STEREOTACTIC RADIOSURGERY IMPROVES LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY IN RATS

Neurosurgery ◽  
2008 ◽  
Vol 63 (5) ◽  
pp. 981-988 ◽  
Author(s):  
Richard J. Zeman ◽  
Xialing Wen ◽  
Nengtai Ouyang ◽  
Ronald Rocchio ◽  
Lynn Shih ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stereotactic Radiosurgery ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Locomotor Recovery ◽  
Locomotor Function ◽  
Cord Injury ◽  
Contusion Injury ◽  
X Irradiation

Abstract OBJECTIVE Currently, because of the precision of stereotactic radiosurgery, radiation can now be delivered by techniques that shape the radiation beam to the tissue target for a variety of clinical applications. This avoids unnecessary and potentially damaging irradiation of surrounding tissues inherent in conventional irradiation, so that irradiation of the minimum volume of tissue necessary for optimal therapeutic benefit can be achieved. Although conventional x-irradiation has been shown to improve recovery from spinal cord injury in animals, the efficacy of targeted irradiation of the injured spinal cord has not been demonstrated previously. The purpose of these studies was to determine whether stereotactic x-irradiation of the injured spinal cord can enhance locomotor function and spare spinal cord tissue after contusion injury in a standard experimental model of spinal cord injury. METHODS Contusion injury was produced in rats at the level of T10 with a weight-drop device, and doses of x-irradiation were delivered 2 hours after injury via a Novalis, 6-MeV linear accelerator shaped beam radiosurgery system (BrainLAB USA, Westchester, IL) in 4 sequential fractions, with beam angles 60 to 70 degrees apart, at a rate of 6.4 Gy/minute. The target volume was a 4 × 15-mm cylinder along the axis of the spinal cord, with the isocenter positioned at the contusion epicenter. Locomotor function was determined for 6 weeks after injury with the 21-point Basso, Beattie, and Bresnahan (BBB) locomotor scale and tissue sparing in histological sections of the spinal cord. RESULTS Locomotor function recovered progressively during the 6-week postinjury observation period. BBB scores were significantly greater in the 10-Gy x-irradiated group compared with controls (9.4 versus 7.3; P < 0.05), indicating hind limb weight support or dorsal stepping in contrast to hind limb joint mobility without weight bearing. Doses in the range of 2 to 10 Gy increased BBB scores progressively, whereas greater doses of 15 to 25 Gy were associated with lower BBB scores. The extent of locomotor recovery after treatment with x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. CONCLUSION These results suggest a beneficial role for stereotactic radiosurgery in a rat model of acute spinal cord contusion injury and raise hopes for human treatment strategies. Additional animal studies are needed to further define potential benefits.

Inhibition of x-irradiation–enhanced locomotor recovery after spinal cord injury by hyperbaric oxygen or the antioxidant nitroxide tempol

2007 ◽  
Vol 6 (4) ◽  
pp. 337-343 ◽  
Author(s):  
Virany H. Hillard ◽  
Hong Peng ◽  
Kaushik Das ◽  
Raj Murali ◽  
Chitti R. Moorthy ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyperbaric Oxygen ◽  
Spinal Cord Tissue ◽  
Irradiation Site ◽  
Injury Site ◽  
Locomotor Recovery ◽  
Locomotor Function ◽  
Cord Injury ◽  
X Irradiation

Object Hyperbaric oxygen (HBO), the nitroxide antioxidant tempol, and x-irradiation have been used to promote locomotor recovery in experimental models of spinal cord injury. The authors used x-irradiation of the injury site together with either HBO or tempol to determine whether combined therapy offers greater benefit to rats. Methods Contusion injury was produced with a weight-drop device in rats at the T-10 level, and recovery was determined using the 21-point Basso-Beattie-Bresnahan (BBB) locomotor scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater after x-irradiation (20 Gy) of the injury site or treatment with tempol (275 mg/kg intraperitoneally) than in untreated rats (final BBB Scores 10.6 [x-irradiation treated] and 9.1 [tempol treated] compared with 6.4 [untreated], p < 0.05). Recovery was not significantly improved by HBO (2 atm for 1 hour [BBB Score 8.2, p > 0.05]). Interestingly, the improved recovery of locomotor function after x-irradiation, in contrast with antiproliferative radiotherapy for neoplasia, was inhibited when used together with either HBO or tempol (BBB Scores 8.2 and 8.3, respectively). The ability of tempol to block enhanced locomotor recovery by x-irradiation was accompanied by prevention of alopecia at the irradiation site. The extent of locomotor recovery following treatment with tempol, HBO, and x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. Conclusions These results suggest that these treatments, when used alone, can activate neuroprotective mechanisms but, in combination, may result in neurotoxicity.

Presence and significance of CD-95 (Fas/APO1) expression after spinal cord injury

2001 ◽  
Vol 94 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Mercedes Zurita ◽  
Jesús Vaquero ◽  
Isabel Zurita
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Gray Matter ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Content Type ◽  
Cord Injury ◽  
Positive Immunostaining ◽  
Fine Print

Object. A glycoprotein, CD95 (Fas/APO1) is widely considered to be implicated in the development of apoptosis in a number of tissues. Based on the hypothesis that apoptosis is related to cell death after spinal cord injury (SCI), the authors studied the presence and distribution of CD95 (Fas/APO1)-positive cells in injured spinal cord tissue for the purpose of determining the significance of this protein during the early phases of SCI. Methods. The presence and distribution of cells showing positive immunostaining for CD95 (Fas/APO1) were studied 1, 4, 8, 24, 48, and 72 hours and 1, 2, and 4 weeks after induction of experimental SCI in rats. Studies were conducted using a monoclonal antibody to the CD95 (Fas/APO1) protein. Positivity for CD95 (Fas/APO1) was observed in apoptotic cells, mainly in the gray matter, 1 hour after trauma, and the number of immunostained cells increased for the first 8 hours, at which time the protein was expressed in both gray and white matter. From 24 to 72 hours postinjury, the number of immunostained cells decreased in the gray matter, but increased in the white matter. From then on, there were fewer CD95 (Fas/APO1)-positive cells, but some cells in the white matter still exhibited positive immunostaining 1 and 2 weeks after injury. At 4 weeks, there remained no CD95 (Fas/APO1)-positive cells in injured spinal cord. Conclusions. These findings indicate that CD95 (Fas/APO1) is expressed after SCI, suggesting a role for this protein in the development of apoptosis after trauma and the possibility of a new therapeutic approach to SCI based on blocking the CD95 (Fas/APO1) system.

scholarly journals Mmu-miR-27a-5p Promotes the Polarization of Macrophages to the M2 Phenotype at the Site of Spinal Cord Injury in Mice

2021 ◽  
Author(s):  
Mingkun Yang ◽  
Xiaoqian Dang ◽  
Xu Zhang ◽  
Chuan Liu ◽  
Min He
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Macrophage Polarization ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Arginase 1 ◽  
Tnf Α ◽  
Cord Injury ◽  
M2 Phenotype

Abstract BackgroundTo investigate the effect of mmu-miR-27a-5p on macrophage polarization in the injured spinal cord and the recovery of motor function after spinal cord injury (SCI) in mice.MethodsA total of 160 specific-pathogen-free male mice were randomly divided into sham, model, mmu-miR-27a-5p, mmu-miR-27a-5p-negative control (NC) groups, with 40 mice in each group. Hindlimb motor function was assessed using the Basso Mouse scale (BMS) before injury and at 1, 3, 7, and 14 days after surgery. Spinal cord tissue samples were obtained at 1, 3, 7, and 14 days after surgery, and macrophage polarization types were detected by using western blot analysis, immunofluorescence, flow cytometry and RT-qPCR.ResultsThe BMS score in the mmu-miR-27a-5p group was significantly higher than that in the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (X2=26.45-57.62, P<0.05). No significant changes in the expression of M1 markers IL-1β, TNF-α and M2 markers IL-10, Arginase-1 at each time point in the sham group (P=0.96). The expression of IL-1β and TNF-α was significantly lower, while the expression of IL-10 and Arginase-1 were significantly higher in the mmu-miR-27a-5p group as compared to the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (P<0.05).ConclusionAdministration of mmu-miR-27a-5p can promote the polarization of macrophages to the M2 phenotype in the injured spinal cord, and improve motor function recovery within 14 days after SCI in mice.

scholarly journals Effect of Electroacupuncture Treatment at Dazhui (GV14) and Mingmen (GV4) Modulates the PI3K/AKT/mTOR Signaling Pathway in Rats after Spinal Cord Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Ke Li ◽  
Juntong Liu ◽  
Liangyu Song ◽  
Wei Lv ◽  
Xi Tian ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Sham Operation ◽  
Spinal Cord Tissue ◽  
Group Model ◽  
Injured Spinal Cord ◽  
Mtor Signaling Pathway ◽  
Cord Injury

Electroacupuncture (EA) is widely recognized as clinical treatment of spinal cord injury (SCI). The purpose of this study is to elucidate whether and how the PI3K/AKT/mTOR signaling pathway plays any role in EA treating SCI. Rats were randomly divided into four equal groups: Control Group, Sham-operation Group, Model Group, and EA Group, then further randomly divided into the following subgroups: 1-day (n=12), 1-day rapamycin (n=6), 14-day (n=18), and 28-day (n=18). A rat model of SCI was established by a modified Allen’s weight-drop method. In the EA Group, rats were stimulated on Dazhui (GV14) and Mingmen (GV4) for 20 min by sterilized stainless steel needles. In the EA Group, the Basso, Beattie, and Bresnahan locomotor rating scale showed obvious improved locomotor function, and hematoxylin-eosin staining and magnetic resonance imaging showed that the histological morphology change of injured spinal cord tissue was obviously alleviated. Also, blocking spinal mTOR by injection of rapamycin showed that mTOR existed in the injured spinal cord, and EA could significantly activate mTOR in SCI rats. And immunohistochemistry and western blot analysis on the PI3K/AKT/mTOR signaling pathway showed that levels of PI3K, AKT, mTOR, and p70S6K in the injured spinal cord tissue were greatly increased in the EA Group, while the levels of PTEN and caspase 3 were decreased. The present study suggests that EA could affect cell growth, apoptosis, and autophagy through the PI3K/AKT/mTOR signaling pathway.

scholarly journals Beneficial effects of IL-37 after spinal cord injury in mice

2016 ◽  
Vol 113 (5) ◽  
pp. 1411-1416 ◽  
Author(s):  
Marina Coll-Miró ◽  
Isaac Francos-Quijorna ◽  
Eva Santos-Nogueira ◽  
Abel Torres-Espin ◽  
Philip Bufler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Locomotor Recovery ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Contusion Injury ◽  
The Central Nervous System ◽  
Locomotor Deficits ◽  
Spinal Cord Contusion

IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37–treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.

Perfusion imaging of spinal cord contusion: injury-induced blockade and partial reversal by β2-agonist treatment in rats

2014 ◽  
Vol 20 (2) ◽  
pp. 164-171 ◽  
Author(s):  
Abraham Brown ◽  
Anna Nabel ◽  
William Oh ◽  
Joseph D. Etlinger ◽  
Richard J. Zeman
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Perfusion Imaging ◽  
Laser Doppler ◽  
Tissue Loss ◽  
Partial Recovery ◽  
Locomotor Function ◽  
Adrenoceptor Agonist ◽  
Cord Injury ◽  
Contusion Injury

Object Traumatic injury to the spinal cord results in considerable delayed tissue loss. The authors investigated the extent to which ischemia occurs following contusion-induced spinal cord injury and whether ischemia exacerbates tissue damage that leads to the loss of locomotor function. They also determined if ischemia is reversed with β2–adrenoceptor agonist treatment, which has been established to be neuroprotective following contusion injury. Methods The extent and role of circulation loss in spinal cord injury was determined in an established experimental model of contusion injury. The spinal cord dura mater of Wistar rats was exposed by performing a laminectomy at T-8 to T-11. Laser Doppler perfusion imaging was then used to measure microcirculation in the exposed spinal cord. After imaging, a moderately severe contusion injury was produced using a weight-drop device unto the exposed dura at T-10. Perfusion imaging was again performed, scans were quantitated, and integrated intensities were compared. Results Postinjury imaging revealed an 18%–27% reduction in perfusion in regions rostral and caudal to the injury site, and a 68% reduction was observed at the contusion epicenter. These perfusion losses persisted for at least 48 hours. At 24 hours after injury, some rats were intraperitoneally injected with 2 mg/kg of the β2–adrenoceptor agonist clenbuterol, which has been shown to promote the partial recovery of locomotor function and spare spinal cord tissue when administered within 2 days after contusion injury. Clenbuterol injection caused a gradual increase in perfusion, which was detectable at 30 minutes postinjection and continued over time, resulting in an 127% overall increase in perfusion at the epicenter 24 hours after treatment. Conclusions These results suggest that the occurrence of chronic perfusion loss after contusion contributes to delayed damage and tissue loss. In contrast, β2–adrenoceptor agonist treatment may exert neuroprotection by restoring perfusion, thereby preventing ischemic neurodegeneration. The ability of laser Doppler imaging to measure the loss of perfusion and its restoration upon treatment suggests that it may have clinical utility in the assessment and treatment of spinal cord injury.

scholarly journals Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1822 ◽  
Author(s):  
Liam M. Koehn ◽  
Qing Dong ◽  
Sing-Yan Er ◽  
Lachlan D. Rash ◽  
Glenn F. King ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Barrier Function ◽  
Hind Limb ◽  
Tissue Loss ◽  
Functional Improvement ◽  
Spinal Cord Tissue ◽  
Post Injury ◽  
Locomotor Function ◽  
Cord Injury

Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a “treatment window” through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.

scholarly journals Jia-Ji Electro-Acupuncture Improves Locomotor Function With Spinal Cord Injury by Regulation of Autophagy Flux and Inhibition of Necroptosis

2021 ◽  
Vol 14 ◽  
Author(s):  
Yin Hongna ◽  
Tian Hongzhao ◽  
Li Quan ◽  
Feng Delin ◽  
Liu Guijun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Acupuncture Treatment ◽  
Spinal Cord Tissue ◽  
Autophagy Flux ◽  
Nissl Staining ◽  
Microscopy Imaging ◽  
Locomotor Function ◽  
Cord Injury

Jia-Ji electro-acupuncture (EA) has been widely applied in clinic to exhibit curative effects on spinal cord injury (SCI). However, its underlying mechanisms leading to improvement of motor function after SCI remain unclear. Allen’s method was made by NYU Impactor M-III equipment to create the SCI rats model. Rats were randomly divided into four groups: Sham (only laminectomy), Model (SCI group), EA (SCI + Jia-Ji EA treatment), EA + CQ (SCI + Jia-Ji EA treatment + inhibitor chloroquine). Basso-Beattie-Bresnahan assessment showed improvement of hind limb motor function after Jia-Ji electro-acupuncture treatment. Histological change of injured spinal cord tissue was alleviated after treatment, observed by hematoxylin-eosin and Nissl staining. The mRNA and protein expression levels of RIPK1, RIPK3 and MLKL were decreased in EA group. Besides, the increased expression of LC3 and reduced expression of P62 after treatment compared with Model group, confirmed that Jia-Ji electro-acupuncture could enhance the autophagy flux. Electron microscopy imaging showed increasing the number of lysosomes, autophagosomes, and autolysosomes after Jia-Ji electro-acupuncture treatment. Furthermore, inhibition of lysosome function with CQ led to partly eliminate the effect of EA on reducing necroptosis. These data make the case that Jia-Ji electro-acupuncture treatment may improve locomotor function by promoting autophagy flux and inhibiting necroptosis.

scholarly journals Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury

2021 ◽  
Author(s):  
Nadezda Lukacova ◽  
Alexandra Kisucka ◽  
Katarina Kiss Bimbova ◽  
Maria Bacova ◽  
Maria Ileninova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Temporal Correlation ◽  
Inflammatory Cells ◽  
Published Data ◽  
Spinal Cord Tissue ◽  
Cellular Functions ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Numerous Cell

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

scholarly journals Regenerated Interneurons Integrate Into Locomotor Circuitry Following Spinal Cord Injury

2020 ◽  
Author(s):  
Deeptha Vasudevan ◽  
Yen-Chyi Liu ◽  
Joshua P. Barrios ◽  
Maya K. Wheeler ◽  
Adam D. Douglass ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Excitatory Input ◽  
Swimming Behavior ◽  
Injured Spinal Cord ◽  
Post Injury ◽  
Locomotor Function ◽  
Zebrafish Larvae ◽  
Physiological Capacity ◽  
Cord Injury

AbstractWhereas humans and other adult mammals lack the ability to regain locomotor function after spinal cord injury, zebrafish are able to recover swimming behavior even after complete spinal cord transection. We have previously shown that zebrafish larvae regenerate lost neurons within 9 days post-injury (dpi), but the functional contribution of these neurons to motor recovery is unknown. Here we show that multiple interneuron subtypes known to play a role in locomotor circuitry are regenerated in injured spinal cord segments during the period of functional recovery. Further, we show that one subtype of newly-generated interneurons receives excitatory input and fires synchronously with motor output by 9 dpi. Taken together, our data show that regenerative neurogenesis in the zebrafish spinal cord produces interneurons with the physiological capacity to participate in the recovery of locomotor function.

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