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Delayed intrathecal delivery of RhoA siRNA to the contused spinal cord inhibits allodynia, preserves white matter, and increases serotonergic fiber growth.
- Source :
-
Journal of neurotrauma [J Neurotrauma] 2011 Jun; Vol. 28 (6), pp. 1063-76. - Publication Year :
- 2011
-
Abstract
- RhoA is a key regulator of the actin cytoskeleton that is upregulated after spinal cord injury (SCI). We analyzed different methods for siRNA delivery and developed siRNAs targeting RhoA (siRhoA) for SCI treatment. Cy 3.5-labeled siRNA delivered at the time of SCI yielded fluorescence in several cell types in the injury site. Intraspinal injections of chemically stabilized siRhoA into the spinal cord of injured rats reduced RhoA protein levels after 1 week and improved hindlimb walking over 6 weeks. To explore a less invasive route, we tested intrathecal injection of Cy 3.5-labeled siRNA via lumbar puncture 1 day after SCI, which resulted in robust uptake in the T9-T10 injury site. Lumbar injection of siRhoA 1 day after SCI reduced RhoA mRNA and protein levels 3 days after injection. Although siRhoA treatment did not yield significant improvement in locomotion, it decreased tactile hypersensitivity significantly compared to controls. Histological analysis at 8 weeks showed significant improvement in white matter sparing with siRhoA compared to control siRNA. siRhoA treatment also resulted in less accumulation of ED1+macrophages, increased PKC-γ immunoreactivity in the corticospinal tract rostral to the injury site, and increased serotonergic fiber growth 12 mm caudal to the contusion site. The ability of siRhoA to preserve white matter and promote serotonergic axonal regrowth caudal to the injury site is likely to suppress allodynia. This provides justification for considering clinical development of RhoA inhibitors to treat SCI sub-acutely to reduce allodynia, which occurs frequently in SCI patients.
- Subjects :
- Animals
Disease Models, Animal
Female
Hyperalgesia genetics
Injections, Spinal
Nerve Regeneration genetics
RNA, Small Interfering genetics
Rats
Rats, Sprague-Dawley
Spinal Cord Injuries genetics
Up-Regulation physiology
rhoA GTP-Binding Protein antagonists & inhibitors
rhoA GTP-Binding Protein genetics
Genetic Therapy methods
Hyperalgesia therapy
RNA, Small Interfering administration & dosage
Serotonin physiology
Spinal Cord Injuries therapy
rhoA GTP-Binding Protein administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1557-9042
- Volume :
- 28
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of neurotrauma
- Publication Type :
- Academic Journal
- Accession number :
- 21443453
- Full Text :
- https://doi.org/10.1089/neu.2010.1568