{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:16:09Z","timestamp":1792610169907,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971055"],"award-info":[{"award-number":["81971055"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471133"],"award-info":[{"award-number":["81471133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801134"],"award-info":[{"award-number":["81801134"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Epilepsy and migraine are among the most prevalent neurological disorders. By being comorbid, the presence of one disorder increases the likelihood of the other. Although several similar clinical features of epilepsy and migraine have been observed as early as the 19th century, only in recent years have researchers engaged in finding a common pathogenic mechanism between them. In this study, the epilepsy\u2013migraine comorbidity rat model was generated, and the pathophysiological basis of epilepsy\u2013migraine comorbidity was examined. Male rats were divided into four groups: control, migraine, epilepsy, epilepsy\u2013migraine comorbidity. After establishing the models, the amount of scratching and the pain threshold of the rats were observed. Western blot and immunofluorescence staining were used to detect the protein expression levels of TLR4 and GABAAR\u03b11 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Subsequently, co-immunoprecipitation of GABAAR\u03b11 and TLR4 was performed. Then, the rats were divided into three groups: comorbidity, comorbidity + TAK-242, and comorbidity + muscimol. After drug intervention, the seizure latency, seizure level, amount of scratching, and pain threshold were observed. Western blot was used to detect the protein expression levels of TLR4 and GABAAR\u03b11 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Our results demonstrate that the seizure attacks in comorbidity and epilepsy groups performed severely, and the comorbidity and migraine groups displayed a remarkable increase in the amount of head-scratching and a noticeable decrease in the facial mechanical withdrawal threshold. Further analysis revealed considerably increased Toll-like receptor 4 (TLR4), associated with reduced \u03b3-aminobutyric acid type A receptor \u03b11 (GABAAR\u03b11) and microglia enhanced in the epilepsy\u2013migraine comorbidity rat. Additionally, co-immunoprecipitation proved GABAAR\u03b11 binding TLR4. Following muscimol to activate GABAAR\u03b11, seizure attacks and migraine-like behavior were rescued. GABAAR\u03b11 level increment was accompanied by the decline of TLR4, while TAK-242, the inhibitor of TLR4, only decreased TLR4 without affecting GABAAR\u03b11 expression. It also ameliorated the migraine-like behavior with no impact on seizure activity. We propose that GABAAR\u03b11 binding and negatively regulating TLR4 contribute to epilepsy\u2013migraine comorbidity; TLR4 is a critical intermediate link in epilepsy\u2013migraine comorbidity; immune-induced neuroinflammation in microglia may be involved in migraine and epilepsy\u2013migraine comorbidity.<\/jats:p>","DOI":"10.3390\/brainsci12111436","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T22:00:27Z","timestamp":1666735227000},"page":"1436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Downregulation of GABAAR\u03b11 Aggravates Comorbidity of Epilepsy and Migraine via the TLR4 Signaling Pathway"],"prefix":"10.3390","volume":"12","author":[{"given":"Yao","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology, Renming Hospital of Wuhan University, Wuhan 430060, China"},{"name":"Central Laboratory, Renming Hospital of Wuhan University, Wuhan 430060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurology, Renming Hospital of Wuhan University, Wuhan 430060, China"},{"name":"Central Laboratory, Renming Hospital of Wuhan University, Wuhan 430060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoyu","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Renming Hospital of Wuhan University, Wuhan 430060, China"},{"name":"Central Laboratory, Renming Hospital of Wuhan University, Wuhan 430060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheman","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Renming Hospital of Wuhan University, Wuhan 430060, China"},{"name":"Central Laboratory, Renming Hospital of Wuhan University, Wuhan 430060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1007\/s11916-013-0402-3","article-title":"Migraine and epilepsy in the pediatric population","volume":"18","author":"Oakley","year":"2014","journal-title":"Curr. 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