Abstract
Backgroundour 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.MethodsMulti-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).Resultsin 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.ConclusionsBoth 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.
Highlights
Experimental focal cerebral ischemia models have been developed in rats to mimic human stroke and serve as an indispensable tool in the stroke research field [1,2]
APACHE II scores on admission as well as 90-day modified Rankin scale (mRS) and Barthel Index (BI) scores were similar in both groups
Of the three biomarkers studied, IL-6 emerges as the most closely related to clinical severity, stroke severity, infarct volume and clinical outcome in stroke patients, Glu correlated with stroke severity and TNF-alpha levels with infarct volume and outcome
Summary
Experimental focal cerebral ischemia models have been developed in rats to mimic human stroke and serve as an indispensable tool in the stroke research field [1,2]. Rats are ideal animals for mimicking human stroke due to the close similarities of their cerebrovascular anatomy and physiology with humans [3,4,5], numerous drugs have demonstrated efficacy in preclinical assessments but not in clinical trials in humans [2]. This failure of translation could be explained, at least in part, by differences in the ischemic response between animals and humans. Glutamate (Glu) is an excitotoxic amino acid (EAA) that has been associated with post-ischemia brain damage in animals as well as with progression of ischemic stroke, END and infarct growth in humans [12,13,14]
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