RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial.
RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial.
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DOI：
10.1186/s12974-018-1262-x
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发表时间：
2018-08-13
影响因子：
9.3
通讯作者：
Fagan SC
中科院分区：
文献类型：
--
作者：
Ahmed HA;Ishrat T;Pillai B;Fouda AY;Sayed MA;Eldahshan W;Waller JL;Ergul A;Fagan SC
随着人口老龄化，脑血管疾病的患病率和发病率将继续上升，血管性认知障碍/痴呆(VCID)的人数也将继续上升。目前尚不存在FDA批准的VCID特定治疗方法。尽管临床证据支持血管紧张素受体阻滞剂(ARB)可以预防老年人的认知衰退，但ARB是否对中风后的VCID有类似的影响尚不清楚。此外，这些药物会降低血压，这在急性卒中期间是不可取的，所以我们认为，在急性期给予C21或推迟ARB给药将使我们能够获得神经血管益处，而不会有意外和潜在危险的急性降压风险。本研究的目的是确定坎地沙坦(ARB)或化合物-21(一种血管紧张素2型受体AT2R激动剂)对自发性高血压大鼠(SHR)卒中后长期认知功能的影响。我们假设，卒中后启动的AT2R刺激，无论是直接用C21刺激，还是通过坎地沙坦阻断血管紧张素1型受体(AT1R)间接刺激，都会减少认知障碍。动物接受60分钟的暂时性大脑中动脉闭塞，并随机分配到生理盐水/C21单一治疗，整个研究持续时间(30天)，或接受从生理盐水/C21开始的序贯治疗(7天)，然后坎地沙坦治疗剩余的研究(21天)。结果测量包括感觉运动/认知功能、淀粉样蛋白-β测定和组织病理学分析。RAS调节剂的治疗有效地保留了认知功能，降低了细胞毒性，并预防了卒中后SHR的慢性反应性小胶质细胞增生症。即使在中风后延迟治疗长达7天的情况下，这些保护作用也是明显的，并且与血压和β-淀粉样蛋白堆积无关。总而言之，我们的发现表明，RAS调节剂有效地预防中风后的认知损害，即使治疗被推迟了。本文的在线版本(10.1186/s12974-0181262-x)包含补充材料，可供授权用户使用。
With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering. The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor––AT2R––agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses. Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation. Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed. The online version of this article (10.1186/s12974-018-1262-x) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
López-Gil X;Amat-Roldan I;Tudela R;Castañé A;Prats-Galino A;Planas AM;Farr TD;Soria G
通讯作者：
Soria G
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
DOI：
10.1124/jpet.108.139618
发表时间：
2008-09-01
影响因子：
3.5
作者：
Kozak, Wieslaw;Kozak, Anna;Fagan, Susan C.
通讯作者：
Fagan, Susan C.
影响因子：
5.1
作者：
Ishrat T;Pillai B;Soliman S;Fouda AY;Kozak A;Johnson MH;Ergul A;Fagan SC
通讯作者：
Fagan SC
影响因子：
1.9
作者：
Guimond MO;Gallo-Payet N
通讯作者：
Gallo-Payet N