Toledo Andrea, Orozco-Suarez Sandra, Paredes Chiquini Yamile, Sanchez Daniel, Maldonado Lorenzo, Flores Jorge, Bautista Sara I, Arellano Alfonso, Moreno Sergio, Martínez Juárez Iris E, Fleury Agnès
Division de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México.
Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, "Bernardo Sepulveda", CMN Siglo XXI, IMSS, Ciudad de México, México.
Epilepsy Behav. 2025 Jan;162:110163. doi: 10.1016/j.yebeh.2024.110163. Epub 2024 Nov 29.
Thirty percent of epilepsy patients are drug-resistant (DR) and, in adults, temporal lobe epilepsy (TLE) is the most common form of DR- epilepsy. Patients with TLE exhibit a neuroinflammatory response associated with blood-brain barrier dysfunction. In this context, the main aim of our study was to evaluate peripheral levels and central expression of MMP-9 and TIMP-1 in TLE patients and assess their association with drug resistance and inflammatory markers.
Three groups of patients were included, 41 DR-TLE patients, 10 non-DR-TLE patients, and 20 healthy controls (HC). MMP-9 and TIMP-1 were assessed by ELISA in sera in all patients, and by immunohistochemistry and immunofluorescence in the cerebral cortex and hippocampus in a subgroup of DR-TLE patients and 3 controls. Peripheral and central cells phenotypes were determined by flow cytometry and immunohistochemistry, respectively, while cytokines were determined in the two compartments by ELISA.
Central expression of MMP-9 and TIMP-1, and peripheral expression of TIMP-1, were higher in DR-TLE patients than in controls, while peripheral levels of MMP-9 and TIMP-1 were higher in DR-TLE patients compared with non-DRE-TLE patients. MMP-9 levels in serum increased with seizure severity and decreased after successful epilepsy surgery. MMP-9 levels in the serum of DR-TLE patients were positively correlated with several markers of peripheral inflammation, which was not the case in the groups of non-DR-TLE patients and healthy controls. MMP-9 and TIMP-1 expression in the hippocampus of DR-TLE patients correlated positively with various markers of central inflammation. Negative correlations between their peripheral levels and central expression were observed.
MMP-9 and TIMP-1 are markers that seem to be associated to the central and peripheral inflammatory reaction occurring in DR-TLE patients. The significant negative correlations between central and peripheral markers are interesting to note, and further studies need to be carried out to fully understand the complex regulation of these proteins during DR epilepsy.
30%的癫痫患者存在耐药性（DR），在成人中，颞叶癫痫（TLE）是最常见的耐药性癫痫形式。TLE患者表现出与血脑屏障功能障碍相关的神经炎症反应。在此背景下，我们研究的主要目的是评估TLE患者外周血中基质金属蛋白酶-9（MMP-9）和金属蛋白酶组织抑制因子-1（TIMP-1）的水平及中枢表达，并评估它们与耐药性及炎症标志物的关联。
纳入三组患者，41例耐药性TLE患者、10例非耐药性TLE患者和20例健康对照（HC）。所有患者均通过酶联免疫吸附测定（ELISA）检测血清中的MMP-9和TIMP-1，在一组耐药性TLE患者和3例对照的大脑皮质及海马体中通过免疫组织化学和免疫荧光法检测。分别通过流式细胞术和免疫组织化学确定外周血和中枢细胞表型，同时通过ELISA检测两个部位的细胞因子。
耐药性TLE患者中MMP-9和TIMP-1的中枢表达以及TIMP-1的外周表达均高于对照组，而耐药性TLE患者外周血中MMP-9和TIMP-1的水平高于非耐药性TLE患者。血清中MMP-9水平随癫痫发作严重程度增加而升高，在癫痫手术成功后降低。耐药性TLE患者血清中MMP-9水平与外周炎症的几种标志物呈正相关，非耐药性TLE患者组和健康对照组则不然。耐药性TLE患者海马体中MMP-9和TIMP-1的表达与中枢炎症的各种标志物呈正相关。观察到它们外周血水平与中枢表达之间呈负相关。
MMP-9和TIMP-1似乎是与耐药性TLE患者中枢和外周炎症反应相关的标志物。中枢和外周标志物之间显著的负相关值得关注，需要进一步开展研究以充分了解这些蛋白在耐药性癫痫期间的复杂调控。
