title: Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing.
abstract: 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.
authors.affiliation: Nanomedicine Laboratory, Center for Drug Delivery Research, School of Pharmacy, University of London, London WC1N 1AX, United Kingdom.
authors.forename: Khuloud T
authors.initials: KT
authors.lastname: Al-Jamal
authors.forename: Lisa
authors.initials: L
authors.lastname: Gherardini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bardi
authors.forename: Antonio
authors.initials: A
authors.lastname: Nunes
authors.forename: Chang
authors.initials: C
authors.lastname: Guo
authors.forename: Cyrill
authors.initials: C
authors.lastname: Bussy
authors.forename: M Antonia
authors.initials: MA
authors.lastname: Herrero
authors.forename: Alberto
authors.initials: A
authors.lastname: Bianco
authors.forename: Maurizio
authors.initials: M
authors.lastname: Prato
authors.forename: Kostas
authors.initials: K
authors.lastname: Kostarelos
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D053148:Caspase 3 / Q000235:genetics*; D061945:Caspase Inhibitors; D002460:Cell Line; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000633:toxicity; D005260:Female; D015316:Genetic Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine; D037742:Nanotubes, Carbon; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011597:Psychomotor Performance; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D061945:Caspase Inhibitors; D019332:Endothelin-1; D037742:Nanotubes, Carbon; D034741:RNA, Small Interfering; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3