Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8684617 | Experimental Neurology | 2018 | 30 Pages |
Abstract
The loss of local spinal glycine-ergic tone has been postulated as one of the mechanisms contributing to the development of spinal injury-induced spasticity. In our present study using a model of spinal transection-induced muscle spasticity, we characterize the effect of spinally-targeted GlyT2 downregulation once initiated at chronic stages after induction of spasticity in rats. In animals with identified hyper-reflexia, the anti-spasticity effect was studied after intrathecal treatment with: i) glycine, ii) GlyT2 inhibitor (ALX 1393), and iii) GlyT2 antisense oligonucleotide (GlyT2-ASO). Administration of glycine and GlyT2 inhibitor led to significant suppression of spasticity lasting for a minimum of 45-60â¯min. Treatment with GlyT2-ASO led to progressive suppression of muscle spasticity seen at 2-3â¯weeks after treatment. Over the subsequent 4-12â¯weeks, however, the gradual appearance of profound spinal hyper-reflexia was seen. This was presented as spontaneous or slight-tactile stimulus-evoked muscle oscillations in the hind limbs (but not in upper limbs) with individual hyper-reflexive episodes lasting between 3 and 5â¯min. Chronic hyper-reflexia induced by GlyT2-ASO treatment was effectively blocked by intrathecal glycine. Immunofluorescence staining and Q-PCR analysis of the lumbar spinal cord region showed a significant (>90%) decrease in GlyT2 mRNA and GlyT2 protein. These data demonstrate that spinal GlyT2 downregulation provides only a time-limited therapeutic benefit and that subsequent loss of glycine vesicular synthesis resulting from chronic GlyT2 downregulation near completely eliminates the tonic glycine-ergic activity and is functionally expressed as profound spinal hyper-reflexia. These characteristics also suggest that chronic spinal GlyT2 silencing may be associated with pro-nociceptive activity.
Keywords
Related Topics
Life Sciences
Neuroscience
Neurology
Authors
Kota Kamizato, Silvia Marsala, Michael Navarro, Manabu Kakinohana, Oleksandr Platoshyn, Tetsuya Yoshizumi, Nadezda Lukacova, Ed Wancewicz, Berit Powers, Curt Mazur, Martin Marsala,