Up‐regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine

Central sensitization is the potential pathogenesis of chronic migraine (CM) and is related to persistent neuronal hyperexcitability. Dysfunction of excitatory amino acid transporter 2 (EAAT2) leads to the accumulation of glutamate in the synaptic cleft, which may contribute to central sensitization by overactivating glutamate N-methyl-D-aspartate receptors and enhancing synaptic plasticity. However, the therapeutic potential of CM by targeting glutamate clearance remains largely unexplored. The purpose of this study was to investigate the role of EAAT2 in CM central sensitization and explore the effect of EAAT2 expression enhancer LDN-212320 in CM rats. The glutamate concentration was measured by high-performance liquid chromatography in a rat model of CM. Then, q-PCR and western blots were performed to detect EAAT2 expression, and the immunoreactivity of astrocytes was detected by immunofluorescence staining. To understand the effect of EAAT2 on central sensitization of CM, mechanical and thermal hyperalgesia and central sensitization-associated proteins were examined after administration of LDN-212320. In addition, the expression of synaptic-associated proteins was examined and Golgi-Cox staining was used to observe the dendritic spine density of trigeminal nucleus caudalis neurons. Also, the synaptic ultrastructure was observed by transmission electron microscope (TEM) to explore the changes of synaptic plasticity. In our study, elevated glutamate concentration and decreased EAAT2 expression were found in the trigeminal nucleus caudalis of CM rats, administration of LDN-212320 greatly up-regulated the protein expression of EAAT2, alleviated hyperalgesia, decreased the concentration of glutamate and the activation of astrocytes. Furthermore, reductions in calcitonin gene-related peptide, substance P(SP), and phosphorylated NR2B were examined after administration of LDN-212320. Moreover evaluation of the synaptic structure, synaptic plasticity-, and central sensitization-related proteins indicated that EAAT2 might participate in the CM central sensitization process by regulating synaptic plasticity. Taken together, up-regulation of EAAT2 expression has a protective effect in CM rats, and LDN-212320 may have clinical therapeutic potential. Cover Image for this issue: https://doi.org/10.1111/jnc.14769.