scholarly journals Early escitalopram administration as a preemptive treatment strategy against spasticity after contusive spinal cord injury in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Youngjae Ryu ◽  
Toru Ogata ◽  
Motoshi Nagao ◽  
Yasuhiro Sawada ◽  
Ryohei Nishimura ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Treatment Strategy ◽  
Spinal Reflex ◽  
Preemptive Treatment ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Cord Injury ◽  
Swimming Test

AbstractIn the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Among various pathological conditions underlying spasticity, upregulated expression of 5-HT receptors (5-HTR) on the spinal motor neurons due to 5-HT denervation is considered one of crucial factors for hyperexcitability of the spinal circuit. As a 5-HT signal modulator, selective serotonin re-uptake inhibitors (SSRIs) are ordinarily prescribed for diseases associated with 5-HT in the CNS, and are known for their ability to increase 5-HT levels as well as to desensitize 5-HTR. Here, we hypothesized that early SSRI administration as a preemptive treatment strategy would effectively prevent the onset of spasticity. We used a rat model of contusive SCI and administered escitalopram during the first 4 weeks after injury, which is the period required for spasticity development in rodent models. We performed a swimming test to quantify spastic behaviors and conducted the Hoffman reflex test as well as histological analyses for 5-HT2AR and KCC2 expressions. Four weeks of escitalopram administration suppressed spastic behaviors during the swimming test and reduced the population of spasticity-strong rats. Moreover, the treatment resulted in decreased immunoreactivity of 5-HT2AR in the spinal motor neurons. Result of the H-reflex test and membrane expression of KCC2 were not significantly altered. In summary, early escitalopram administration could prevent the onset of spastic behaviors via regulation of 5-HT system after SCI, but could not modulate exaggerated spinal reflex. Our results suggest a novel application of SSRIs for preventative treatment of spasticity.

scholarly journals Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael D. Sunshine ◽  
Antonino M. Cassarà ◽  
Esra Neufeld ◽  
Nir Grossman ◽  
Thomas H. Mareci ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Drug Overdose ◽  
Cervical Spinal Cord ◽  
Opioid Overdose ◽  
Electrode Position ◽  
Spinal Motor Neurons ◽  
Cord Injury ◽  
Low Amplitude

AbstractRespiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

scholarly journals The manipulation of spinal motor neuron axonal growth promotes spinal cord repair

2021 ◽  
Author(s):  
Feng Wang ◽  
Xinya Fu ◽  
Meiemei Li ◽  
Xingran Wang ◽  
Jile Xie ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Axonal Regeneration ◽  
Axonal Growth ◽  
Treatment Method ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Cord Injury ◽  
Spinal Cord Repair

The loss of motor function in patients with spinal cord injury (SCI) is primarily due to the severing of the corticospinal tract (CST). Spinal motor neurons are located in the anterior horn of the spinal cord, and as the lower neurons of the CST, they control voluntary movement. Furthermore, its intrinsic axonal growth ability is significantly stronger than that of cerebral cortex pyramid neurons, which are the upper CST neurons. Therefore, we established an axonal regeneration model of spinal motor neurons to investigate the feasibility of repairing SCI by promoting axonal regeneration of spinal motor neurons. We demonstrated that conditionally knocking out pten in mature spinal motor neurons drastically enhanced axonal regeneration in vivo, and the regenerating axons of the spinal motor neurons re-established synapses with other cells in the damaged spinal cord. Thus, this strategy may serve as a novel and effective treatment method for SCI.

scholarly journals Intramuscular Injection of Adenoassociated Virus Encoding Human Neurotrophic Factor 3 and Exercise Intervention Contribute to Reduce Spasms after Spinal Cord Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Yu-Xin Chang ◽  
Yan Zhao ◽  
Su Pan ◽  
Zhi-Ping Qi ◽  
Wei-Jian Kong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Spinal Cord Injury ◽  
Combination Therapy ◽  
Motor Neurons ◽  
Neurotrophic Factor ◽  
Hind Limb ◽  
Cord Injury ◽  
Swimming Test ◽  
Adenoassociated Virus

Limb spasms are phenomena of hyperreflexia that occur after spinal cord injury. Currently, the clinical treatment is less than ideal. Our goal is to develop a combination therapy based on individualized medicine to reduce spasticity after spinal cord injury. In this study, rats received a severe contusive injury at the T9 segment of the spinal cord, followed by gene therapy with adenoassociated virus encoding human neurotrophic factor 3 (AAV-NT3) and a 2-week exercise program starting at 4 weeks after injury. We quantified the frequency of spasms during a swimming test at 4 and 6 weeks after injury and confirmed the results of the swimming test by measuring the H-reflex of the plantar muscle. We obtained weekly hind limb exercise scores to assess the effect of the interventions in hind limb motor function improvement. Then, we used immunofluorescence to observe the immunoreactivity of spinal motor neurons, synaptophysin, cholinergic interneurons, and GABAergic interneurons. We also measured the expression of KCC2 in the spinal cord by western blot. We found that AAV-NT3 gene therapy, exercise, and combination therapy all attenuated the frequency of spasms in the swimming test conducted at 6 weeks after spinal cord injury and increased rate-dependent depression of H-reflex. Combination therapy was significantly superior to AAV-NT3 alone in protecting motor neurons. Recovery of KCC2 expression was significantly greater in rats treated with combination therapy than in the exercise group. Combination therapy was also significantly superior to individual therapies in remodeling spinal cord neurons. Our study shows that the combination of AAV-NT3 gene therapy and exercise can alleviate muscle spasm after spinal cord injury by altering the excitability of spinal interneurons and motor neurons. However, combination therapy did not show a significant additive effect, which needs to be improved by adjusting the combined strategy.

scholarly journals CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Li ◽  
Heyangzi Li ◽  
Simin Cai ◽  
Shi Bai ◽  
Huabo Cai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Motor Neurons ◽  
Functional Recovery ◽  
Mitochondrial Transfer ◽  
Cord Injury ◽  
Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

scholarly journals Efficacy of autologous bone marrow mononuclear cell transplantation in dogs with chronic spinal cord injury

2020 ◽  
Vol 10 (2) ◽  
pp. 206-215
Author(s):  
Katsutoshi Tamura ◽  
Noritaka Maeta
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Cell Transplantation ◽  
Mononuclear Cell ◽  
Motor Neurons ◽  
Research Work ◽  
Autologous Bone Marrow ◽  
Bone Marrow Mononuclear Cell ◽  
Cord Injury

Background: Spinal cord injury (SCI) is relatively common in dogs and is a devastating condition involving loss of sensory neurons and motor  neurons. However, the main clinical protocol for the management of SCI is surgery to decompress and stabilize the vertebra. Cell transplantation therapy is a very promising strategy for the treatment of chronic SCI, but extensive preclinical and clinical research work remains.Aim: The aim of this study is to confirm the effect of bone marrow-derived mononuclear cell (BM-MNC) transplantation for chronic SCI in dogs.Methods: We tested the treatment efficiency of chronic SCI in 12 dogs using BM-MNC transplantation. Neurological evaluation used the Texas Spinal Cord Injury Scale (TSCIS). Concurrently, we characterized the transplanted cells by evaluation using quantitative real-time polymerase chain reaction, flow cytometry, and enzyme-linked immunosorbent assay.Result: All dogs had a pre-transplantation TSCIS score of 0. Two animals did not show any improvement in their final TSCIS scores. The remaining 10 dogs (83.4%) achieved improvement in the final TSCIS scores. Five of them (41.7%) regained ambulatory function with a TSCIS score greater than 10. We determined that canine BM-MNCs expressed hepatocyte growth factor (HGF) mRNA at higher levels than other cytokines, with significant  increases in HGF levels in cerebrospinal fluid within 48 hours after autologous BM-MNC transplantation into the subarachnoid space of the spinal dura matter in dogs.Conclusions: BM-MNC transplantation may be effective for at least some cases of chronic SCI. Keywords: Bone marrow-derived mononuclear cell, Cell therapy, Spinal cord injury.

scholarly journals Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Qi Han ◽  
Josue D. Ordaz ◽  
Nai-Kui Liu ◽  
Zoe Richardson ◽  
Wei Wu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Enhanced Recovery ◽  
Neural Pathways ◽  
Locomotor Recovery ◽  
Neurotrophin 3 ◽  
Cord Injury ◽  
Dendritic Atrophy ◽  
Descending Projections

AbstractLocomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.

scholarly journals Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury

2015 ◽  
Vol 113 (5) ◽  
pp. 1598-1615 ◽  
Author(s):  
Samira P. Bandaru ◽  
Shujun Liu ◽  
Stephen G. Waxman ◽  
Andrew M. Tan
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Dendritic Spine ◽  
Specific Inhibitor ◽  
H Reflex ◽  
Spine Density ◽  
Sprague Dawley ◽  
Cord Injury ◽  
Spinal Stretch Reflex

Hyperreflexia and spasticity are chronic complications in spinal cord injury (SCI), with limited options for safe and effective treatment. A central mechanism in spasticity is hyperexcitability of the spinal stretch reflex, which presents symptomatically as a velocity-dependent increase in tonic stretch reflexes and exaggerated tendon jerks. In this study we tested the hypothesis that dendritic spine remodeling within motor reflex pathways in the spinal cord contributes to H-reflex dysfunction indicative of spasticity after contusion SCI. Six weeks after SCI in adult Sprague-Dawley rats, we observed changes in dendritic spine morphology on α-motor neurons below the level of injury, including increased density, altered spine shape, and redistribution along dendritic branches. These abnormal spine morphologies accompanied the loss of H-reflex rate-dependent depression (RDD) and increased ratio of H-reflex to M-wave responses (H/M ratio). Above the level of injury, spine density decreased compared with below-injury spine profiles and spine distributions were similar to those for uninjured controls. As expected, there was no H-reflex hyperexcitability above the level of injury in forelimb H-reflex testing. Treatment with NSC23766, a Rac1-specific inhibitor, decreased the presence of abnormal dendritic spine profiles below the level of injury, restored RDD of the H-reflex, and decreased H/M ratios in SCI animals. These findings provide evidence for a novel mechanistic relationship between abnormal dendritic spine remodeling in the spinal cord motor system and reflex dysfunction in SCI.

Sign in / Sign up

Export Citation Format

Share Document