title: Biochemical and inflammatory biomarkers in ischemic stroke: translational study between humans and two experimental rat models.
abstract: BACKGROUND
  our objective was to examine the plasma levels of three biological markers involved in cerebral ischemia (IL-6, glutamate and TNF-alpha) in stroke patients and compare them with two different rat models of focal ischemia (embolic stroke model- ES and permanent middle cerebral artery occlusion ligation model-pMCAO) to evaluate which model is most similar to humans.
  
  
  OBJECTIVE
  1) to analyze the relationship of these biological markers with the severity, volume and outcome of the brain infarction in humans and the two stroke models; and 2) to study whether the three biomarkers are also increased in response to damage in organs other than the central nervous system, both in humans and in rats.
  
  
  METHODS
  Multi-center, prospective, case-control study including acute stroke patients (n=58) and controls (n=19) with acute non-neurological diseases
  
  
  METHODS
  plasma biomarker levels on admission and at 72 h; stroke severity (NIHSS scale) and clinical severity (APACHE II scale); stroke volume; functional status at 3 months (modified Rankin Scale [mRS] and Barthel index [BI]). Experimental groups: ES (n=10), pMCAO (n=6) and controls (tissue stress by leg compression) (n=6).
  
  
  METHODS
  plasma biomarker levels at 3 and 72 h; volume of ischemic lesion (H&E) and cell death (TUNEL).
  
  
  RESULTS
  in stroke patients, IL-6 correlated significantly with clinical severity (APACHE II scale), stroke severity (NIHSS scale), infarct volume (cm3) and clinical outcome (mRS) (r=0.326, 0.497, 0.290 and 0.444 respectively; P<0.05). Glutamate correlated with stroke severity, but not with outcome, and TNF-alpha levels with infarct volume. In animals, The ES model showed larger infarct volumes (median 58.6% vs. 29%, P<0.001) and higher inflammatory biomarkers levels than pMCAO, except for serum glutamate levels which were higher in pMCAO. The ES showed correlations between the biomarkers and cell death (r=0.928 for IL-6; P<0.001; r=0.765 for TNF-alpha, P<0.1; r=0.783 for Glutamate, P<0.1) and infarct volume (r=0.943 for IL-6, P<0.0001) more similar to humans than pMCAO. IL-6, glutamate and TNF-α levels were not higher in cerebral ischemia than in controls.
  
  
  CONCLUSIONS
  Both models, ES and pMCAO, show differences that should be considered when conducting translational studies. IL-6, Glutamate and TNF-α are not specific for cerebral ischemia either in humans or in rats.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martínez-Sánchez
authors.forename: María
authors.initials: M
authors.lastname: Gutiérrez-Fernández
authors.forename: Blanca
authors.initials: B
authors.lastname: Fuentes
authors.forename: Jaime
authors.initials: J
authors.lastname: Masjuán
authors.forename: María Alonso de Leciñana
authors.initials: MA
authors.lastname: Cases
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Novillo-López
authors.forename: Exuperio
authors.initials: E
authors.lastname: Díez-Tejedor
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002545:Brain Ischemia / Q000097:blood* / Q000150:complications / Q000473:pathology; D016923:Cell Death; D002544:Cerebral Infarction / Q000097:blood / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D004617:Embolism / Q000150:complications / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000150:complications / Q000473:pathology; D008297:Male; D020318:Rats, Long-Evans; D012307:Risk Factors; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers
references.citation: Am J Physiol. 1989 Feb;256(2 Pt 2):H589-93
references.pmid: 2492771
references.citation: Clin Sci (Lond). 2012 Feb;122(4):143-59
references.pmid: 22029668
references.citation: Stroke. 2000 Oct;31(10):2325-9
references.pmid: 11022058
references.citation: Pain Res Treat. 2013;2013:742407
references.pmid: 24303215
references.citation: J Intern Med. 1997 Nov;242(5):361-5
references.pmid: 9408063
references.citation: Stroke. 2002 Apr;33(4):982-7
references.pmid: 11935048
references.citation: Stroke. 2007 May;38(5):1655-711
references.pmid: 17431204
references.citation: Mol Med. 1997 Nov;3(11):765-81
references.pmid: 9407552
references.citation: Psychiatr Danub. 2013 Mar;25(1):55-61
references.pmid: 23470607
references.citation: Neuroscience. 2011 Feb 23;175:394-405
references.pmid: 21144885
references.citation: Stroke. 2009 Jun;40(6):2244-50
references.pmid: 19246690
references.citation: BMC Neurol. 2004 Jan 15;4:2
references.pmid: 14725719
references.citation: Curr Opin Neurol. 2008 Jun;21(3):353-7
references.pmid: 18451722
references.citation: Brain Res. 1995 Dec 15;704(1):42-50
references.pmid: 8750960
references.citation: Stroke. 1997 Oct;28(10):2060-5; discussion 2066
references.pmid: 9341719
references.citation: Stroke. 1996 Jun;27(6):1060-5
references.pmid: 8650715
references.citation: Stroke. 1997 Apr;28(4):708-10
references.pmid: 9099183
references.citation: Stroke. 1995 Oct;26(10):1888-92
references.pmid: 7570744
references.citation: Stroke. 1999 Aug;30(8):1538-41
references.pmid: 10436097
references.citation: Rom J Intern Med. 2009;47(4):393-6
references.pmid: 21179922
references.citation: Acta Neurol Scand. 2005 Jun;111(6):360-5
references.pmid: 15876336
references.citation: Stroke. 1986 Jul-Aug;17(4):738-43
references.pmid: 2943059
references.citation: J Neuroinflammation. 2011 Aug 28;8:107
references.pmid: 21871121
references.citation: Nature. 1986 Apr 24-30;320(6064):769-70
references.pmid: 3703004
references.citation: J Neurosurg. 2009 Oct;111(4):701-11
references.pmid: 19425899
references.citation: Pharmacol Biochem Behav. 2007 May;87(1):179-97
references.pmid: 17521716
references.citation: NeuroRx. 2005 Jul;2(3):396-409
references.pmid: 16389304
references.citation: Lancet. 1997 Jan 11;349(9045):79-83
references.pmid: 8996418
references.citation: Neuroradiology. 2007 Feb;49(2):93-102
references.pmid: 17177065
references.citation: J Cereb Blood Flow Metab. 1981;1(1):53-60
references.pmid: 7328138
references.citation: Neurology. 1998 Sep;51(3 Suppl 3):S62-8
references.pmid: 9744839
references.citation: Stroke. 2001 May;32(5):1154-61
references.pmid: 11340225
references.citation: J Neurol Sci. 2006 Sep 25;247(2):121-9
references.pmid: 16797595
references.citation: Neurosurgery. 1992 Jul;31(1):100-6; discussion 106-7
references.pmid: 1641086
references.citation: Gut. 1991 Dec;32(12):1478-81
references.pmid: 1773952
references.citation: J Cereb Blood Flow Metab. 1992 May;12(3):484-90
references.pmid: 1569141
references.citation: J Neurol Sci. 1994 Apr;122(2):135-9
references.pmid: 8021695
references.citation: Cerebrovasc Dis. 2004;17 Suppl 1:7-18
references.pmid: 14694276
references.citation: Neuroscience. 1996 Mar;71(1):1-16
references.pmid: 8834388
references.citation: Brain Res. 1995 Feb 27;673(1):83-92
references.pmid: 7757483
references.citation: Neurology. 2008 Dec 2;71(23):1862-8
references.pmid: 18971451
references.citation: Br J Clin Pharmacol. 1992 Oct;34(4):302-8
references.pmid: 1457262
references.citation: J Cereb Blood Flow Metab. 2005 Apr;25(4):513-9
references.pmid: 15660099
references.citation: Burns. 1997 Feb;23(1):6-10
references.pmid: 9115613
references.citation: Stroke. 1990 Sep;21(9):1280-2
references.pmid: 2396263