PDF(Pubmed)
Abstract：
The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.
摘要：
神经血管单元（NVU）由血管细胞组成，glia,和构成血脑屏障基本组成部分的神经元。这种复杂的结构迅速调整脑血流量，以满足大脑活动的代谢需求。然而,NVU对损坏非常敏感，并且在中风后显示有限的维修。为了有效治疗中风，因此,保护和修复NVU被认为是至关重要的。线粒体钙（Ca2）的摄取通过缓冲Ca2和刺激能量产生来支持NVU功能。然而,过量的线粒体Ca2+摄取导致有毒的线粒体Ca2+过载,触发许多破坏NVU的细胞死亡途径。线粒体损伤是卒中最早的病理事件之一。因此,保持线粒体完整性和功能的药物应通过阻断许多损伤事件的开始而赋予深远的NVU保护。我们已经证明，脑中线粒体Ca2+的摄取和外排是由线粒体Ca2+单转运复合物(MCUcx)和钠/Ca2+/锂交换体(NCLX)介导的，分别。此外，我们最近的药理学研究表明，MCUcx抑制和NCLX激活通过阻断线粒体Ca2+过载来抑制缺血性和兴奋性毒性神经元细胞死亡。这些发现表明，将MCUcx抑制与NCLX激活相结合应显着保护NVU。在推广NVU修复方面，核激素受体激活是一种有前途的方法。类视黄醇X受体（RXR）和甲状腺激素受体（TR）激动剂激活刺激线粒体生物发生的互补转录程序，抑制炎症，增强新血管细胞的产生，glia,和神经元。因此，RXR和TR激动作用应通过增加NVU修复进一步改善MCUcx抑制和NCLX活化的临床益处。然而,抑制MCUcx的药物，或者刺激NCLX，或激活RXR或TR，遭受不良作用引起的健康组织。为了克服这个问题，我们描述了在缺血性或出血性卒中后优先靶向代谢受损和受损的NVU的纳米颗粒药物制剂的使用.这些基于纳米颗粒的方法具有通过最大化对患病NVU的药物递送和最小化健康脑和外周组织中的药物暴露来提高临床安全性和功效的潜力。
