Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.
Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.
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DOI：
10.1523/jneurosci.0933-21.2021
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发表时间：
2022-01-12
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影响因子：
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通讯作者：
Doyle KP
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作者：
Becktel DA;Zbesko JC;Frye JB;Chung AG;Hayes M;Calderon K;Grover JW;Li A;Garcia FG;Tavera-Garcia MA;Schnellmann RG;Wu HJ;Nguyen TV;Doyle KP
在全球范围内，超过6700万人生活在缺血性中风的影响下。重要的是，许多中风幸存者发展出慢性炎症反应，这可能导致认知障碍，这是一种常见的、使人衰弱的中风后遗症，研究不足，目前无法治疗。2-羟丙基-β-环糊精（HPβCD）是FDA批准的环状寡糖，可增溶和截留亲脂性物质。本研究的目的是确定HPβCD重复给药是否通过减少远端大脑中动脉闭塞卒中小鼠模型中卒中梗死内的脂质蓄积来减少对卒中的慢性炎症反应。为了实现这一目标，我们每周3次皮下注射年轻成年和老年雄性小鼠溶剂或HPβCD，在卒中后1周开始治疗。我们使用免疫染色、RNA测序、脂质组学和行为分析评估了中风后7周的小鼠。HPβ CD治疗小鼠的慢性卒中梗死和梗死周围区域的特征是参与脂质代谢的基因上调和参与先天性和适应性免疫、反应性星形胶质细胞增生和趋化性的基因下调。相应地，HPβCD减少了脑梗死中脂滴、T淋巴细胞、B淋巴细胞和浆细胞的积聚。HPβCD重复给药还保留了纹状体和丘脑中的NeuN免疫反应性以及海马区域中的c-Fos免疫反应性。此外，HPβCD通过保护大脑半球依赖的空间工作记忆和减少冲动性来改善恢复。这些结果表明，卒中后全身HPβCD治疗可减轻慢性炎症和继发性神经退行性变，并预防卒中后认知功能下降。痴呆是中风后常见的使人衰弱的后遗症。目前，中风后痴呆症没有可用的治疗方法。我们的研究表明，脂质代谢在慢性中风梗死中被破坏，这导致未清除的脂质碎片的积累，并与慢性炎症反应相关。据我们所知，这些脂质体内平衡的实质性变化以前没有被认识到或在缺血性卒中的背景下进行研究。我们还提供了一个原理证明，即使用HPβCD溶解和包埋亲脂性物质可能是治疗中风和其他CNS损伤后慢性炎症的有效策略。提示HPβCD预防脑卒中后痴呆可促进脑卒中患者的康复，提高其长期生活质量。
Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPβCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPβCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPβCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HPβCD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents poststroke cognitive decline. SIGNIFICANCE STATEMENT Dementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for poststroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HPβCD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HPβCD for the prevention of poststroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.