MINOCYCLINE ATTENUATES MIGRAINE-LIKE FEATURES VIA MICROGLIA-DRIVEN NEUROINFLAMMATORY MECHANISMS IN MICE

Migraine is a disabling neurological disorder involving neuroinflammatory mechanisms. Microglia, the brain resident immune cells, are key regulators of inflammation and may contribute to migraine pathophysiology beyond neuronal dysfunction.
We hypothesized that minocycline, a microglial activation inhibitor, attenuates nitroglycerin-induced migraine-like features by suppressing microglia-driven inflammatory signalling in a mouse model.
Eight-week-old female and male C57BL/6J mice were assigned to four groups: control+saline, control+minocycline, migraine+saline and migraine+minocycline. Migraine groups received five intraperitoneal injections of nitroglycerin (10mg/kg) every other day over nine days. At the same time, either minocycline (50 mg/kg) or saline was administered daily for seven days.
Migraine-like features were assessed using orofacial mechanical von Frey test, light aversion test, cortical spreading depression (CSD) recordings, and calcitonin-gene related-peptide (CGRP) quantification. Microglial activation was evaluated by Iba1 immunohistochemistry. Data were analyzed using mixed-effects models with correction for multiple comparisons.
Nitroglycerin significantly reduced orofacial mechanical thresholds compared to controls (P<0.0001), an effect that was reversed 47% by minocycline treatment (P=0.0027). No differences were observed in light aversion behavior. CSD susceptibility was significantly increased in the migraine group only in females (P=0.0005) and was normalized by minocycline (P=0.9756). CGRP levels were increased by 17% in the migraine group (P=0.0094) and normalized by minocycline (P=0. 94). Notably, Iba1 expression was significantly reduced by minocycline to 17% only in female mice (P=0.0093).
Minocycline reduced migraine-like phenotypes, including mechanical hypersensitivity, CSD susceptibility, and CGRP expression, supporting a role for microglia-driven neuroinflammation in migraine. The sex-specific effects on microglial activation suggest biological differences relevant for targeted therapies.