A potent anti-spastic effect after intrathecal NK1 antisense oligonucleotide or subpial AAV9-NK1-ShRNA delivery in rats with chronic spinal transection-induced muscle spasticity

Mariana Bravo Hernandez

BACKGROUND: The spinal NK1 receptor system has been demonstrated to play an important role in the development and maintenance of chronic pain states after peripheral nerve injury. In contrast, its role in the development of spinal hyper-reflexia and muscle spasticity resulting from spinal traumatic injury is not well defined. The goal of the present study was to assess the treatment effect of: i) spinal intrathecal (IT) delivery of NK1 antisense oligonucleotide (NK1-ASO), and ii) subpial (SP) delivery of AAV9-NK1-shRNA in rats with chronic spinal cord transection-induced muscle spasticity. METHODS: Adult Sprague-Dawley (SD) rats (female, 200-300 g) had the Th9 spinal segment transected to induce muscle spasticity. The presence of spasticity was defined as exacerbated EMG response recorded from the gastrocnemius muscle after applying progressively increased paw pressures using von Frey filaments (0.6-26 grams). After baseline spasticity measurement, animals received: i) a single lumbar intrathecal bolus of NK-1-ASO or control antisense oligonucleotide (Cont-ASO), or ii) subpial (SP) AAV9-NK1-shRNA or control AAV9-GFP. Before and after treatment, the presence of spasticity response was measured in 1-week intervals for up to 12 weeks. The effect of each treatment on spinal NK1 expression was evaluated by immunofluorescence and confocal microscopy or by qPCR. RESULTS:In spastic animals receiving IT injection of NK1-ASO, a progressive decrease in measured surface EMG activity after paw tactile stimulation was seen with the maximum effect measured at 2 weeks after injection (p<0.05). A significant anti-spastic affect was still present at 10 weeks after treatment. No changes in spasticity response were measured in animals receiving control ASO. In animals injected SP with AAV9-NK1-shRNA, a comparable anti-spasticity effect was seen at 2 weeks after treatment. Histological and qPCR analysis of the lumbar spinal cord showed a 75-85% reduction in NK1 signal with no change in substance P expression. CONCLUSIONS: These data show that NK1-ASO or AAV9-NK1-shRNA-mediated suppression of spinal NK1 receptor expression may represent a novel therapeutic approach for modulation of chronic spinal injury-induced muscle spasticity and hyper-reflexia.

Abstract Authors
1Anesthesiol., 2Neursurgery, Univ. of California San Diego, LA Jolla, CA; 3Ionis Pharmaceuticals, Carlsbad, CA
M. Bravo Hernandez: None. T. Yoshiozumi: None. M.R. Navarro: None. K. Kamizato: None. T. Tadokoro: None. O. Platoshyn: None. S. Marsala: None. J.D. Ciacci: None. C. Mazur: None. M. Marsala: None.

LINK: Session 320 – Injury Responses after Spinal Cord Injury

This entry was posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Stem Cell Research and tagged , , . Bookmark the permalink.

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