Abstract Body: Background: Calcitonin gene-related peptide (CGRP) is a potent vasodilator that plays a role in migraine. Monoclonal antibodies targeting CGRP, such as fremanezumab, is now widely used for migraine prevention. However, inhibition of CGRP system may also lead to vasoconstriction, raising concerns about whether the long-term treatment with these antibodies in migraine patients might increase the risk of stroke or worsen outcomes if a stroke occurs while taking these medications. Here, we aimed to investigate whether fremanezumab exacerbates stroke outcomes in a mouse model of ischemic stroke.
Methods: Two middle cerebral artery occlusion (MCAO) models were used: a 12-minute occlusion simulating a transient ischemic attack (TIA) and a 60-minute occlusion representing a conventional stroke model. Fremanezumab was administered intraperitoneally at either 2 days or 7 days before MCAO induction in both models; one cohort received treatment 28 and 7 days before MCAO. On day 2 after reperfusion, brain tissues were harvested for TTC staining to evaluate infarct volume. Neurological function was assessed using a neuro score and corner test. Additionally, an angiogram using black ink was performed to visualize cerebral vasculature, and vessel diameters were measured to determine the impact of fremanezumab on vascular dimensions.
Results: Angiographic arterial diameters in the fremanezumab arm did not differ from the saline arm, suggesting that fremanezumab does not cause vasoconstriction. In the TIA model, the fremanezumab group exhibited a trend towards increased infarct incidence and volume and hemorrhagic transformation, although these did not reach statistical significance. Additionally, there were no substantial changes in neurological scores and the corner test. In the 60-minute MCAO model, no significant changes or trends were observed in infarct volume or other outcomes between the two treatment arms. Outcomes were similar when fremanezumab was administered 2 or 7 days before MCAO.
Conclusion: Despite previous concerns that long-term use of fremanezumab might exacerbate stroke risk by promoting vasoconstriction, our findings do not support this hypothesis and suggest that fremanezumab does not worsen stroke outcomes in these models. These findings have important implications for the management of stroke risk in patients using fremanezumab for migraine prevention, suggesting that it may be used with confidence regarding its impact on stroke risk.