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The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2023

Open Access 01-12-2023 | Medication Overuse Headache | Research

Medication overuse headache is associated with elevated lipopolysaccharide binding protein and pro-inflammatory molecules in the bloodstream

Authors: Hale Gök Dağıdır, Elif Topa, Doga Vuralli, Hayrunnisa Bolay

Published in: The Journal of Headache and Pain | Issue 1/2023

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Abstract

Objective

Medication overuse headache (MOH) is a secondary headache that accompanies chronic migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used analgesics worldwide and they are known to induce leaky gut. In this study, we aimed to investigate whether NSAID induced MOH is associated with altered circulating lipopolysaccharide binding protein (LBP) levels and inflammatory molecules.

Materials and methods

Piroxicam (10 mg/kg/day, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain behavior was evaluated by periorbital withdrawal thresholds, head-face grooming, freezing, and head shake behavior. Serum samples and brain tissues were collected to measure circulating LBP, tight junction protein occludin, adherens junction protein vascular endothelial (VE)-cadherin, calcitonin gene-related peptide (CGRP), IL-6 levels and brain high mobility group box-1 (HMGB1) and IL-17 levels.

Results

Chronic piroxicam exposure resulted in decreased periorbital mechanical withdrawal thresholds, increased head-face grooming, freezing, and head shake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was positively correlated with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618) and head shakes (r = 0.921), and negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.740).

Conclusion

Elevated serum LBP, VE-cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation were shown in female rats with MOH. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules such as HMGB1, IL-6, IL-17 and CGRP may play a role in the development and maintenance of MOH. Interference with leaky gut and pro-inflammatory nociceptive molecules could also be a target for sustained management of MOH.
Literature
1.
Carlsen LN et al (2020) Comparison of 3 Treatment Strategies for Medication Overuse Headache: A Randomized Clinical Trial. JAMA Neurol 77(9):1069–1078PubMedCrossRef
2.
Mathew NT, Kurman R, Perez F (1990) Drug induced refractory headache–clinical features and management. Headache 30(10):634–638PubMedCrossRef
3.
Evlice A et al (2023) Secondary headache disorders in Turkey, the Middle East, Asia, and Africa: A cross-sectional, multicenter study. Cephalalgia 43(8):3331024231194024PubMedCrossRef
4.
Law S, Derry S, Moore RA (2013) Naproxen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013(10):CD009455PubMedPubMedCentral
5.
Bhatt AP et al (2018) Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells. ACS Infect Dis 4(1):46–52PubMedCrossRef
6.
d'Angelo M et al (2023) Differential effects of nonsteroidal anti-inflammatory drugs in an in vitro model of human leaky gut. Cells 12(5):728
7.
8.
Usuda H, Okamoto T, Wada K (2021) Leaky gut: effect of dietary fiber and fats on microbiome and intestinal barrier. Int J Mol Sci 22(14):7613
9.
Ryu JK et al (2017) Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14, and TLR4-MD2 for efficient LPS recognition and transfer. Immunity 46(1):38–50PubMedCrossRef
10.
Rorato R et al (2017) LPS-induced low-grade inflammation increases hypothalamic JNK expression and causes central insulin resistance irrespective of body weight changes. Int J Mol Sci 18(7):1431
11.
12.
Kudoh K et al (2020) Lipopolysaccharide-binding protein is a distinctive biomarker of abnormal pain threshold in the general Japanese population. BMJ Open Diab Res Care 8(1):e001739
13.
Vuralli D et al (2022) Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition. J Headache Pain 23(1):36PubMedPubMedCentralCrossRef
14.
Buonvicino D et al (2018) Trigeminal ganglion transcriptome analysis in 2 rat models of medication-overuse headache reveals coherent and widespread induction of pronociceptive gene expression patterns. Pain 159(10):1980–1988PubMedCrossRef
15.
Edogawa S et al (2018) Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota. Faseb J 32(12):fj201800560RPubMedCrossRef
16.
Navratilova E et al (2020) Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache. Cephalalgia 40(9):892–902PubMedPubMedCentralCrossRef
17.
Reuter U et al (2001) Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124(12):2490–2502PubMedCrossRef
18.
19.
Chen H et al (2022) IL-17 crosses the blood-brain barrier to trigger neuroinflammation: a novel mechanism in nitroglycerin-induced chronic migraine. J Headache Pain 23(1):1PubMedPubMedCentralCrossRef
20.
21.
Bolay H et al (2021) HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism. J Headache Pain 22(1):94PubMedPubMedCentralCrossRef
22.
Chen PY et al (2023) Neuronal NLRP3 inflammasome mediates spreading depolarization-evoked trigeminovascular activation. Brain 146(7):2989–3002PubMedCrossRef
23.
Harriott AM et al (2023) The effect of sex and estrus cycle stage on optogenetic spreading depression induced migraine-like pain phenotypes. J Headache Pain 24(1):85PubMedPubMedCentralCrossRef
24.
25.
Alpay B et al (2023) Levcromakalim provokes an acute rapid-onset migraine-like phenotype without inducing cortical spreading depolarization. J Headache Pain 24(1):93PubMedPubMedCentralCrossRef
26.
Columb M, Stevens A (2008) Power analysis and sample size calculations. Curr Anaesth Crit Care 19:12–14CrossRef
27.
Wang Y et al (2023) Activation of the microglial P2X7R/NLRP3 inflammasome mediates central sensitization in a mouse model of medication overuse headache. Front Mol Neurosci 16:1177171PubMedPubMedCentralCrossRef
28.
29.
Olsson A et al (2021) Circulating levels of tight junction proteins in multiple sclerosis: Association with inflammation and disease activity before and after disease modifying therapy. Mult Scler Relat Disord 54:103136PubMedCrossRef
30.
Yuan S et al (2021) Serum Occludin Level Combined With NIHSS Score Predicts Hemorrhage Transformation in Ischemic Stroke Patients With Reperfusion. Front Cell Neurosci 15:714171PubMedPubMedCentralCrossRef
31.
Chang Z et al (2022) Improvement of gut-vascular barrier by terlipressin reduces bacterial translocation and remote organ injuries in gut-derived sepsis. Front Pharmacol 13:1019109PubMedPubMedCentralCrossRef
32.
Socała K et al (2021) The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res 172:105840PubMedCrossRef
33.
Tang Y et al (2020) Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation. Mol Neurobiol 57(1):461–468PubMedCrossRef
34.
Seethaler B et al (2021) Biomarkers for assessment of intestinal permeability in clinical practice. Am J Physiol Gastrointest Liver Physiol 321(1):G11-g17PubMedCrossRef
35.
Zweigner J et al (2002) High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood 98:3800–3808CrossRef
36.
Schumann RR (2011) Old and new findings on lipopolysaccharide-binding protein: a soluble pattern-recognition molecule. Biochem Soc Trans 39(4):989–993PubMedCrossRef
37.
Kuzma JN et al (2019) Intraindividual variation in markers of intestinal permeability and adipose tissue inflammation in healthy normal-weight to obese adults. Cancer Epidemiol Biomarkers Prev 28(3):610–615PubMedCrossRef
38.
Otani T, Furuse M (2020) Tight Junction Structure and Function Revisited: (Trends in Cell Biology 30, 805-817, 2020). Trends Cell Biol 30(12):1014PubMedCrossRef
39.
40.
41.
Langer V et al (2019) IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. J Clin Invest 129(11):4691–4707PubMedPubMedCentralCrossRef
42.
He X et al (2017) Clinical significance of serum MCP-1 and VE-cadherin levels in patients with acute cerebral infarction. Eur Rev Med Pharmacol Sci 21(4):804–808PubMed
43.
44.
Gomes JMG, Costa JA, Alfenas RCG (2017) Metabolic endotoxemia and diabetes mellitus: A systematic review. Metabolism 68:133–144PubMedCrossRef
45.
46.
Kochi T et al (2021) Pretreatment with high mobility group box-1 monoclonal antibody prevents the onset of trigeminal neuropathy in mice with a distal infraorbital nerve chronic constriction injury. Molecules 26(7):2035
47.
Vuralli D, Bolay H (2023) Migraine chronification is associated with higher body mass index and elevated serum interleukin-6 levels. Annals of Medical Research 30(9):1149–1152
48.
Karadaş Ö et al (2021) Latent class cluster analysis identified hidden headache phenotypes in COVID-19: impact of pulmonary infiltration and IL-6. Neurol Sci 42(5):1665–1673PubMedPubMedCentralCrossRef
49.
50.
Chantong C et al (2013) Increases of pro-inflammatory cytokine expression in hippocampus following chronic paracetamol treatment in rats. Asian Arch Pathol 9:137–146
51.
Raddant AC, Russo AF (2011) Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med 13:e36PubMedPubMedCentralCrossRef
52.
53.
Metadata
Title
Medication overuse headache is associated with elevated lipopolysaccharide binding protein and pro-inflammatory molecules in the bloodstream
Authors
Hale Gök Dağıdır
Elif Topa
Doga Vuralli
Hayrunnisa Bolay
Publication date
01-12-2023
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2023
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-023-01672-4

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