FKN/CX3CR1 Axis Facilitated Migraine-like Behaviors via Activating Thalamic-cortical Network Microglia in SE Rat Models

Abstract

Background: The incidence of migraines is higher among people with epilepsy than healthy people, and these two common diseases are proposed to have some shared pathophysiological mechanisms. Excitation/inhibition imbalance plays an essential role in the comorbidity of epilepsy and migraine. Microglia activation is crucial for abnormal neuronal signal transmission. However, whether and how microglia are activated, and their role in comorbidities after activation remains unclear. This study aimed to explore the characteristics and mechanism of microglia activation after seizures and its effect on migraine.Methods: Status epilepticus (SE) rat models induced by lithium chloride (LiCl)-pilocarpine intraperitoneal injection and migraine rat models induced by repeated inflammatory soup (IS) dural injections were generated and assessed for molecular and histopathologic evidence of microglial activation target of fractalkine (FKN) signaling. HT22-BV2 transwell coculture was used to explore the interaction between neurons and microglia. LPS (a microglia agonist) and FKN stimulation of BV2 microglia cells were used to evaluate changes in BDNF content after microglia activation.Results: Microglia were specifically hyperplasia and activation in the cortical-thalamus-sp5c neural circuit, which were pain-related brain regions, accompanied by the upregulation of FKN and CX3CR1 four days after seizures. Meanwhile, SE-induced increased nociceptive behavior and the FKN/CX3CR1 axis in migraine rat models. AZD8797 (a CX3CR1 inhibitor) prevented the worsening of hyperalgesia and microglia activation in migraine rat models after seizures, while FKN infusion in migraine rat models exacerbated hyperalgesia and microglia activation associated with BDNF-Trkb signaling. Furthermore, in neuron-BV2 coculture, microglial activation and FKN/CX3CR1/BDNF/iba1 expression were increased. Activating microglia with LPS and FKN stimulation increased BDNF synthesis in BV2 microglia.Conclusions: Our results indicated that epilepsy facilitated migraine through the cortical-thalamus-sp5c microglia activated and interactions with neurons by the FKN/CX3CR1 axis, resulting in BDNF release. Blocking the FKN/CX3CR1 axis and microglia activation are potential therapeutic targets for preventing and treating migraine in patients with epilepsy.