scholarly journals Limited changes in locomotor recovery and unaffected white matter sparing after spinal cord contusion at different times of day

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0249981
Author(s):  
Lukasz P. Slomnicki ◽  
George Wei ◽  
Darlene A. Burke ◽  
Emily R. Hodges ◽  
Scott A. Myers ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Time Of Day ◽  
Independent Study ◽  
Post Injury ◽  
Locomotor Recovery ◽  
Acute Injuries ◽  
Cord Injury ◽  
Spinal Cord Contusion ◽  
Blood Spinal Cord Barrier

The circadian gene expression rhythmicity drives diurnal oscillations of physiological processes that may determine the injury response. While outcomes of various acute injuries are affected by the time of day at which the original insult occurred, such influences on recovery after spinal cord injury (SCI) are unknown. We report that mice receiving moderate, T9 contusive SCI at ZT0 (zeitgeber time 0, time of lights on) and ZT12 (time of lights off) showed similar hindlimb function recovery in the Basso mouse scale (BMS) over a 6 week post-injury period. In an independent study, no significant differences in BMS were observed after SCI at ZT18 vs. ZT6. However, the ladder walking test revealed modestly improved performance for ZT18 vs. ZT6 mice at week 6 after injury. Consistent with those minor effects on functional recovery, terminal histological analysis revealed no significant differences in white matter sparing at the injury epicenter. Likewise, blood-spinal cord barrier disruption and neuroinflammation appeared similar when analyzed at 1 week post injury at ZT6 or ZT18. Therefore, locomotor recovery after thoracic contusive SCI is not substantively modulated by the time of day at which the neurotrauma occurred.

scholarly journals Unaffected functional recovery after spinal cord contusions at different circadian times

2021 ◽  
Author(s):  
Lukasz Slomnicki ◽  
George Wei ◽  
Darlene Burke ◽  
Scott Whittemore ◽  
Sujata Saraswat Ohri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Time Of Day ◽  
Acute Injury ◽  
Spinal Cord Tissue ◽  
Post Injury ◽  
Locomotor Recovery ◽  
Physiological Processes ◽  
Acute Injuries ◽  
Cord Injury

The circadian rhythms of gene expression drive diurnal oscillations of physiological processes that determine the acute injury response including immunity, inflammation and hemostasis. While outcomes of various acute injuries are affected by the time of day at which the original insult occurred, such diurnal influences on recovery after spinal cord injury (SCI) are unknown. We report that several key regulators of circadian gene expression are differentially expressed in uninjured spinal cord tissue of naïve mice at Zeitgeber time 1 (ZT1) or ZT12, where ZT0 or ZT12 are times when lights are turned on or off, respectively. However, mice that received moderate, T9 contusive SCI at ZT0 or ZT12 showed similar recovery of locomotion as determined using the ladder walking test and the Basso mouse scale (BMS) over a 6 week post-injury period. Consistent with those findings, terminal histological analysis revealed no significant differences in white matter sparing at the injury epicenter. Therefore, locomotor recovery after thoracic contusive SCI is not affected by the time of day at which the neurotrauma occurred at least when comparing the beginning to the end of the mouse active period.

scholarly journals D-dopachrome tautomerase activates COX2/PGE2 pathway of astrocytes to mediate inflammation following spinal cord injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Huiyuan Ji ◽  
Yuxin Zhang ◽  
Chen Chen ◽  
Hui Li ◽  
Bingqiang He ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signal Pathways ◽  
Post Injury ◽  
Dopachrome Tautomerase ◽  
Protein Levels ◽  
Cytokines And Chemokines ◽  
Cord Injury ◽  
Mitogen Activated Protein ◽  
Spinal Cord Contusion

Abstract Background Astrocytes are the predominant glial cell type in the central nervous system (CNS) that can secrete various cytokines and chemokines mediating neuropathology in response to danger signals. D-dopachrome tautomerase (D-DT), a newly described cytokine and a close homolog of macrophage migration inhibitory factor (MIF) protein, has been revealed to share an overlapping function with MIF in some ways. However, its cellular distribution pattern and mediated astrocyte neuropathological function in the CNS remain unclear. Methods A contusion model of the rat spinal cord was established. The protein levels of D-DT and PGE2 synthesis-related proteinase were assayed by Western blot and immunohistochemistry. Primary astrocytes were stimulated by different concentrations of D-DT in the presence or absence of various inhibitors to examine relevant signal pathways. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. Results D-DT was inducibly expressed within astrocytes and neurons, rather than in microglia following spinal cord contusion. D-DT was able to activate the COX2/PGE2 signal pathway of astrocytes through CD74 receptor, and the intracellular activation of mitogen-activated protein kinases (MAPKs) was involved in the regulation of D-DT action. The selective inhibitor of D-DT was efficient in attenuating D-DT-induced astrocyte production of PGE2 following spinal cord injury, which contributed to the improvement of locomotor functions. Conclusion Collectively, these data reveal a novel inflammatory activator of astrocytes following spinal cord injury, which might be beneficial for the development of anti-inflammation drug in neuropathological CNS.

scholarly journals Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2942
Author(s):  
Anissa Elahi ◽  
Jacen Emerson ◽  
Jacob Rudlong ◽  
Jeffrey W. Keillor ◽  
Garrick Salois ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Functional Recovery ◽  
Molecular Mechanisms ◽  
Genetic Model ◽  
Transglutaminase 2 ◽  
Cns Injury ◽  
Post Injury ◽  
Metabolic Coupling ◽  
Cord Injury ◽  
Spinal Cord Contusion

Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/− TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

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.

scholarly journals Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1943
Author(s):  
Alexandra Kisucká ◽  
Katarína Bimbová ◽  
Mária Bačová ◽  
Ján Gálik ◽  
Nadežda Lukáčová
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Lesion Site ◽  
Post Injury ◽  
Reactive Microglia ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Polarization States ◽  
Anti Inflammatory ◽  
Adjacent Segments

Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied time-dependent gene expression in naive and injured spinal cord. The relationship between astrocytes and microglia and their polarization states were studied in a rat model after Th9 compression (40g/15 min) in acute and subacute stages at the lesion site, and both cranially and caudally. The gene expression of microglia/macrophages and M1 microglia was strongly up-regulated at the lesion site and caudally one week after SCI, and attenuated after two weeks post-SCI. GFAP and S100B, and A1 astrocytes were profoundly expressed predominantly two weeks post-SCI at lesion site and cranially. Gene expression of anti-inflammatory M2a microglia (CD206, CHICHI, IL1rn, Arg-1), M2c microglia (TGF-β, SOCS3, IL4R α) and A2 astrocytes (Tgm1, Ptx3, CD109) was greatly activated at the lesion site one week post-SCI. In addition, we observed positive correlation between neurological outcome and expression of M2a, M2c, and A2 markers. Our findings indicate that the first week post‑injury is critical for modulation of reactive microglia/astrocytes into their neuroprotective phenotypes.

scholarly journals Hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibition after contusive spinal cord injury does not improve locomotor recovery

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249591
Author(s):  
George Z. Wei ◽  
Sujata Saraswat Ohri ◽  
Nicolas K. Khattar ◽  
Adam W. Listerman ◽  
Catherine H. Doyle ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Locomotor Recovery ◽  
Genetic Ablation ◽  
Cord Injury ◽  
Prolyl Hydroxylase Domain

Traumatic spinal cord injury (SCI) is a devastating neurological condition that involves both primary and secondary tissue loss. Various cytotoxic events including hypoxia, hemorrhage and blood lysis, bioenergetic failure, oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation contribute to secondary injury. The HIF prolyl hydroxylase domain (PHD/EGLN) family of proteins are iron-dependent, oxygen-sensing enzymes that regulate the stability of hypoxia inducible factor-1α (HIF-1α) and also mediate oxidative stress caused by free iron liberated from the lysis of blood. PHD inhibition improves outcome after experimental intracerebral hemorrhage (ICH) by reducing activating transcription factor 4 (ATF4)-driven neuronal death. As the ATF4-CHOP (CCAAT-enhancer-binding protein homologous protein) pathway plays a role in the pathogenesis of contusive SCI, we examined the effects of PHD inhibition in a mouse model of moderate T9 contusive SCI in which white matter damage is the primary driver of locomotor dysfunction. Pharmacological inhibition of PHDs using adaptaquin (AQ) moderately lowers acute induction of Atf4 and Chop mRNAs and prevents the acute decline of oligodendrocyte (OL) lineage mRNAs, but does not improve long-term recovery of hindlimb locomotion or increase chronic white matter sparing. Conditional genetic ablation of all three PHD isoenzymes in OLs did not affect Atf4, Chop or OL mRNAs expression levels, locomotor recovery, and white matter sparing after SCI. Hence, PHDs may not be suitable targets to improve outcomes in traumatic CNS pathologies that involve acute white matter injury.

scholarly journals D-Dopachrome Tautomerase Activates COX2/PGE2 Pathway of Astrocytes to Mediate Inflammation Following Spinal Cord Injury

2021 ◽  
Author(s):  
Huiyuan Ji ◽  
Yuxin Zhang ◽  
Chen Chen ◽  
Hui Li ◽  
Bingqiang He ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signal Pathways ◽  
Post Injury ◽  
Dopachrome Tautomerase ◽  
Protein Levels ◽  
Cytokines And Chemokines ◽  
Cord Injury ◽  
Mitogen Activated Protein ◽  
Spinal Cord Contusion

Abstract BackgroundAstrocytes are immune-competent cells able to secrete various cytokines and chemokines mediating neuropathology of central nervous system (CNS) in response to danger signals. D-dopachrome tautomerase (D-DT), a newly described cytokine and a close homolog of macrophage migration inhibitory factor (MIF) protein, has been revealed to share an overlapping function with MIF in some ways. However, its cellular distribution pattern and mediated astrocyte neuropathological function in the CNS remain unclear. MethodsContusion model of rat spinal cord was established. The protein levels of D-DT and PGE2 synthesis-related proteinase were assayed by Western blot and immunohistochemistry. Primary astrocytes were stimulated by different concentration of D-DT in the presence or absence of various inhibitors to examine relevant signal pathways. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. ResultsD-DT was inducibly expressed within astrocytes and neurons, rather than in microglia following spinal cord contusion. D-DT was able to activate the COX2/PGE2 signal pathway of astrocytes through CD74 receptor, and the intracellular activation of mitogen-activated protein kinases (MAPKs) was involved in the regulation of D-DT action. The selective inhibitor of D-DT was efficient in attenuating D-DT-induced astrocyte production of PGE2 following spinal cord injury, which contributed to the improvement of locomotor functions.ConclusionCollectively, these data reveal a novel inflammatory activator of astrocytes following SCI, which might be beneficial for the development of anti-inflammation drug in neuropathological CNS.

scholarly journals Improved locomotor recovery after contusive spinal cord injury in Bmal1−/− mice is associated with protection of the blood spinal cord barrier

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lukasz P. Slomnicki ◽  
Scott A. Myers ◽  
Sujata Saraswat Ohri ◽  
Molly V. Parsh ◽  
Kariena R. Andres ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Contusive Spinal Cord Injury ◽  
Blood Spinal Cord Barrier

scholarly journals Spleen tyrosine kinase facilitates neutrophil activation and worsens long-term neurologic deficits after spinal cord injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Dylan A. McCreedy ◽  
Clare L. Abram ◽  
Yongmei Hu ◽  
Sun Won Min ◽  
Madison E. Platt ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Death ◽  
White Matter ◽  
Functional Recovery ◽  
Barrier Disruption ◽  
Neurologic Deficits ◽  
Cord Injury ◽  
Blood Spinal Cord Barrier

Abstract Background Spinal cord injury elicits widespread inflammation that can exacerbate long-term neurologic deficits. Neutrophils are the most abundant immune cell type to invade the spinal cord in the early acute phase after injury, however, their role in secondary pathogenesis and functional recovery remains unclear. We have previously shown that neutrophil functional responses during inflammation are augmented by spleen tyrosine kinase, Syk, a prominent intracellular signaling enzyme. In this study, we evaluated the contribution of Syk towards neutrophil function and long-term neurologic deficits after spinal cord injury. Methods Contusive spinal cord injury was performed at thoracic vertebra level 9 in mice with conditional deletion of Syk in neutrophils (Sykf/fMRP8-Cre). Hindlimb locomotor recovery was evaluated using an open-field test for 35 days following spinal cord injury. Long-term white matter sparing was assessed using eriochrome cyanide staining. Blood-spinal cord barrier disruption was evaluated by immunoblotting. Neutrophil infiltration, activation, effector functions, and cell death were determined by flow cytometry. Cytokine and chemokine expression in neutrophils was assessed using a gene array. Results Syk deficiency in neutrophils improved long-term functional recovery after spinal cord injury, but did not promote long-term white matter sparing. Neutrophil activation, cytokine expression, and cell death in the acutely injured spinal cord were attenuated by the genetic loss of Syk while neutrophil infiltration and effector functions were not affected. Acute blood-spinal cord barrier disruption was also unaffected by Syk deficiency in neutrophils. Conclusions Syk facilitates specific neutrophil functional responses to spinal cord injury including activation, cytokine expression, and cell death. Long-term neurologic deficits are exacerbated by Syk signaling in neutrophils independent of acute blood-spinal cord barrier disruption and long-term white matter sparing. These findings implicate Syk in pathogenic neutrophil activities that worsen long-term functional recovery after spinal cord injury.

scholarly journals Longitudinal changes of spinal cord grey and white matter following spinal cord injury

2021 ◽  
pp. jnnp-2021-326337
Author(s):  
Gergely David ◽  
Dario Pfyffer ◽  
Kevin Vallotton ◽  
Nikolai Pfender ◽  
Alan Thompson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Grey Matter ◽  
Spatiotemporal Dynamics ◽  
Assessment Tools ◽  
Traumatic Spinal Cord Injury ◽  
Post Injury ◽  
Tissue Specific ◽  
Cord Injury

ObjectivesTraumatic and non-traumatic spinal cord injury produce neurodegeneration across the entire neuraxis. However, the spatiotemporal dynamics of spinal cord grey and white matter neurodegeneration above and below the injury is understudied.MethodsWe acquired longitudinal data from 13 traumatic and 3 non-traumatic spinal cord injury patients (8–8 cervical and thoracic cord injuries) within 1.5 years after injury and 10 healthy controls over the same period. The protocol encompassed structural and diffusion-weighted MRI rostral (C2/C3) and caudal (lumbar enlargement) to the injury level to track tissue-specific neurodegeneration. Regression models assessed group differences in the temporal evolution of tissue-specific changes and associations with clinical outcomes.ResultsAt 2 months post-injury, white matter area was decreased by 8.5% and grey matter by 15.9% in the lumbar enlargement, while at C2/C3 only white matter was decreased (−9.7%). Patients had decreased cervical fractional anisotropy (FA: −11.3%) and increased radial diffusivity (+20.5%) in the dorsal column, while FA was lower in the lateral (−10.3%) and ventral columns (−9.7%) of the lumbar enlargement. White matter decreased by 0.34% and 0.35% per month at C2/C3 and lumbar enlargement, respectively, and grey matter decreased at C2/C3 by 0.70% per month.ConclusionsThis study describes the spatiotemporal dynamics of tissue-specific spinal cord neurodegeneration above and below a spinal cord injury. While above the injury, grey matter atrophy lagged initially behind white matter neurodegeneration, in the lumbar enlargement these processes progressed in parallel. Tracking trajectories of tissue-specific neurodegeneration provides valuable assessment tools for monitoring recovery and treatment effects.

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