Granulocyte Colony-Stimulating Factor Improves Motor Function in Rats Developing Compression Myelopathy

Yoshizumi, Tetsuya; Murata, Hidetoshi; Yamamoto, Shinji; Kurokawa, Ryu; Kim, Phyo; Kawahara, Nobutaka

doi:10.1097/brs.0000000000001659

Cited by 13 publications

(16 citation statements)

References 25 publications

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“…We previously demonstrated that blood flow in the compressed segment is markedly reduced, indicating the presence of local spinal cord ischemia in the chronic compression myelopathy model [32]. Consistent with our previous studies [9, 10], this study also demonstrated that chronic spinal cord compression induces apoptotic cell death. In hypoxic stress conditions, endogenous EPO is produced in response to low oxygen partial pressure and protects neurons [34].…”

Section: Discussionsupporting

confidence: 91%

“…Rotarod performance was assessed by using the rotarod device (ENV-557, Med Associates Inc., St. Albans, VT). Based on our previous research, a moderate rotation speed of 10 rpm was set [7–10]. All rats could walk on the rotarod for more than 300 seconds before surgery.…”

Section: Methodsmentioning

confidence: 99%

“…The spinal cord segment at C5-6 was removed en bloc and placed in 4% paraformaldehyde solution for 3 days. After this process, these C5-6 segments were embedded in paraffin and sectioned at a slice thickness of 5 µm and a gap interval of 5 µm over 1000 µm length, according to stereological considerations of motor neurons [7–10]. One hundred specimens of all rats were stained with H-E. Motor neurons have large nuclei and well-developed, densely stained Nissl bodies in the cytoplasm.…”

Section: Methodsmentioning

confidence: 99%

“…We recently confirmed that granulocyte colony–stimulating factor (G-CSF) improves motor function in the progressive phase of compression myelopathy and preserves anterior horn motor neurons in the rat chronic spinal cord compression model [10]. However, in healthy people, G-CSF causes marked leukocytosis, which commonly results in fever, arthralgia, and rarely, thromboembolism and splenomegaly [11].…”

Section: Introductionmentioning

confidence: 99%

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Human recombinant erythropoietin improves motor function in rats with spinal cord compression myelopathy

Tanaka

Murata

Miyazaki

et al. 2019

Preprint

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OBJECTIVEErythropoietin (EPO) is a clinically available hematopoietic cytokine. The aim of this study was to evaluate the effect of EPO on a rat model of cervical cord compression myelopathy and to explore the possibility of its use as a pharmacological treatment. METHODSTo produce the chronic cervical cord compression model, thin polyurethane sheets were implanted under the C5-C6 laminae of rats and gradually expanded due to water absorption. In this model, motor functions significantly declined from 7 weeks after surgery. Based on the result, EPO administration was started 8 weeks after surgery.Motor function as seen with rotarod performance and grip strength was measured 16 weeks after surgery, and then motor neurons were stained with H-E and NeuN staining, and counted. Apoptotic cell death was assessed with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining. To assess transfer of EPO into spinal cord tissue, the EPO level in spinal cord tissue was measured with an enzyme-linked immunosorbent assay for each group after subcutaneous injection of EPO. RESULTS 4High-dose EPO (5000 IU/kg) administered from 8 weeks after surgery markedly restored and maintained motor function in the Compression groups (P < 0.01). EPO significantly prevented loss of motor neurons in the anterior horn (P < 0.05) and significantly decreased the number of TUNEL-positive apoptotic cells (P < 0.05). The EPO level in spinal cord tissue was significantly higher in the High-dose EPO group than other groups. CONCLUSIONSEPO improves motor function in rats with progressive chronic compression myelopathy. EPO protects anterior horn motor neurons and inhibits neuronal cell apoptosis in spinal cord compression. The neuroprotective effects can be produced through transfer of EPO into spinal cord tissue. These findings suggest that EPO has high potential as a treatment for developing compression myelopathy. 1 Introduction 2 As the population ages, degenerative changes in the cervical spine progress. The spinal 3 canal gradually narrows due to cervical spondylosis, disc hernia, and ossification of the 4 posterior longitudinal ligament [1, 2]. This chronic compression of the cervical spinal 5 cord causes cervical myelopathy. The symptoms of chronic compression myelopathy 6 such as motor weakness, sensory disturbances, decreased fine motor coordination, and 7 spastic gait gradually progress over time. The main pathogenesis is presumed to be local 8 compression and spinal cord ischemia at the compressed segment [3]. At this time, 9 surgical decompression is often performed to treat cervical compression myelopathy [4-10 6]. However, no optimal medical treatment is available to improve the neurological status 11 in patients with worsening compression myelopathy. 12To elucidate the biological mechanism of chronic compression myelopathy and develop 13 a treatment strategy for it, a co-author, Kim, established a novel experimental model of 14 chronic cervical cord compression [7]. This model is...

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human recombinant erythropoietin improves motor function in rats with spinal cord compression myelopathy

Tanaka

Murata

Miyazaki

et al. 2019

Preprint

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“…More recently, it has demonstrated a role in neuroprotection, neural tissue repair, and sensorimotor recovery [92]. In rat SCI models, it reduces cell apoptosis and promotes motor recovery [93,94].…”

Section: Granulocyte Colony-stimulating Factormentioning

confidence: 99%

Clinical Trials in Traumatic Spinal Cord Injury

Donovan

Kirshblum

2018

Neurotherapeutics

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Traumatic spinal cord injury (SCI) results in impaired neurologic function that for many individuals is permanent and significantly impacts health, function, quality of life, and life expectancy. Many efforts have been taken to develop effective treatments for SCI; nevertheless, proven therapies targeting neurologic regeneration and functional recovery have been limited. Existing therapeutic approaches, including early surgery, strict blood pressure control, and consideration of treatment with steroids, remain debated and largely focus on mitigating secondary injury after the primary trauma has occurred. Today, there is more research being performed in SCI than ever before. Current clinical trials are exploring pharmacologic, cell-based, physiologic, and rehabilitation approaches to reduce secondary injury and also overcome barriers to neurorecovery. In the future, it is likely that tailored treatments combining many of these strategies will offer significant benefits for persons with SCI. This article aims to review key past, current and emerging neurologic and rehabilitation therapeutic approaches for adults with traumatic SCI.

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A sheep model of chronic cervical compressive myelopathy via an implantable wireless compression device

et al. 2022

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Purpose This study aimed to establish an animal model in which we can precisely displace the spinal cord and therefore mimic the chronic spinal compression of cervical spondylotic myelopathy. Methods In vivo intervertebral compression devices (IVCDs) connected with subcutaneous control modules (SCCMs) were implanted into the C2-3 intervertebral disk spaces of sheep and connected by Bluetooth to an in vitro control system. Sixteen sheep were divided into four groups: (Group A) control; (Group B) 10-week progressive compression, then held; (Group C) 20-week progressive compression, then held; and (Group D) 20-week progressive compression, then decompression. Electrophysiological analysis (latency and amplitude of the N1-P1-N2 wave in somatosensory evoked potentials, SEP), behavioral changes (Tarlov score), imaging test (encroachment ratio (ER) of intraspinal invasion determined by X-ray and CT scan), and histological examinations (hematoxylin and eosin, Nissl, and TUNEL staining) were performed to assess the efficacy of our model. Results Tarlov scores gradually decreased as compression increased with time and partially recovered after decompression. The Pearson correlation coefficient between ER and time was r = 0.993 (p < 0.001) in Group B at 10 weeks and Groups C and D at 20 weeks. And ER was negatively correlated with the Tarlov score (r = -0.878, p < 0.001). As compression progressed, the SEP latency was significantly extended (p < 0.001), and the amplitude significantly decreased (p < 0.001), while they were both partially restored after decompression. The number of abnormal motor neurons and TUNEL-positive cells increased significantly (p < 0.001) with compression. Conclusion Our implantable and wireless intervertebral compression model demonstrated outstanding controllability and reproducibility in simulating chronic cervical spinal cord compression in animals.

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Granulocyte Colony-Stimulating Factor Improves Motor Function in Rats Developing Compression Myelopathy

Abstract: N/A.

Cited by 13 publications

References 25 publications

Human recombinant erythropoietin improves motor function in rats with spinal cord compression myelopathy

Human recombinant erythropoietin improves motor function in rats with spinal cord compression myelopathy

Clinical Trials in Traumatic Spinal Cord Injury

A sheep model of chronic cervical compressive myelopathy via an implantable wireless compression device

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