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Updated: Jul 11, 2025
Sub-acute Cerebral Microhemorrhages Induced by Lipopolysaccharide Injection in Rats
Published on: October 17, 2018
Medication overuse headache is associated with elevated lipopolysaccharide binding protein and pro-inflammatory
Hale Gök Dağıdır1, Elif Topa2, Doga Vuralli1,2,3
1Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Beşevler, Ankara, Türkiye.
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.
Insights
Nonsteroidal anti-inflammatory drug (NSAID) induced medication overuse headache (MOH) in rats is linked to a leaky gut. This study found elevated lipopolysaccharide binding protein (LBP) and inflammatory markers, suggesting a role for gut barrier disruption in MOH.
Area of Science:
- Neuroscience
- Gastroenterology
- Pharmacology
Background:
- Medication overuse headache (MOH) is a common complication of chronic migraine.
- Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for pain relief, are known to disrupt intestinal barrier function.
- The link between NSAID-induced leaky gut and MOH pathophysiology remains unclear.
Purpose of the Study:
- To investigate the association between NSAID-induced MOH and alterations in circulating lipopolysaccharide binding protein (LBP) levels.
- To examine the role of inflammatory molecules in the development of MOH.
- To explore the impact of NSAID exposure on intestinal barrier integrity and systemic inflammation.
Main Methods:
- Medication overuse headache (MOH) was induced in female Sprague Dawley rats using piroxicam (10 mg/kg/day) for 5 weeks.
- Pain behaviors were assessed, and serum and brain tissues were collected for analysis.
- Levels of LBP, tight junction proteins (occludin, VE-cadherin), and inflammatory markers (CGRP, IL-6, HMGB1, IL-17) were measured.
Main Results:
- Piroxicam exposure significantly increased pain behaviors indicative of MOH.
- Rats with MOH exhibited elevated serum levels of LBP, CGRP, IL-6, IL-17, occludin, and VE-cadherin.
- Increased levels of IL-17 and HMGB1 were observed in the brain tissue of the piroxicam-treated group.
- Serum LBP showed positive correlations with intestinal barrier markers and inflammatory molecules, and negative correlation with pain thresholds.
Conclusions:
- NSAID-induced MOH in rats is associated with disrupted intestinal barrier function and increased systemic LPS.
- Elevated LBP, VE-cadherin, and occludin levels indicate gut leakage contributing to MOH.
- Inflammatory mediators like HMGB1, IL-6, IL-17, and CGRP may play a crucial role in MOH pathogenesis.
- Targeting leaky gut and pro-inflammatory pathways offers potential therapeutic strategies for MOH management.
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