Effects of anti-inflammatory treatments on stroke outcome in animal models

Background: Stroke is a devastating disease with over 5.5 million yearly casualties worldwide. Acute treatment strategies are limited. The acute inflammatory response following stroke has been demonstrated to be detrimental on stroke outcome, for both ischemic and hemorrhagic stroke subtypes. Pre-clinical evaluation of anti-inflammatory treatment on stroke outcome should therefore be pursued. Aim: Within this thesis we aim to demonstrate improved outcome after experimental stroke by the use of specific anti-inflammatory treatment strategies. Methods: Treatments were tested in two clinically relevant rat stroke models. First, an experimental subarachnoid hemorrhage model in which a blood-supplying artery of the brain is punctured releasing blood into the subarachnoid space. Second, an embolic ischemic stroke model in which an artery is occluded by an autologous thrombotic embolus, followed by administration of the thrombolytic drug rTPA to induce reperfusion. Animals were treated with clinically approved immunomodulatory drugs: interferon-β or dexamethasone. The latter drug was also evaluated in an advanced approach, in which dexamethasone was encapsulated in long-circulating liposomes to improve pharmacokinetics. Outcome measures were functional neurological status, established with behavioral tests, and brain tissue status, measured with multiparametric magnetic resonance imaging. In addition, additional analyses were done to measure inflammatory markers and blood disposition in brain tissue. Results: The applied interferon-β treatment did not improve neurological function, nor led to brain tissue recovery in the subarachnoid hemorrhage and ischemic stroke models. However lung inflammation after experimental subarachnoid hemorrhage, was significantly reduced after interferon-β treatment. In the embolic stroke model, dexamethasone treatment resulted in improvement of neurological and brain tissue status when administrated encapsulated within liposomes. High-field MRI techniques gave new insights into blood perfusion patterns in the subarachnoid hemorrhage model, as well as an increased sensitivity of the detection of enhanced and treatment induced tissue recovery after an infarct. Conclusions: The results of our experiments emphasize that anti-inflammatory treatment with interferon-β requires further evaluation before translation to clinical stroke trials. However, promising effects against lung inflammation after subarachnoid hemorrhage may open up additional treatment opportunities. Dexamethasone-loaded long-circulating liposomes in combination with thrombolysis provides a promising treatment strategy after ischemic stroke, which should be further explored pre-clinically