera C, Pailera S, Kieslinger P, et al. Increased matrix metalloproteinase activity is associated with migraine and migraine-related metabolic dysfunctions. European Journal of Neurology 2011; 18: 571-576.

Minagar A., Alexander JS., Schwendimann RN., et al, Combination Therapy With Interferon Beta-1a and Doxycycline in Multiple Sclerosis. Arch Neurol 2008; 65(2):199-204.

Machado LS, Sazonova I, Kozak A, et al. Minocycline and tissue plasminogen activator for stroke: Assessment of interaction potential. Stroke 2009; 40(9): 3028-3033.

Kim GM, Jin K-S, Chung CS. Differential Effects of Corticosteroids on The Expression of Cyclooxygenase-2, Tumour Necrosis Factor-Alpha and Matrix Metalloproteinase-9 in An Animal Model of Migraine. Cephalalgia 2008, 28, 1179-1187.

Rozen TD. Doxycycline for treatment resistant new daily persistant headache. Neurology 2008; 70 (Suppl 1):A348 (abstract).

Rozen TD. New Daily Persistent Headache: Clinical Perspective. Headache 2011;51:650-653.

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Published

2015-02-07

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Section

Neurology