CXCL1-CXCR1/2 signaling is induced in human temporal lobe epilepsy and contributes to seizures in a murine model of acquired epilepsy

NEUROBIOLOGY OF DISEASE

卷:158

Article

Di Sapia, Rossella¹  Zimmer, Till S.²  Kebede, Valentina¹  Balosso, Silvia¹  Ravizza, Teresa¹  Sorrentino, Diletta¹  Castillo, Manuel Alejandro Montano¹  Porcu, Luca³  Cattani, Franca⁴  Ruocco, Anna⁴  Aronica, Eleonora^2,5  Allegretti, Marcello⁴  Brandolini, Laura⁴  Vezzani, Annamaria¹ 

[1] Ist Ric Farmacol Mario Negri IRCCS, Dept Neurosci, Via Mario Negri 2, Milan, Italy

[2] Amsterdam UMC, Amsterdam Neurosci, Dept Neuropathol, Amsterdam, Netherlands

[3] Ist Ric Farmacol Mario Negri IRCCS, Dept Oncol, Milan, Italy

[4] Dompe Farmaceut SpA, R&D Dept, Laquila, Italy

[5] Stichting Epilepsie Instellingen Nederland SEIN, Heemstede, Netherlands

关键词: Chemokine;    Glia;    Neuroinflammation;    Neurodegeneration;    Reparixin;    Status epilepticus;   

DOI  :  10.1016/j.nbd.2021.105468

来源: Elsevier

【 摘 要 】

CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors. We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE. Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring. Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel.