Journal of neurotrauma
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Journal of neurotrauma · Feb 2021
Acute neural and proteostasis mRNA levels predict chronic locomotor recovery after contusive spinal cord injury.
One of the difficulties in identifying novel therapeutic strategies to manage central nervous system (CNS) trauma is the need for behavioral assays to assess chronic functional recovery. In vitro assays and/or acute behavioral assessments cannot accurately predict long-term functional outcome. Using data from 13 independent T9 moderate contusive spinal cord injury (SCI) studies, we asked whether the ratio of acute (24-72 h post-injury) changes in the levels of neuron-, oligodendrocyte-, astrocyte-specific and/or endoplasmic reticulum stress response (ERSR) messenger ribonucleic acids (mRNAs) could predict the extent of chronic functional recovery. ⋯ This approach can be used to confirm biological action of injected drugs in vivo and to optimize dose and therapeutic window. It may prove useful in cervical and lumbar SCI and in other traumatic CNS injuries such as traumatic brain injury and stroke, where prevention of neuronal loss is paramount to functional recovery. Although the current analysis was directed toward ERSR whose activity was targeted in all but one study, acute mRNA markers for other pathophysiological cascades may be as predictive of chronic recovery when those cascades are targeted for neuroprotection.
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Journal of neurotrauma · Feb 2021
Autophagy induction contributes to the neuroprotective impact of intermittent fasting on the acutely injured spinal cord.
Spinal cord injury (SCI) is one of the leading causes of neurological disability and death. So far, there is no satisfactory treatment for SCI, because of its complex and ill-defined pathophysiology. Recently, autophagy has been implicated as protective in acute SCI rat models. ⋯ Treatment with 3-methyladenine (3-MA), a selective inhibitor of autophagy, reversed the downregulated apoptosis-related markers by IF. Finally, IF could activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway and enhance lysosome function by upregulating transcription factor (TF)EB expression. Altogether, the present findings suggest that IF exerts a neuroprotective effect after acute SCI via the upregulation of autophagy, and further points to dietary interventions as a promising combinatorial treatment for SCI.
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Journal of neurotrauma · Feb 2021
Utx regulates the NF-κB signalling pathway of NSCs to modulate macrophage migration during spinal cord injury.
Neural stem cells (NSCs) play vital roles in the homeostasis of neurological function. Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) is an important regulator of stem cell phenotypes. In our current study, we aimed to investigate whether the conditional knockout of UTX on neural stem cells alters macrophage assembly in response to spinal cord injury (SCI). ⋯ With a 45-fold pathway array and Western blot, we found that Utx-KO could significantly inhibit NF-κB signaling activation and promote the synthesis and secretion of macrophage migration inhibitory factor (MIF) in NSCs. Administration of the selective NF-κB p65 activator betulinic acid and the selective MIF inhibitor ISO-1 confirmed that the activation of NF-κB p65 phosphorylation or inhibition of MIF could eliminate the benefits of Utx-KO in SCI, such as inhibition of macrophage aggregation and reduction in scar proliferation. This study confirmed that UTX in NSCs could alter macrophage migration and improve neurological function recovery after SCI in mice.
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Journal of neurotrauma · Feb 2021
Nanoparticle based estrogen delivery to spinal cord injury site reduces local parenchymal destruction and improves functional recovery.
Spinal cord injury (SCI) patients sustain significant functional impairments; this is causally related to restricted neuronal regeneration after injury. The ensuing reactive gliosis, inflammatory cascade, and glial scar formation impede axonal regrowth. Although systemic anti-inflammatory agents (steroids) have been previously administered to counteract this, no current therapeutic is approved for post-injury neuronal regeneration, in part because of related side effects. ⋯ However, axonal regeneration, vascular endothelial growth factor production, and glial-cell-derived neurotrophic factor levels were increased with estrogen administration. Concomitantly improved locomotor and bladder functional recovery were observed with estrogen administration after injury. Therefore, low-dose site-directed estrogen may provide a future approach for enhanced neuronal repair and functional recovery in SCI patients.
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Journal of neurotrauma · Feb 2021
A longitudinal assessment of autonomic function during the acute phase of spinal cord injury: Use of low frequency blood pressure variability as a quantitative measure of autonomic function.
High-level spinal cord injury (SCI) can disrupt cardiovascular autonomic function. However, the evolution of cardiovascular autonomic function in the acute phase following injury is unknown. We evaluated the timing, severity, progression, and implications of cardiovascular autonomic injury following acute SCI. ⋯ Risk of arrhythmia increased immediately after SCI, and remained elevated throughout the acute phase. Acute SCI is associated with severe cardiovascular dysfunction. LF SAP provides a simple, non-invasive, translatable, quantitative assessment of autonomic function, and is most informative 1 month after injury.