Acta Neurobiol Exp (Wars). 2018;78(4):358-374.

Anti-inflammatory compound curcumin and mesenchymal stem cells in the treatment of spinal cord injury in rats.

Ruzicka J1, Urdzikova LM2, Kloudova A2, Amin AG3, Vallova J1, Kubinova S2, Schmidt MH3, Jhanwar-Uniyal M3, Jendelova P4.
1 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Department of Neuroscience, Charles University, Second Faculty of Medicine, Prague, Czech Republic.
2 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
3 New York Medical College/Westchester Medical Center, Valhalla New York, USA.
4 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Department of Neuroscience, Charles University, Second Faculty of Medicine, Prague, Czech Republic; pavla.jendelova@iem.cas.cz.

 

Abstract

Spinal cord injury leads to a robust inflammatory response that is an unfavorable environment for stem cell implantation. In this study, we evaluated the effect of combined therapy of curcumin and mesenchymal stem cells (MSC) on behavioral recovery and tissue sparing, glial scar formation, axonal sprouting and inflammatory responses in a rat experimental model of spinal cord injury (SCI). Balloon-induced compression lesion was performed at thoracic (Th8-9) spinal level. Out of the four groups studied, two groups received curcumin on the surface of the spinal cord immediately after SCI and then once a week for 3 weeks together with an intraperitoneal daily curcumin injection for 28 days. The other two groups received saline. Seven days after SCI, human MSC were intrathecally implanted in one curcumin and one saline group. Both curcumin and curcumin combined with MSC treatment improved locomotor ability in comparison to the saline treated animals. The combined treatment group showed additional improvement in advanced locomotor performance. The combined therapy facilitated axonal sprouting, and modulated expression of pro-regenerative factors and inflammatory responses, when compared to saline and single treatments. These results demonstrate that preconditioning with curcumin, prior to the MSC implantation could have a synergic effect in the treatment of experimental SCI.

PMID: 30624435

Supplement

Spinal cord injury (SCI) is a devastating disease with large social and economy impact. Only in the U.S. the estimated number of patients with SCI is between 250,000 and 450,000. In addition, it affects mainly young people, due to car crashes, falls, violence and sport-related accidents. Generally, traumatic injury to the spinal cord is defined by two broad components: a primary component (also called primary SCI), attributable to the mechanical impact and shear forces themselves, and a secondary component (secondary SCI) that consists of a series of systemic and local neurochemical changes that occur in the nervous tissue after the initial traumatic shock [1]. Any mechanical deformation of the spinal cord leads to the rupture of neuronal cell membranes causing the massive death of all cells in the injury epicenter. All these processes trigger a chain of events that are accompanied by an inflammatory reaction leading to secondary necrotic cell death (mainly of oligodenrocytes) at the core of the injury site and apoptotic cell death in the surrounding areas [2, 3]. Currently, there is no cure for SCI. However, ongoing research to test surgical and drug therapies continues to make progress. Drug treatments, decompression surgery, nerve cell transplantation, nerve regeneration, stem cells and complex drug therapies are all being examined in clinical trials as ways to overcome the effects of SCI. However, novel therapeutic strategies, which would create an anti-inflammatory treatment that provides neuroprotective support for the remaining host and/or grafted cells, are still needed. Stem cell therapy can potentially enhance the quality of life of SCI patients. They are able to provide a large repertoire of signaling molecules, including anti-inflammatory cytokines and growth factors, which may modulate the inhibitory environment of SCI while increasing the trophic support to the resident cells [4-6]. Nearly all studies reporting the use of human bone marrow mesenchymal stem cells (MSC) in SCI have observed some locomotor function improvement, although the mechanisms have been explained differently. Designing the optimal combination of stem cells and anti-inflammatory treatment can enhance the stem cell effect in the SCI treatment. Our recent publication addresses this issue, combining the use of anti-inflammatory curcumin and human bone marrow MSC in a rat experimental model of SCI. Curcumin was injected weekly for 28 days, while MSC were applied via lumbar puncture 7 days after SCI. The combined therapy led to reduced number of protoplasmic reactive astrocytes (Fig 1A), increased number of newly sprouting axonal fibers (Fig 1B) and changes in secretion of pro and anti-inflammatory cytokines 10-14 days after SCI (Fig 1C). All these changes resulted in significant improvement in advanced locomotor skills (Fig 1D), such as coordination ability and balance, when compared with animals with SCI only.

 

 

Figure legend: Distribution of protoplasmic astrocytes revealed decrease in curcumin+MSC group (A). The effect of combined therapy on axonal sprouting, two months after SCI was observed (B). Ten days after SCI, a significant increase in levels of IL4, IL1β, IL12p70 and TNFα, and a significant decrease in RANTES were observed in the curcumin MSC group, when compared to saline as well as single treatment groups (C). Combined therapy showed significantly enhanced coordination and balance, tested in flat beam test (D).  Statistical significance was marked with * when p<0.05.

 

 

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