Lewis, Fischer 344, and Sprague-Dawley Rats Display Differences in Lipid Peroxidation, Motor Recovery, and Rubrospinal Tract Preservation after Spinal Cord Injury

Ideal therapy for lower urinary tract dysfunction in patients with spinal cord injury (SCI) should decrease detrusor overactivity, thereby promoting urine storage at low intravesical pressure and promoting efficient voiding at low pressure by decreasing detrusor-sphincter dyssynergia. Here we investigated blockade of various α-adrenoceptors to determine the subtype that was principally responsible for improving the voiding dysfunction. The effects of the intravenous α-blocker naftopidil, the α-blocker BMY 7378, and the α-blocker silodosin were evaluated using cystometrography and external urethral sphincter-electromyography (EMG) in decerebrated, unanesthetized female Sprague-Dawley rats with chronic SCI following transection at Th8. Parameters measured included the voided volume, residual volume, voiding efficiency, and burst and silent periods on EMG. Compared with values in decerebrated non-SCI rats, EMG of decerebrated SCI rats revealed more prominent tonic activity, significantly shorter periods of bursting activity, and a reduced ratio of the silent to active period during bursting. Compared with the value before drug administration (control), the voiding efficiency was significantly increased by naftopidil (1 and 3 mg/kg) (<0.05 each), and the burst (<0.01 and <0.05, respectively) and silent periods (<0.01 each) on EMG were significantly lengthened. BMY 7378 (1 mg/kg) significantly increased voiding efficiency and lengthened the burst periods (<0.05 each). Silodosin did not affect any parameters. These results suggest that α-blockade reduces the urethral resistance associated with detrusor-sphincter dyssynergia, thus improving voiding efficiency in SCI rats.

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Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury

Journal of Neurosurgery Spine ◽

10.3171/2015.9.spine15628 ◽

2016 ◽

Vol 25 (1) ◽

pp. 114-124 ◽

Cited By ~ 13

Author(s):

Sergiy V. Kushchayev ◽

Morgan B. Giers ◽

Doris Hom Eng ◽

Nikolay L. Martirosyan ◽

Jennifer M. Eschbacher ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuroprotective Effect ◽

Scar Tissue ◽

Treated Group ◽

Secondary Injury ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Cord Injury ◽

Behavioral Assessments

OBJECTIVE Spinal cord injury occurs in 2 phases. The initial trauma is followed by inflammation that leads to fibrous scar tissue, glial scarring, and cavity formation. Scarring causes further axon death around and above the injury. A reduction in secondary injury could lead to functional improvement. In this study, hyaluronic acid (HA) hydrogels were implanted into the gap formed in the hemisected spinal cord of Sprague-Dawley rats in an attempt to attenuate damage and regenerate tissue. METHODS A T-10 hemisection spinal cord injury was created in adult male Sprague-Dawley rats; the rats were assigned to a sham, control (phosphate-buffered saline), or HA hydrogel–treated group. One cohort of 23 animals was followed for 12 weeks and underwent weekly behavioral assessments. At 12 weeks, retrograde tracing was performed by injecting Fluoro-Gold in the left L-2 gray matter. At 14 weeks, the animals were killed. The volume of the lesion and the number of cells labeled from retrograde tracing were calculated. Animals in a separate cohort were killed at 8 or 16 weeks and perfused for immunohistochemical analysis and transmission electron microscopy. Samples were stained using H & E, neurofilament stain (neurons and axons), silver stain (disrupted axons), glial fibrillary acidic protein stain (astrocytes), and Iba1 stain (mononuclear cells). RESULTS The lesions were significantly smaller in size and there were more retrograde-labeled cells in the red nuclei of the HA hydrogel–treated rats than in those of the controls; however, the behavioral assessments revealed no differences between the groups. The immunohistochemical analyses revealed decreased fibrous scarring and increased retention of organized intact axonal tissue in the HA hydrogel–treated group. There was a decreased presence of inflammatory cells in the HA hydrogel–treated group. No axonal or neuronal regeneration was observed. CONCLUSIONS The results of these experiments show that HA hydrogel had a neuroprotective effect on the spinal cord by decreasing the magnitude of secondary injury after a lacerating spinal cord injury. Although regeneration and behavioral improvement were not observed, the reduction in disorganized scar tissue and the retention of neurons near and above the lesion are important for future regenerative efforts. In addition, this gel would be useful as the base substrate in the development of a more complex scaffold.

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Reducing neuronal apoptosis in pontine micturition center by nerve root transfer to reconstruct bladder function after spinal cord injury

10.21203/rs.2.17382/v1 ◽

2019 ◽

Author(s):

Ronghua Yu ◽

Gang Yin ◽

Jianguo Zhao ◽

Huihao Chen ◽

Depeng Meng ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Nerve Root ◽

Neuronal Apoptosis ◽

Nerve Transfer ◽

Bladder Function ◽

Sprague Dawley ◽

Nerve Roots ◽

Sprague Dawley Rats ◽

Cord Injury

Abstract Background: The neuronal apoptosis is increased after spinal cord injury (SCI), but anastomosing the normal nerve roots above SCI level to the injury sacral nerve roots can enhance functional recovery of neurons. Therefore, we evaluated the effect of sacral nerve root transfer after SCI on pontine neuronal survival and restoration of bladder function. Methods: Adult female Sprague Dawley rats (N = 90, 9–10 weeks old, 240-260 grams weight) were randomly divided into three groups (N = 30). We anastomosed the dorsal and ventral roots of proximal L4 and distal S2 to reconstruct the rat bladder–spinal cord–cerebral nerve afferent and efferent pathways in Sprague Dawley rats after spinal cord transection. We examined pontine neuronal morphology and apoptosis using hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) at different time points (1 day, 1 week, and 1, 3, or 6 months) after SCI and nerve transfer. Bcl-2 and Bax protein expression changes in the pontine micturition center were quantified by immunohistochemistry. Results: After nerve roots reconstruction, Group A compared with Group B, Bcl-2 expression increased significantly, Bax expression decreased significantly, Bcl-2/Bax ratio increased, the number of apoptotic neurons decreased, and the number of apoptotic bodies within neurons decreased significantly as observed by TEM.Conclusion: These findings demonstrate that lumbosacral nerve transfer can reduce neuronal apoptosis in the pontine micturition center and enhance functional recovery of neurons. This method can be used as a new approach for reconstructing bladder function after spinal cord injury.

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Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

10.1101/2020.04.25.061176 ◽

2020 ◽

Author(s):

Jadwiga N. Bilchak ◽

Kyle Yeakle ◽

Guillaume Caron ◽

Dillon C. Malloy ◽

Marie-Pascale Côté

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Side Effects ◽

Sprague Dawley ◽

Rehabilitation Programs ◽

Rate Dependent ◽

Chloride Homeostasis ◽

Sprague Dawley Rats ◽

Early Implementation ◽

Cord Injury

AbstractAfter spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.Significance StatementSpasticity is a condition that develops after spinal cord injury (SCI) and causes major complications for individuals. We have previously reported that exercise attenuates spastic symptoms after SCI through an increase in expression of the chloride co-transporter KCC2, suggesting that restoring chloride homeostasis contributes to alleviating spasticity. However, the early implementation of rehabilitation programs in the clinic is often problematic due to co-morbidities. Here, we demonstrate that pharmacologically enhancing KCC2 activity after chronic SCI reduces multiple signs of spasticity, without the need for rehabilitation.

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Knockdown of long non-coding RNA LEF1-AS1 attenuates apoptosis and inflammatory injury of microglia cells following spinal cord injury

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-020-02041-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Sheng-Yu Cui ◽

Wei Zhang ◽

Zhi-Ming Cui ◽

Hong Yi ◽

Da-Wei Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Viability ◽

Microglial Cells ◽

Protective Effects ◽

Loss Of Function ◽

Sprague Dawley ◽

Cord Injury ◽

Apoptosis And Inflammation

Abstract Background Spinal cord injury (SCI) is associated with health burden both at personal and societal levels. Recent assessments on the role of lncRNAs in SCI regulation have matured. Therefore, to comprehensively explore the function of lncRNA LEF1-AS1 in SCI, there is an urgent need to understand its occurrence and development. Methods Using in vitro experiments, we used lipopolysaccharide (LPS) to treat and establish the SCI model primarily on microglial cells. Gain- and loss of function assays of LEF1-AS1 and miR-222-5p were conducted. Cell viability and apoptosis of microglial cells were assessed via CCK8 assay and flow cytometry, respectively. Adult Sprague-Dawley (SD) rats were randomly divided into four groups: Control, SCI, sh-NC, and sh-LEF-AS1 groups. ELISA test was used to determine the expression of TNF-α and IL-6, whereas the protein level of apoptotic-related markers (Bcl-2, Bax, and cleaved caspase-3) was assessed using Western blot technique. Results We revealed that LncRNA LEF1-AS1 was distinctly upregulated, whereas miR-222-5p was significantly downregulated in LPS-treated SCI and microglial cells. However, LEF1-AS1 knockdown enhanced cell viability, inhibited apoptosis, as well as inflammation of LPS-mediated microglial cells. On the contrary, miR-222-5p upregulation decreased cell viability, promoted apoptosis, and inflammation of microglial cells. Mechanistically, LEF1-AS1 served as a competitive endogenous RNA (ceRNA) by sponging miR-222-5p, targeting RAMP3. RAMP3 overexpression attenuated LEF1-AS1-mediated protective effects on LPS-mediated microglial cells from apoptosis and inflammation. Conclusion In summary, these findings ascertain that knockdown of LEF1-AS1 impedes SCI progression via the miR-222-5p/RAMP3 axis.

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Statin use is associated with reduced motor recovery after spinal cord injury

Spinal Cord Series and Cases ◽

10.1038/s41394-020-00378-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Erin M. Triplet ◽

Isobel A. Scarisbrick

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Recovery ◽

Motor Deficit ◽

Historical Cohort ◽

Cholesterol Lowering ◽

Severity Of Injury ◽

Cord Injury ◽

The Impact ◽

Statin Use

Abstract Study design We completed retrospective analysis of statin use in individuals with neurologically significant spinal cord injury in a historical cohort study. Objective Our objective was to establish the prevalence of cholesterol-lowering agent use following spinal cord injury (SCI) and to determine the impact on recovery of motor function. Setting Patients enrolled in the Rochester Epidemiology Project in Olmsted County, Minnesota, USA from 2005 to 2018 were included in analysis. Methods Exclusion criteria: age <18, comorbid neurological disease, prior neurological deficit, nontraumatic injury, survival <1 year, or lack of motor deficit. Demographics and cholesterol-lowering agent use in 83 individuals meeting all criteria were recorded. A total of 68/83 individuals were then assessed for change in function over the first 2 months after injury using the ISNCSCI motor subscore. Statistical comparison between control and statin groups was done by two-sided Chi-squared test or two-tailed Student’s t test. Generalized regression was performed to assess associations between independent variables and functional outcome. Results 30% of individuals with SCI had a prescription for a cholesterol-lowering agent. No significant differences were observed in severity of injury or demographic composition between groups. The change in motor subscore was reduced in the statin group compared to controls (p = 0.03, Mann–Whitney). Both severity of injury and statin were significant predictors of reduced motor recovery (p = 0.001, and p = 0.04, respectively). Conclusions Both severity of SCI and statins were significant predictors of reduced motor recovery. Additional investigation is needed to address potential impact of statin-therapy in the context of CNS injury and repair.

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Functional motor recovery with transplants of a human serotonergic cell line following severe contusive spinal cord injury

Experimental Neurology ◽

10.1016/j.expneurol.2006.02.022 ◽

2006 ◽

Vol 198 (2) ◽

pp. 560

Author(s):

Y.A. Berrocal ◽

J.S. McBroom ◽

D.D. Pearse ◽

M.J. Eaton

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Line ◽

Motor Recovery ◽

Cord Injury ◽

Contusive Spinal Cord Injury ◽

Line Following ◽

Serotonergic Cell

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Contusion, dislocation, and distraction: primary hemorrhage and membrane permeability in distinct mechanisms of spinal cord injury

Journal of Neurosurgery Spine ◽

10.3171/spi.2007.6.3.255 ◽

2007 ◽

Vol 6 (3) ◽

pp. 255-266 ◽

Cited By ~ 85

Author(s):

Anthony M. Choo ◽

Jie Liu ◽

Clarrie K. Lam ◽

Marcel Dvorak ◽

Wolfram Tetzlaff ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

White Matter ◽

Animal Models ◽

Membrane Permeability ◽

High Speed ◽

Test System ◽

Fracture Dislocation ◽

Sprague Dawley ◽

Cord Injury

Object In experimental models of spinal cord injury (SCI) researchers have typically focused on contusion and transection injuries. Clinically, however, other injury mechanisms such as fracture–dislocation and distraction also frequently occur. The objective of the present study was to compare the primary damage in three clinically relevant animal models of SCI. Methods Contusion, fracture–dislocation, and flexion–distraction animal models of SCI were developed. To visualize traumatic increases in cellular membrane permeability, fluorescein–dextran was infused into the cerebrospi-nal fluid prior to injury. High-speed injuries (approaching 100 cm/second) were produced in the cervical spine of deeply anesthetized Sprague–Dawley rats (28 SCI and eight sham treated) with a novel multimechanism SCI test system. The animals were killed immediately thereafter so that the authors could characterize the primary injury in the gray and white matter. Sections stained with H & E showed that contusion and dislocation injuries resulted in similar central damage to the gray matter vasculature whereas no overt hemorrhage was detected following distraction. Contusion resulted in membrane disruption of neuronal somata and axons localized within 1 mm of the lesion epicenter. In contrast, membrane compromise in the dislocation and distraction models was observed to extend rostrally up to 5 mm, particularly in the ventral and lateral white matter tracts. Conclusions Given the pivotal nature of hemorrhagic necrosis and plasma membrane compromise in the initiation of downstream SCI pathomechanisms, the aforementioned differences suggest the presence of mechanism-specific injury regions, which may alter future clinical treatment paradigms.

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Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota

Journal of Neuroinflammation ◽

10.1186/s12974-021-02123-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Emma K. A. Schmidt ◽

Pamela J. F. Raposo ◽

Abel Torres-Espin ◽

Keith K. Fenrich ◽

Karim Fouad

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Spinal Cord Injury ◽

Nervous System ◽

Gut Microbiota ◽

Microglial Activation ◽

Motor Recovery ◽

Long Term Effects ◽

Cord Injury ◽

Anti Inflammatory

Abstract Background Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug’s direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline’s antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression. Methods Here, we sought to determine minocycline’s effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter. Results We found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery. Conclusion We show that minocycline’s microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.

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Olfactory bulb transplantation in complete spinal cord injury: axonal regeneration and locomotor recovery

Coluna/Columna ◽

10.1590/s1808-1851201514010r128 ◽

2015 ◽

Vol 14 (1) ◽

pp. 50-52

Author(s):

Carlos Abraham Arellanes-Chávez ◽

Ariana Martínez Bojórquez ◽

Ernesto Ramos Martínez

Keyword(s):

Spinal Cord ◽

Axonal Regeneration ◽

Sufficient Evidence ◽

Spinal Cord Regeneration ◽

Sprague Dawley ◽

Locomotor Recovery ◽

Randomized Controlled ◽

Sprague Dawley Rats ◽

Cord Injury ◽

Complete Spinal Cord Injury

OBJECTIVES: To determine whether the intervention in rats is effective in terms of spinal cord regeneration and locomotor recovery, in order to obtain sufficient evidence to apply the therapy in humans. METHODS: a randomized, controlled, experimental, prospective, randomized trial was conducted, with a sample of 15 adult female Sprague-Dawley rats weighing 250 gr. They were divided into three equal groups, and trained for 2 weeks based on Pavlov's classical conditioning method, to strengthen the muscles of the 4 legs, stimulate the rats mentally, and keep them healthy for the surgery. RESULTS: It was observed that implantation of these cells into the site of injury may be beneficial to the process of spinal cord regeneration after spinal trauma, to mediate secretion of neurotrophic and neuroprotective chemokines, and that the OECs have the ability to bridge the repair site and decrease the formation of gliosis, creating a favorable environment for axonal regeneration. CONCLUSION: It is emphasized that the olfactory ensheathing glial cells possess unique regenerative properties; however, it was not until recently that the activity of promoting central nervous system regeneration was recognized.

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