Immune Responses and Anti-inflammatory Strategies in a Clinically Relevant Model of Thromboembolic Ischemic Stroke with Reperfusion

AbstractThe poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1  h) or late (48 h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24 h and 5 days after stroke. Immune cell responses peaked 48 h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already in creased 24 h after stroke onset, peaked at 48 h, and remained increased—although to a lesser extent—5 days after stroke onset. CD8+ and CD4+ T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48  h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24 h after stroke onset. Lesion volume was maximal 24–48 h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after st roke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of ...
Source: Translational Stroke Research - Category: Neurology Source Type: research