Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis.
Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis.
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DOI：
10.1007/s12975-020-00844-7
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发表时间：
2021-08
影响因子：
6.9
通讯作者：
Ergul A
中科院分区：
文献类型：
--
作者：
Abdul Y;Li W;Ward R;Abdelsaid M;Hafez S;Dong G;Jamil S;Wolf V;Johnson MH;Fagan SC;Ergul A
糖尿病患者的卒中结局非常差，这是临床上公认的事实。然而，基本的机制在很大程度上仍然未知。我们以前的研究表明，雄性糖尿病动物表现出更大的出血性转化（HT），在恢复期脑血管系统的严重损失和缺血性卒中后的感觉运动和认知结果差。本研究旨在确定铁螯合与去铁胺（DFX）对对照组和糖尿病大鼠卒中后1）脑血管形成模式和2）功能结局的影响。在通过高脂肪饮食和低剂量链脲佐菌素的组合诱导的2型糖尿病8周后，使雄性对照动物和糖尿病动物经受血栓栓塞性大脑中动脉闭塞（MCAO），并随机分配至媒介物、DFX或tPA/DFX，并随后进行14天的行为测试。测量血管指数（血管体积和表面积）、神经血管重塑（AQP 4极性）和小胶质细胞活化。评价来自对照和糖尿病动物的脑微血管内皮细胞（BMVEC）的DFX对铁凋亡细胞死亡的影响。在糖尿病大鼠中，DFX治疗在第14天防止血管退化和小胶质细胞活化，同时改善AQP 4极性以及血脑屏障通透性。这些病理变化与功能结局的改善相关。在对照组大鼠中，DFX没有效果。铁在糖尿病动物的BMVECs中更大程度地增加了铁凋亡和脂质活性氧（ROS）的标志物，这是由DFX预防的。这些结果强烈表明：1）HT影响糖尿病患者卒中后血管形成模式和恢复反应，2）铁螯合治疗出血对共病疾病的结局有不同的影响，3）铁螯合和可能抑制铁缺乏可能为预防糖尿病卒中后认知障碍提供一种新的疾病改善治疗策略。
It is a clinically well-established fact that patients with diabetes have very poor stroke outcomes. Yet, the underlying mechanisms remain largely unknown. Our previous studies showed that male diabetic animals show greater hemorrhagic transformation (HT), profound loss of cerebral vasculature in the recovery period and poor sensorimotor and cognitive outcomes after ischemic stroke. This study aimed to determine the impact of iron chelation with deferoxamine (DFX) on 1) cerebral vascularization patterns and 2) functional outcomes after stroke in control and diabetic rats. After 8 week of type 2 diabetes induced by a combination of high fat diet and low dose streptozotocin, male control and diabetic animals were subjected to thromboembolic middle cerebral artery occlusion (MCAO) and randomized to vehicle, DFX or tPA/DFX and followed for 14 days with behavioral tests. Vascular indices (vascular volume and surface area), neurovascular remodeling (AQP4 polarity), and microglia activation were measured. Brain microvascular endothelial cells (BMVEC) from control and diabetic animals were evaluated for the impact of DFX on ferroptotic cell death. DFX treatment prevented vasoregression and microglia activation while improving AQP4 polarity as well as blood brain barrier permeability by day 14 in diabetic rats. These pathological changes were associated with improvement of functional outcomes. In control rats, DFX did not have an effect. Iron increased markers of ferroptosis and lipid reactive oxygen species (ROS) to a greater extent in BMVECs from diabetic animals, and this was prevented by DFX. These results strongly suggest that 1) HT impacts post-stroke vascularization patterns and recovery responses in diabetes, 2) treatment of bleeding with iron chelation has differential effects on outcomes in comorbid disease conditions, and 3) iron chelation and possibly inhibition of ferroptosis may provide a novel disease-modifying therapeutic strategy in the prevention of post-stroke cognitive impairment in diabetes.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
6.9
作者：
Jackson, Ladonya;Dong, Guangkuo;Ergul, Adviye
通讯作者：
Ergul, Adviye
影响因子：
9.9
作者：
Bruno, A;Levine, SR;Fineberg, SE
通讯作者：
Fineberg, SE
影响因子：
5.3
作者：
Li W;Valenzuela JP;Ward R;Abdelbary M;Dong G;Fagan SC;Ergul A
通讯作者：
Ergul A
影响因子：
8.3
作者：
Gorelick PB;Furie KL;Iadecola C;Smith EE;Waddy SP;Lloyd-Jones DM;Bae HJ;Bauman MA;Dichgans M;Duncan PW;Girgus M;Howard VJ;Lazar RM;Seshadri S;Testai FD;van Gaal S;Yaffe K;Wasiak H;Zerna C;American Heart Association/American Stroke Association
通讯作者：
American Heart Association/American Stroke Association