PMID- 31872442 OWN - NLM STAT- MEDLINE DCOM- 20210310 LR - 20210310 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 155 IP - 4 DP - 2020 Nov TI - Up-regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine. PG - 370-389 LID - 10.1111/jnc.14944 [doi] AB - 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. CI - (c) 2019 International Society for Neurochemistry. FAU - Zhou, Xue AU - Zhou X AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Liang, Jie AU - Liang J AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Wang, Jiang AU - Wang J AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Fei, Zhaoyang AU - Fei Z AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Qin, Guangcheng AU - Qin G AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Zhang, Dunke AU - Zhang D AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Zhou, Jiying AU - Zhou J AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Chen, Lixue AU - Chen L AUID- ORCID: 0000-0001-8213-8828 AD - Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200107 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (Inflammation Mediators) RN - 0 (LDN-OSU-0212320) RN - 0 (Neuroprotective Agents) RN - 0 (Pyridazines) RN - 0 (Pyridines) RN - 0 (Slc1a2 protein, rat) SB - IM MH - Animals MH - Astrocytes/*metabolism MH - Chronic Disease MH - Craniotomy/adverse effects/methods MH - *Disease Models, Animal MH - Excitatory Amino Acid Transporter 2/*biosynthesis MH - Inflammation Mediators/adverse effects/metabolism MH - Male MH - Migraine Disorders/drug therapy/etiology/*metabolism MH - Neuroprotective Agents/pharmacology/therapeutic use MH - Pyridazines/pharmacology/therapeutic use MH - Pyridines/pharmacology/therapeutic use MH - Random Allocation MH - Rats MH - Rats, Sprague-Dawley MH - Up-Regulation/*physiology OTO - NOTNLM OT - astrocyte OT - central sensitization OT - chronic migraine OT - glutamate OT - glutamate transporters OT - synaptic plasticity EDAT- 2019/12/25 06:00 MHDA- 2021/03/11 06:00 CRDT- 2019/12/25 06:00 PHST- 2019/10/08 00:00 [received] PHST- 2019/11/20 00:00 [revised] PHST- 2019/12/17 00:00 [accepted] PHST- 2019/12/25 06:00 [pubmed] PHST- 2021/03/11 06:00 [medline] PHST- 2019/12/25 06:00 [entrez] AID - 10.1111/jnc.14944 [doi] PST - ppublish SO - J Neurochem. 2020 Nov;155(4):370-389. doi: 10.1111/jnc.14944. Epub 2020 Jan 7.