Fluoxetine attenuates UPR-activation, neuroinflammation, and oxidative stress in a nitroglycerin-induced rat model of migraine

Document Type : Original Article

Authors

1 Department of Clinical Biochemistry, Autophagy Research Centre School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Anatomical Sciences, Histomorphometry and Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran

10.22038/ijbms.2026.90321.19468

Abstract

Objective(s): Migraine is a debilitating neurological disorder characterized by oxidative stress, neuroinflammation, and dysregulation of the unfolded protein response (UPR) in the brain. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has demonstrated neuroprotective properties, but its effects on UPR activation, neuroinflammation, and oxidative stress in migraine are not well defined. This study evaluates the effects of fluoxetine on UPR-related gene expression, inflammatory cytokines, and oxidative stress markers in a nitroglycerin (NTG)-induced chronic migraine rat model.
Materials and Methods: Rats were divided into control, NTG-induced chronic migraine, and fluoxetine-treated groups. Behavioral light aversion was assessed. Trigeminal ganglion tissues were analyzed for expression of UPR-associated genes (Bip, XBP-1, CHOP) and inflammatory markers (IL-6, IL-1β, IL-10, NF-κB, TNF-α) using molecular techniques. Serum levels of oxidative stress indicators, including catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (TAC), were measured.
Results: Our results demonstrate that fluoxetine treatment effectively tempered the maladaptive UPR by modulating the expression of Bip, XBP-1, and CHOP. It also suppressed neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and enhancing the anti-inflammatory cytokine IL-10. Fluoxetine also counteracted oxidative stress by restoring the activity of antioxidant enzymes (SOD, CAT), reducing lipid peroxidation (MDA), and enhancing overall antioxidant capacity (TAC). Importantly, these positive biochemical changes were correlated with a significant reduction in light aversion behavior. 
Conclusion: Fluoxetine exerts protective effects in an NTG-induced migraine model by modulating UPR pathways, reducing neuroinflammation, and alleviating oxidative stress. These findings highlight its potential as a therapeutic agent targeting multiple pathways in migraine pathophysiology.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences
Volume 29, Issue 3
March 2026
Pages 458-467

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