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.