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Proof-of Concept that an Acute Trophic Factors Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin-Expressing Progenitors and Regeneration

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An Erratum to this article was published on 14 May 2016

Abstract

Trophic factor treatment has been shown to improve the recovery of brain and spinal cord injury (SCI). In this study, we examined the effects of TSC1 (a combination of insulin-like growth factor 1 and transferrin) 4 and 8 h after SCI at the thoracic segment level (T12) in nestin-GFP transgenic mice. TSC1 treatment for 4 and 8 h increased the number of nestin-expressing cells around the lesion site and prevented Wallerian degeneration. Treatment with TSC1 for 4 h significantly increased heat shock protein (HSP)-32 and HSP-70 expression 1 and 2 mm from lesion site (both, caudal and rostral). Conversely, the number of HSP-32 positive cells decreased after an 8-h TSC1 treatment, although it was still higher than in both, non-treated SCI and intact spinal cord animals. Furthermore, TSC1 increased NG2 expressing cell numbers and preserved most axons intact, facilitating remyelination and repair. These results support our hypothesis that TSC1 is an effective treatment for cell and tissue neuroprotection after SCI. An early intervention is crucial to prevent secondary damage of the injured SC and, in particular, to prevent Wallerian degeneration.

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Acknowledgments

We are grateful to Dr. Michael Sofroniew and his team for teaching us the spinal cord injury technique. We also thank Dr. Nuanchan Jutapakdeegul for their contribution to improve the quality of the article, Dorwin Birt for help with computer support and figure composites. This work was supported by NIH Grants: HD004612, HD006576 and scholarship from the University Development Program (UDP), Thailand.

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Authors and Affiliations

  1. Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, 635 Charles E. Young Drive South, Suite 375E, Los Angeles, CA, 90095-7332, USA

    Warin Krityakiarana, Paul M. Zhao, Kevin Nguyen, Jean de Vellis & Araceli Espinosa-Jeffrey

  2. Division of Physiotherapy, Faculty of Health Science, Srinakharinwirot University, Bangkok, Thailand

    Warin Krityakiarana

  3. Department of Physiological Sciences and Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA

    Fernando Gomez-Pinilla

  4. Department of Physiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Fernando Gomez-Pinilla

  5. Neuro-Behavioural Biology Center, Institute of Science and Technology for Research and Development, Mahidol University, 999 Phutthamonthol 4 Road, Salaya, Phutthamonthol, Nakornpathom, 73170, Thailand

    Naiphinich Kotchabhakdi

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  1. Warin Krityakiarana
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  2. Paul M. Zhao
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  3. Kevin Nguyen
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  4. Fernando Gomez-Pinilla
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  5. Naiphinich Kotchabhakdi
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  6. Jean de Vellis
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  7. Araceli Espinosa-Jeffrey
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Correspondence to Araceli Espinosa-Jeffrey.

Appendix

Appendix

There are various signaling pathways involved in IGF-1 normal activity in the CNS. Ligand binding to IGF-1 receptors (IGF1Rs) triggers receptor autophosphorylation and association with docking proteins (not shown; for review see [82]. Upon cell injury (center of diagram) apoptosome formation is triggered by the release of cytochrome c from damaged mitochondria in response to either intrinsic or extrinsic cell death stimuli. The cytochrome binds to ATP-dependent proteolysis factor 1(Apf-1) monomeres which then create APF heptameres or heptamere apoptosomes. Recruitment of pro-caspase-9, either in the apoptosome or binding directly to Apf1, activates caspase 9, cleaves pro-caspase-3 and activates it. Caspase-3 breaks down cellular components for their recycling. Based on the reports from Wood and collaborators one can infer that in our experimental paradigm exogenous IGF-1 contained in TSC1 may prevent mitochondrial damage and cytochrome release blocking the caspase chain of events that lead to apoptosis (see text for details). The amount of iron (left part of the diagram) in cells is controlled by the cell surface transferrin receptor (TfR)-mediated uptake of iron as transferrin-iron. [83] TfR synthesis is regulated by interaction of the iron regulatory protein (IRP) with the iron-responsive element (IRE) present on the 3′ untranslated region of TfR mRNA. IRPs serve as sensors of cellular iron. [83–85]. The cellular oxidative damage caused by reactive oxygen species and reactive nitrogen species is critically controlled by cellular iron homeostasis [85]. Exposure to H2O2, enhances the expression of TfR mRNA, where TfR appears to be the link between oxidative stress and TfR-mediated iron uptake. Transferrin (Tf) (left part of the diagram) is the iron carrier glycoprotein for all normal cells of mammalians. In circulation, it is saturated to around 30 % in adults. Thus, allowing for the chelation of iron radicals released after cell injury. In the CNS, Tf is synthesized by OLs and choroid plexus. Iron (Fe) is found in OLs and myelin in high density and both iron and Tf are required for myelin production [22, 85, 86]. As discussed by [87] and other authors, excess and/of free iron can be cytotoxic, by catalyzing the production of hydoxyl radicals from hydrogen peroxide [88]. Increased iron concentrations in the brain have been shown in neurodegenerative diseases, e.g. Alzheimer’s disease and Parkinson’s disease [89, 90] where oxidative stress has been proposed as a pathogenic mechanism of neurodegeneration. Conversely, brain Tf levels decrease with age and the decrease is dramatic when Alzheimer’s and Parkinson’s disease are superimposed on the aging process [91]. This stoichiometry of the iron related proteins Tf, ferritin and transferrin receptor (TFR) is essential to maintain CNS function. Upon OLPs and or myelin breakdown free iron is released. In our experimental model, Tf may act as a transient chelator while “Ferritin”, the iron storage protein, is synthesized (circle with red dots) helping prevent oxidative stress and lipid peroxidation. Heat shock factors (HSF) are transcriptional activators of heat shock HSP (P) genes [92]. These activators bind specifically to Heat Shock sequence Elements (HSE) throughout the genome [93–98]. The Heat shock factor (HSF/HSF1) mediates the stress-induced expression of heat shock or stress proteins (HSPs). HSF/HSF1 is inactive in unstressed cells and it is activated during stress. Activation includes its hyperphosphorylation. Twelve Serine residues are phosphorylated in heat-activated HSF1 from which phosphorylation of HSF1 residue Ser326 plays a critical role in the induction of the factor’s transcriptional competence by heat stress and chemical stress. The functional role of other newly identified phosphor Ser residues remains unknown [99]. The Heat Shock sequence Element is highly conserved from yeast to humans. Heat shock factors (HSF) are transcriptional activators of heat shock genes. These activators bind specifically to Heat Shock sequence Elements (HSE) throughout the genome [93]. Although not shown in the diagram, eat shock proteins bind to the misfolded proteins and dissociate from HSF-1. This allows HSF1 to form trimers and translocate to the cell nucleus and activate transcription [7]. Its function is not only critical to overcome the proteotoxic effects of thermal stress, but also needed for proper animal development and the overall survival of cancer cells [100, 101]. It is worth mentioning that we have previously shown a synergistic effects of TSC1 as a neuroprotective agent. In the present work, we showed that a single dose of TSC1 was necessary and sufficient to increase the number of HSP-32-expressing cells most likely by HSF phosphorylation, hence promoting mitochondria homeostasis and energy management (Fig. 8).

Fig. 8
figure 8

Schematic representation of some mechanisms that may be modulated by TSC1 with respect to apoptosis and iron homeostasis

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Krityakiarana, W., Zhao, P.M., Nguyen, K. et al. Proof-of Concept that an Acute Trophic Factors Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin-Expressing Progenitors and Regeneration. Neurochem Res 41, 431–449 (2016). https://doi.org/10.1007/s11064-016-1850-z

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