Restricted accessResearch articleFirst published online 2020-02
Possible Strategies to Optimize a Biomarker Discovery Approach to Correlate with Neurological Outcome in Patients with Spinal Cord Injury: A Pilot Study
The lack of reliable diagnostic and prognostic markers for spinal cord injured (SCI) patients is a severe obstacle in development and testing of new therapies, and it also impairs appropriate rehabilitation care. The sparse available data on the biochemical composition of cerebrospinal fluid (CSF) during the acute and/or chronic phase of the lesion provide, up until now, inconsistent results. In this pilot study, we then explored the possibility of combining a multi-parametric and bioinformatic analysis of CSF for its biological properties tested on different cells types, suitable for investigating inflammation and re-myelination. The patient enrollment was based on stringent inclusion criteria; that is, cervical and thoracic SCI trauma, CSF collection within 24 h of trauma, type of surgical approach for spine stabilization, and absence of steroid therapy before CSF collection. Eleven SCI patients and four healthy controls were included, and in three patients, CSF was also collected at 3 months after lesion. We identified 19 proteins among the 60 investigated cytokines, chemokines, growth factors, and structural biomarkers, which are transiently regulated 24 h after SCI. A bioinformatic analysis indicated that interleukin (IL)-6 and IL-10 are in the core of the interconnected net of activated proteins. Cell-based experiments indicate that CSF from SCI patients stimulates astroglia derivation from neural precursor cells, and an inverse correlation between IL-8 CSF level and oligodendrocyte precursor cells generated from neural stem cells was also observed. Results from this pilot study suggest that using a combined bioanalytic and biological approach to analyze SCI CSF at different times after injury could be a useful approach for identifying reliable diagnostic and prognostic markers in SCI.
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References
1.
RossignolS., SchwabM., SchwartzM., and FehlingsM.G., (2007). Spinal cord injury: time to move?. J. Neurosci., 27, 11,782–11,792.
2.
van den BergM.E., CastelloteJ.M., de Pedro-CuestaJ., and Mahillo-FernándezI. (2010) Survival after spinal cord injury: a systematic review. J. Neurotrauma, 27, 1517–1528.
3.
National Spinal Cord Injury Statistical Center (2018). Facts and Figures at a Glance. University of Alabama at Birmingham: Birmingham.
4.
StahelP.F., VanderHeidenT., and FinnM.A., (2012). Management strategies for acute spinal cord injury: current options and future perspectives. Curr. Opin. Crit. Care, 18, 651–660.
5.
RabchevskyA.G., PatelS.P., and SpringerJ.E. (2011). Pharmacological interventions for spinal cord injury: where do we stand?. How might we step forward?. Pharmacol. Ther. 132, 15–29.
6.
TranA.P., WarrenP.M., and SilverJ. (2018). The biology of regeneration failure and success after spinal cord injury. Physiol. Rev. 98, 881–917.
7.
JamesN.D., BartusK., GristJ., BennettD.L., McMahonS.B., and BradburyE.J. (2011). Conduction failure following spinal cord injury: functional and anatomical changes from acute to chronic stages. J. Neurosci. 31, 18543–1855.
8.
McDonaldJ.W., and BeleguV. (2006). Demyelination and remyelination after spinal cord injury. J. Neurotrauma, 23, 345–359.
9.
FernándezM., BaldassarroV.A., SiviliaS., GiardinoL., and CalzàL. (2016). Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure. Glia, 64, 1573–1589.
10.
BadhiwalaJ.H., WilsonJ.R., KwonB.K., CashaS., and FehlingsM.G. (2018). A review of clinical trials in spinal cord injury including biomarkers. J. Neurotrauma, 35, 1906–1917.
11.
RodriguesL.F., Moura-NetoV., E. and SpohrT.C.L.S. (2018). Biomarkers in spinal cord injury: from prognosis to treatment. Mol. Neurobiol. 55, 6436–6448.
12.
AhleniusH., and KokaiaZ. (2010). Isolation and generation of neurosphere cultures from embryonic and adult mouse brain. Methods Mol. Biol. 633, 241–252.
13.
PouwM.H., KwonB.K., VerbeekM.M., VosP.E., van KampenA., FisherC.G., StreetJ., PaquetteS.J., DvorakM.F., BoydM.C., HosmanA.J., and van de MeentH. (2014). Structural biomarkers in the cerebrospinal fluid within 24 h after a traumatic spinal cord injury: a descriptive analysis of 16 subjects. Spinal Cord, 52, 428–433.
14.
YokoboriS., ZhangZ., MoghiebA., MondelloS., GajavelliS., DietrichW.D., BramlettH., HayesR.L., WangM., WangK.K., and BullockM.R. (2015). Acute diagnostic biomarkers for spinal cord injury: review of the literature and preliminary research report. World Neurosurg. 83, 867–878.
15.
HulmeC.H., BrownS.J., FullerH.R., RiddellJ., OsmanA., ChowdhuryJ., KumarN., JohnsonW.E., and WrightK.T. (2017). The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood. Spinal Cord, 5, 114–125.
16.
ElizeiS.S., and KwonB.K. (2017). The translational importance of establishing biomarkers of human spinal cord injury. Neural Regen. Res. 12, 385–388.
17.
YdensE., PalmersI., HendrixS., and SomersV. (2017). The next generation of biomarker research in spinal cord injury. Mol. Neurobiol. 54, 1482–1499.
18.
GenselJ.C., ZhangB. (2015) Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 1619, 1–11.
19.
KwonB.K., StammersA.M., BelangerL.M., BernardoA., ChanD., BishopC.M., SlobogeanG.P., ZhangH., UmedalyH., GiffinM., StreetJ., BoydM.C., PaquetteS.J., FisherC.G., and DvorakM.F. (2010). Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J. Neurotrauma, 27, 669–682.
20.
KwonB.K., StreijgerF., FallahN., NoonanV.K., BélangerL.M., RitchieL., PaquetteS.J., AilonT., BoydM.C., StreetJ., FisherC.G., and DvorakM.F. (2017). Cerebrospinal fluid biomarkers to stratify injury severity and predict outcome in human traumatic spinal cord injury. J. Neurotrauma, 34, 567–580.
21.
LabombardaF., JureI., GonzalezS., LimaA., RoigP., GuennounR., SchumacherM., and De NicolaA.F. (2015). A functional progesterone receptor is required for immunomodulation, reduction of reactive gliosis and survival of oligodendrocyte precursors in the injured spinal cord. J. Steroid Biochem. Mol. Biol. 154, 274–284.
22.
KellandE.E., GilmoreW., WeinerL.P., and LundB.T. (2011). The dual role of CXCL8 in human CNS stem cell function: multipotent neural stem cell death and oligodendrocyte progenitor cell chemotaxis. Glia, 59, 1864–1878.
23.
MatejčíkováZ., MarešJ., SládkováV., SvrčinováT., VysloužilováJ., Zapletalová. J., and KaňovskýP. (2017). Cerebrospinal fluid and serum levels of interleukin-8 in patients with multiple sclerosis and its correlation with Q-albumin. Mult. Scler. Relat. Disord. 14, 12–15.
24.
GalassoJ.M., LiuY., Szaflarski, WarrenJ.S., and SilversteinF.S. (2000). Monocyte chemoattractant protein-1 is a mediator of acute excitotoxic injury in neonatal rat brain. Neuroscience, 101, 737–744.
25.
DooleyD., LemmensE., VangansewinkelT., Le BlonD., HoornaertC., PonsaertsP., and HendrixS. (2016). Cell-based delivery of interleukin-13 directs alternative activation of macrophages resulting in improved functional outcome after spinal cord injury. Stem Cell Rep. 7, 1099–1115.
26.
MukhamedshinaY.O., AkhmetzyanovaE.R., MartynovaE.V., KhaiboullinaS.F., GalievaL.R., and RizvanovA.A. (2017). Systemic and local cytokine profile following spinal cord injury in rats: a multiplex analysis. Front. Neurol. 8, 581.
27.
ErtaM., QuintanaA., and HidalgoJ. (2012) Interleukin-6, a major cytokine in the central nervous system. Int. J. Biol. Sci. 8, 1254–1266.
28.
PeferoenL., KippM., van der ValkP., can NoortJ.M., and AmorS. (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology, 141, 302–313.
29.
EckertM.J., and MartinM.J. (2017) Trauma: spinal cord injury. surgical clinics of north america 97, 1031–1045.
30.
LiY., WangX., RenJ., LanX., LiJ., YiJ., LiuL., HanY., ZhangS., LiD., and LuS. (2017) Identification and application of anti-inflammatory compounds screening system based on RAW264.7 cells stably expressing NF-κB-dependent SEAP reporter gene. BMC Pharmacol. Toxicol. 18, 5.
31.
MaS., YadaK., LeeH., FukudaY., IidaA., and SuzukiK. (2017) Taheebo polyphenols attenuate free fatty acid-induced inflammation in murine and human macrophage cell lines as inhibitor of cyclooxygenase-2. Front. Nutr. 4, 63.
32.
CuiD., LyuJ., LiH., LeiL., BianT., LiL., and YanF. (2017) Human β-defensin 3 inhibits periodontitis development by suppressing inflammatory responses in macrophages.Mol. Immunol. 91, 65–74.
33.
RiemschneiderS., HerzbergM., and LehmannJ. (2015) Subtoxic doses of cadmium modulate inflammatory properties of murine RAW 264.7 macrophages. Biomed. Res. Int. 2015, Article ID 295303, 8 pp.
34.
FernándezM., ParadisiM., Del VecchioG., GiardinoL., and CalzàL. (2009) Thyroid hormone induces glial lineage of primary neurospheres derived from non-pathological and pathological rat brain: implications for remyelination-enhancing therapies. Int. J. Dev. Neurosci. 27, 769–778.
35.
BaldassarroV.A., LizzoG., ParadisiM., FernándezM., GiardinoL., and CalzàL. (2013) Neural stem cells isolated from amyloid precursor protein-mutated mice for drug discovery. World J. Stem Cells. 5, 229–237.
36.
BaldassarroV.A., MarchesiniA., GiardinoL., and CalzàL. (2017) PARP activity and inhibition in fetal and adult oligodendrocyte precursor cells: effect on cell survival and differentiation. Stem Cell Res. 22, 54–60.
37.
LorenteL., MartínM.M., González-RiveroA.F., RamosL., ArguesoM., CáceresJ.J., Solé-ViolánJ., SerranoN., RodríguezS.T., JiménezA., and Borreguero-LeónJ.M. (2014). Serum soluble CD40 Ligand levels are associated with severity and mortality of brain trauma injury patients. Thromb. Res. 134, 832–836.
38.
HoffmannC. (2000). COX-2 in brain and spinal cord implications for therapeutic use. Curr. Med. Chem. 7, 1113–1120.
39.
OkunoT., NakatsujiY., KumanogohA., KoguchiK., MoriyaM., FujimuraH., KikutaniH., and SakodaS. (2004) Induction of cyclooxygenase-2 in reactive glial cells by the CD40 pathway: relevance to amyotrophic lateral sclerosis. J. Neurochem. 91, 404–412.
40.
MekhailM., AlmazanG., and TabrizianM. (2012). Oligodendrocyte-protection and remyelination post-spinal cord injuries: a review. Prog. Neurobiol. 96, 322–339.
41.
LiuN.K., and XuX.M. (2012). Neuroprotection and its molecular mechanism following spinal cord injury. Neural Regen. Res. 7, 2051–2062.
42.
AlizadehA., DyckS.M., and Karimi-AbdolrezaeeS. (2015). Myelin damage and repair in pathologic CNS: challenges and prospects. Front. Mol. Neurosci. 8, 35.
43.
CalzàL., BaldassarroV.A., FernándezM., GiulianiA., LorenziniL., and GiardinoL. (2018) Thyroid Hormone and the white matter of the central nervous system: from development to repair. Vitam. Horm., 106, 253–281.
44.
MarshD.R., and FlemmingJ.M. (2011). Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury. Spinal Cord, 49, 337–344.
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