An injectable recombinant human milk fat globule–epidermal growth factor 8–loaded copolymer system for spinal cord injury reduces inflammation through NF-κB and neuronal cell death

Abstract Spinal cord injury (SCI) causes neuronal cell death and vascular damage, which contribute to neurological dysfunction. Given that many biochemical changes contribute to such secondary injury, treatment approaches have increasingly focused on combined therapies or use of multi-functional drugs. MicroRNAs (miRs) are small (20–23 nucleotide), non-protein-coding RNAs and can negatively regulate target gene expression at the post-transcriptional level. As individual miRs can potentially modulate expression of multiple relevant proteins after injury, they are attractive candidates as upstream regulators of the secondary SCI progression. In the present study we examined the role of miR-711 modulation after SCI. Levels of miR-711 were increased in injured spinal cord early after SCI, accompanied by rapid downregulation of its target angiopoietin-1 (Ang-1), an endothelial growth factor. Changes of miR-711 were also associated with downregulation of the pro-survival protein Akt (protein kinase B), another target of miR-711, with sequential activation of glycogen synthase kinase 3 and the pro-apoptotic BH3-only molecule PUMA. Central administration of a miR-711 hairpin inhibitor after SCI limited decreases of Ang-1/Akt expression and attenuated apoptotic pathways. Such treatment also reduced neuronal/axonal damage, protected microvasculature and improved motor dysfunction following SCI. In vitro, miR-711 levels were rapidly elevated by neuronal insults, but not by activated microglia and astrocytes. Together, our data suggest that post-traumatic miR-711 elevation contributes to neuronal cell death after SCI, in part by inhibiting Ang-1 and Akt pathways, and may serve as a novel therapeutic target.

Download Full-text

Insulin with Chondroitinase ABC Treats the Rat Model of Acute Spinal Cord Injury

Journal of International Medical Research ◽

10.1177/147323000903700414 ◽

2009 ◽

Vol 37 (4) ◽

pp. 1097-1107 ◽

Cited By ~ 9

Author(s):

Y-G Yang ◽

D-M Jiang ◽

Z-X Quan ◽

Y-S Ou

Keyword(s):

Traumatic Brain Injury ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Combined Treatment ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Acute Spinal Cord Injury ◽

Chondroitinase Abc ◽

Cord Injury

Traumatic brain injury is often associated with acute spinal cord injury (ASCI). Insulin and chondroitinase ABC (ChABC) are both therapeutically effective, but the combined therapeutic effect of insulin and ChABC is still not clear. A combination of insulin and ChABC were used to treat a rat model of ASCI. This combination therapy prevented neuronal cell death by improving motor function, increasing cell growth and inhibiting cell apoptosis in ASCI rats. Expression of growth-associated protein 43, a marker of axonal re-growth, increased after combined treatment with insulin and ChABC. These results may provide a basis for a future method of treating ASCI.

Download Full-text

FBXW7alpha Promotes the Recovery of Traumatic Spinal Cord

Current Molecular Medicine ◽

10.2174/1566524020666191223164916 ◽

2020 ◽

Vol 20 (6) ◽

pp. 494-504

Author(s):

Hong Zhang ◽

Tao Yang

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Neurotrophic Factors ◽

Expression Patterns ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Thoracic Vertebrae ◽

Cord Injury ◽

Underlying Mechanisms

Background: White matter damage and neuronal cell death are incurred by spinal cord injury (SCI). FBXW7α, an important mediator of cell division and growth was investigated to explore its role in repairing the traumatic spinal cord in rats. Underlying mechanisms such as oxidative stress and inflammasomes signaling were also studied. Methods: Spinal cord injury in rats was established by longitudinal surgical incision from the lower to mid-thoracic vertebrae on the backside, followed by 20-g weight placed on the exposed Th12 surface for 30 min. AAV-delivered FBXW7α and -sh-FBXW7α were intrathecally injected into the rat spinal cord. Indices of oxidation, neurotrophic factors, and pyroptosis were measured by Western blot, Elisa, and RT-PCR. Results: We found the overexpression of FBXW7α in spinal cord rescue neuronal death triggered by the injury. Specifically, the nutritional condition, oxidative stress, and pyroptosis were improved. A synchronization of BNDF and GDNF expression patterns in various groups indicated the secretion of neurotrophic factors affect the outcome of SCI. The SOD1, CAT, and GSH-px were suppressed after trauma but all restored in response to FBXW7α overexpression. Inflammasomes-activated pyroptosis was incurred after the injury, and relevant biomarkers such as GSDMD, caspase-1, caspase- 11, IL-1β, and IL-18 were down-regulated after the introduction of FBXW7α into the injured cord. Additionally, up-regulating FBXW7α also repaired the mitochondria dysfunction. Conclusion: Our data indicate FBXW7α probably serves as an important molecular target for the therapy of spinal cord injury.

Download Full-text