Biochemical and inflammatory biomarkers in ischemic stroke: translational study between humans and two experimental rat models.

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.

Secondary Objectives: 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

Main Variables: 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).

Main Variables: 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.