Nanomedicine Laboratory, Center for Drug Delivery Research, School of Pharmacy, University of London, London WC1N 1AX, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):10952-7. doi: 10.1073/pnas.1100930108. Epub 2011 Jun 20.
Stroke is the second cause of death worldwide with ischemic stroke accounting for 80% of all stroke insults. Caspase-3 activation contributes to brain tissue loss and downstream biochemical events that lead to programmed cell death after traumatic brain injury. Alleviation of symptoms following ischemic neuronal injury can be potentially achieved by either genetic disruption or pharmacological inhibition of caspases. Here, we studied whether silencing of Caspase-3 using carbon nanotube-mediated in vivo RNA interference (RNAi) could offer a therapeutic opportunity against stroke. Effective delivery of siRNA directly to the CNS has been shown to normalize phenotypes in animal models of several neurological diseases. It is shown here that peri-lesional stereotactic administration of a Caspase-3 siRNA (siCas 3) delivered by functionalized carbon nanotubes (f-CNT) reduced neurodegeneration and promoted functional preservation before and after focal ischemic damage of the rodent motor cortex using an endothelin-1 induced stroke model. These observations illustrate the opportunity offered by carbon nanotube-mediated siRNA delivery and gene silencing of neuronal tissue applicable to a variety of different neuropathological conditions where intervention at well localized brain foci may offer therapeutic and functional benefits.
中风是全球范围内的第二大致死原因，其中缺血性中风占所有中风的 80%。半胱天冬酶-3 的激活导致脑损伤后细胞程序性死亡的下游生化事件，导致脑组织丢失。通过基因敲除或半胱天冬酶的药理学抑制，可以减轻缺血性神经元损伤后的症状。在这里，我们研究了使用碳纳米管介导的体内 RNA 干扰 (RNAi) 沉默 Caspase-3 是否可以为中风提供治疗机会。已经证明，将 siRNA 直接递送到中枢神经系统可以使几种神经疾病动物模型的表型正常化。这里显示，通过功能化碳纳米管 (f-CNT) 进行局部立体定向给药的 Caspase-3 siRNA (siCas 3) 可减少神经退行性变，并在使用内皮素-1 诱导的中风模型对啮齿动物运动皮层进行局灶性缺血损伤之前和之后促进功能保存。这些观察结果说明了碳纳米管介导的 siRNA 递送至神经元组织的机会，以及基因沉默在各种不同的神经病理学条件下的应用，其中在大脑局部焦点进行干预可能提供治疗和功能益处。
