Combination treatment with cilostazol and isosorbide mononitrate attenuates microemboli-mediated vascular cognitive impairment and improves imaging and plasma biomarkers in diabetic rats

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2024-10-25 DOI:10.1016/j.expneurol.2024.115030

Weiguo Li , Alice A. Li , Xingju Nie , Joshua Voltin , Lianying He , Eda Karakaya , Jazlyn Edwards , Sarah Jamil , Kareem Abdelsaid , Maria Fatima Falangola , Adviye Ergul

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Abstract

Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID.

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西洛他唑和单硝酸异山梨酯联合治疗可减轻微栓子介导的血管认知障碍，并改善糖尿病大鼠的成像和血浆生物标志物

糖尿病是所有类型痴呆症的主要风险因素。其根本原因尚不完全清楚，也缺乏预防性治疗策略。此前，我们已经证明，在微栓子（ME）认知障碍& 痴呆（VCID）的血管作用模型中，糖尿病大鼠而非对照组大鼠会出现进行性认知功能下降。鉴于脑血管功能障碍是糖尿病和 VCID 之间的共同病理变化，我们假设可以通过改善糖尿病大鼠的内皮功能来预防 ME 模型中的认知功能障碍。我们的治疗范式基于 LACI-2 试验，该试验评估了单硝酸异山梨酯（ISMN）和西洛他唑（Cil）治疗小血管疾病进展的疗效。对照组和糖尿病大鼠接受 ISMN/Cil 或药物治疗 4 周，然后注射胆固醇晶体 ME 并监测行为结果。通过弥散核磁共振成像评估大脑微观结构的完整性。血浆生物标志物采用 MarkVCID 联盟推荐的血管生成、神经学和淀粉样β 42/40 面板进行评估。在本研究中，接受治疗的动物没有出现之前在未经治疗的糖尿病大鼠身上观察到的行为障碍和组织完整性丧失。治疗改善了组织灌注，但血浆生物标志物并无差异。这些结果表明，在注射ME前用ISMN/Cil恢复内皮功能可通过改善内皮完整性来防止ME对糖尿病大鼠可能产生的有害影响，是一种实用的VCID预防和治疗策略。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.