Pathological changes of distal motor neurons after complete spinal cord injury

Yokota, Kazuya; Kubota, Kensuke; Kobayakawa, Kazu; Saito, Takeyuki; Hara, Michiya; Kijima, Ken; Maeda, Takeshi; Katoh, Hiroyuki; Ohkawa, Yasuyuki; Nakashima, Yasuharu; Okada, Seiji

doi:10.1186/s13041-018-0422-3

Cited by 43 publications

(36 citation statements)

References 53 publications

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“…In contrast, some beneficial effects of testosterone have been found when analyzing systems away from the SCI lesion. SCI induces dendritic atrophy of lower motor neurons when de-innervated from supra-spinal connections ( 107 ). Adult female rats treated with testosterone abrogated this shortening of dendritic length in lower-motoneurons following SCI ( 47 , 108 ).…”

Section: Resultsmentioning

confidence: 99%

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

et al. 2020

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In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.

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Section: Resultsmentioning

confidence: 99%

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

et al. 2020

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“…Fresh injured spinal cords were immediately frozen in dry ice/hexane and stored in a deep freezer at − 80 °C, as previously described [ 5 , 18 ]. The tissues were sectioned into 16-μm-thick slices using a cryostat at − 20 °C and mounted on polyethylene naphthalate membrane slides.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was isolated from the lesional microglia with FACS or from the glial scars and astrocytes with LMD using the RNeasy Micro Kit (Qiagen) as previously described [ 5 , 18 ]. For the complementary DNA (cDNA) synthesis, a reverse transcription reaction was performed using PrimeScript Reverse Transcriptase (TaKaRa, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Microglial inflammation after chronic spinal cord injury is enhanced by reactive astrocytes via the fibronectin/β1 integrin pathway

Yoshizaki

Tamaru

Hara

et al. 2021

J Neuroinflammation

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Background After spinal cord injury (SCI), glial scarring is mainly formed around the lesion and inhibits axon regeneration. Recently, we reported that anti-β1 integrin antibody (β1Ab) had a therapeutic effect on astrocytes by preventing the induction of glial scar formation. However, the cellular components within the glial scar are not only astrocytes but also microglia, and whether or not β1Ab treatment has any influence on microglia within the glial scar remains unclear. Methods To evaluate the effects of β1Ab treatment on microglia within the glial scar after SCI, we applied thoracic contusion SCI to C57BL/6N mice, administered β1Ab in the sub-acute phase, and analyzed the injured spinal cords with immunohistochemistry in the chronic phase. To examine the gene expression in microglia and glial scars, we selectively collected microglia with fluorescence-activated cell sorting and isolated the glial scars using laser-captured microdissection (LMD). To examine the interaction between microglia and astrocytes within the glial scar, we stimulated BV-2 microglia with conditioned medium of reactive astrocytes (RACM) in vitro, and the gene expression of TNFα (pro-inflammatory M1 marker) was analyzed via quantitative polymerase chain reaction. We also isolated both naïve astrocytes (NAs) and reactive astrocytes (RAs) with LMD and examined their expression of the ligands for β1 integrin receptors. Statistical analyses were performed using Wilcoxon’s rank-sum test. Results After performing β1Ab treatment, the microglia were scattered within the glial scar and the expression of TNFα in both the microglia and the glial scar were significantly suppressed after SCI. This in vivo alteration was attributed to fibronectin, a ligand of β1 integrin receptors. Furthermore, the microglial expression of TNFα was shown to be regulated by RACM as well as fibronectin in vitro. We also confirmed that fibronectin was secreted by RAs both in vitro and in vivo. These results highlighted the interaction mediated by fibronectin between RAs and microglia within the glial scar. Conclusion Microglial inflammation was enhanced by RAs via the fibronectin/β1 integrin pathway within the glial scar after SCI. Our results suggested that β1Ab administration had therapeutic potential for ameliorating both glial scar formation and persistent neuroinflammation in the chronic phase after SCI.

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“…After SCI, axons and dendrites that lose connection to their original neural pathways degenerate from the site of injury in a direction away from the injury epicenter: (Bareyre et al, 2005; Kerschensteiner et al, 2005) the anterograde degenerative process is called Wallerian degeneration, while the retrograde degeneration of axons is referred to as axonal dieback. The spinal cord mass decreases both rostral and caudal to the lesion following SCI, suggesting that the anterograde and retrograde degeneration of neural fibers may be a major factor in the reduction of tissue mass in the injured spinal cord (Seif et al, 2007; Yokota et al, 2019). Long-distance retraction of injured axons coincides with the infiltration of monocytes/macrophages, whose phenotypes transition from anti-inflammatory to pro-inflammatory in response to myelin debris (Wang et al, 2015).…”

Section: Wallerian Degeneration and Axonal Diebackmentioning

confidence: 99%

Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds

Katoh

Yokota

Fehlings

2019

Front. Cell. Neurosci.

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141

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Significant progress has been made in the treatment of spinal cord injury (SCI). Advances in post-trauma management and intensive rehabilitation have significantly improved the prognosis of SCI and converted what was once an “ailment not to be treated” into a survivable injury, but the cold hard fact is that we still do not have a validated method to improve the paralysis of SCI. The irreversible functional impairment of the injured spinal cord is caused by the disruption of neuronal transduction across the injury lesion, which is brought about by demyelination, axonal degeneration, and loss of synapses. Furthermore, refractory substrates generated in the injured spinal cord inhibit spontaneous recovery. The discovery of the regenerative capability of central nervous system neurons in the proper environment and the verification of neural stem cells in the spinal cord once incited hope that a cure for SCI was on the horizon. That hope was gradually replaced with mounting frustration when neuroprotective drugs, cell transplantation, and strategies to enhance remyelination, axonal regeneration, and neuronal plasticity demonstrated significant improvement in animal models of SCI but did not translate into a cure in human patients. However, recent advances in SCI research have greatly increased our understanding of the fundamental processes underlying SCI and fostered increasing optimism that these multiple treatment strategies are finally coming together to bring about a new era in which we will be able to propose encouraging therapies that will lead to appreciable improvements in SCI patients. In this review, we outline the pathophysiology of SCI that makes the spinal cord refractory to regeneration and discuss the research that has been done with cell replacement and biomaterial implantation strategies, both by itself and as a combined treatment. We will focus on the capacity of these strategies to facilitate the regeneration of neural connectivity necessary to achieve meaningful functional recovery after SCI.

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Pathological changes of distal motor neurons after complete spinal cord injury

Cited by 43 publications

References 53 publications

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

Microglial inflammation after chronic spinal cord injury is enhanced by reactive astrocytes via the fibronectin/β1 integrin pathway

Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds

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