Immunocytoprotection after reperfusion with Kv1.3 inhibitors has an extended treatment window for ischemic stroke.
Immunocytoprotection after reperfusion with Kv1.3 inhibitors has an extended treatment window for ischemic stroke.
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DOI：
10.3389/fphar.2023.1190476
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
引言：机械血栓切除术改善了急性缺血性卒中伴大动脉闭塞的治疗选择和结局。然而，随着血管内血栓切除术的时间窗延长，越来越需要开发免疫细胞保护疗法，以减少半暗带中的炎症并防止再灌注损伤。我们之前证明，通过减少神经炎症，KV1.3抑制剂不仅可以改善年轻雄性啮齿动物的结局，还可以改善雌性和老年动物的结局。为了进一步探索KV1.3抑制剂用于中风治疗的治疗潜力，我们在此直接比较了肽和小分子KV1.3阻断剂，并询问在再灌注后72小时开始时KV1.3抑制是否仍然有益。 方法：采用大鼠短暂性大脑中动脉闭塞（tMCAO，90 min）模型，每日进行神经功能缺损评分。在第8天，通过T2加权MRI和定量PCR确定脑中的炎症标记物表达来确定梗死。采用显色试验在体外评价了与组织纤溶酶原激活剂（tPA）的潜在相互作用。 结果如下：在与再灌注后2小时开始给药的直接比较中，小分子PAP-1显著改善了第8天的结果，而肽ShK-223尽管减少了炎症标志物表达，但未能减少梗死和神经功能缺损。PAP-1在再灌注后72小时开始时仍然提供益处。PAP-1不降低tPA的蛋白水解活性。 讨论内容：我们的研究表明，KV1.3抑制缺血性卒中后的免疫细胞保护具有广泛的治疗窗口，可以挽救炎症半暗带，并且需要脑渗透性小分子。
Introduction: Mechanical thrombectomy has improved treatment options and outcomes for acute ischemic stroke with large artery occlusion. However, as the time window of endovascular thrombectomy is extended there is an increasing need to develop immunocytoprotective therapies that can reduce inflammation in the penumbra and prevent reperfusion injury. We previously demonstrated, that by reducing neuroinflammation, KV1.3 inhibitors can improve outcomes not only in young male rodents but also in female and aged animals. To further explore the therapeutic potential of KV1.3 inhibitors for stroke therapy, we here directly compared a peptidic and a small molecule KV1.3 blocker and asked whether KV1.3 inhibition would still be beneficial when started at 72 hours after reperfusion. Methods: Transient middle cerebral artery occlusion (tMCAO, 90-min) was induced in male Wistar rats and neurological deficit assessed daily. On day-8 infarction was determined by T2-weighted MRI and inflammatory marker expression in the brain by quantitative PCR. Potential interactions with tissue plasminogen activator (tPA) were evaluated in-vitro with a chromogenic assay. Results: In a direct comparison with administration started at 2 hours after reperfusion, the small molecule PAP-1 significantly improved outcomes on day-8, while the peptide ShK-223 failed to reduce infarction and neurological deficits despite reducing inflammatory marker expression. PAP-1 still provided benefits when started 72 hours after reperfusion. PAP-1 does not reduce the proteolytic activity of tPA. Discussion: Our studies suggest that KV1.3 inhibition for immunocytoprotection after ischemic stroke has a wide therapeutic window for salvaging the inflammatory penumbra and requires brain-penetrant small molecules.
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DOI：
10.1177/0271678x17709185
发表时间：
2017-11
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Percie du Sert N;Alfieri A;Allan SM;Carswell HV;Deuchar GA;Farr TD;Flecknell P;Gallagher L;Gibson CL;Haley MJ;Macleod MR;McColl BW;McCabe C;Morancho A;Moon LD;O'Neill MJ;Pérez de Puig I;Planas A;Ragan CI;Rosell A;Roy LA;Ryder KO;Simats A;Sena ES;Sutherland BA;Tricklebank MD;Trueman RC;Whitfield L;Wong R;Macrae IM
通讯作者：
Macrae IM
影响因子：
64.8
作者：
DECOURSEY, TE;CHANDY, KG;CAHALAN, MD
通讯作者：
CAHALAN, MD
影响因子：
2.4
作者：
Kang Y;Wu Z;Cai D;Lu B
通讯作者：
Lu B
影响因子：
14.5
作者：
Maezawa, Izumi;Nguyen, Hai M.;Jin, Lee-Way
通讯作者：
Jin, Lee-Way
DOI：
10.1073/pnas.0605136103
发表时间：
2006-11-14
影响因子：
11.1
作者：
Beeton, Christine;Wulff, Heike;Chandy, K. George
通讯作者：
Chandy, K. George