A06 Novel Steroid-Based Strategy to Restore Blood Brain Barrier Integrity and combat Tissue Edema after Ischemic Brain Injury

Background: Disruption of the blood-brain barrier (BBB) and successive edema formation are pathological hallmarks of various disorders of the central nervous system (CNS) and can dramatically deteriorate neurological outcome especially in stroke patients. Glucocorticoids (GC) are frequently applied to fight BBB leakage in different CNS disorders, but GC efficacy is highly variable. While GC diminish edema formation in neuroinflammatory diseases, such as acute multiple sclerosis lesions, and in certain brain tumors, this substance class is ineffective or even harmful in ischemic brain diseases like acute ischemic stroke or traumatic brain injury (TBI). This is unfortunate because excessive edema formation is a frequent cause of secondary infarct growth and successive disability or death in stroke and trauma patients. Methods: In vitro (oxygen glucose deprivation, OGD, cEND cells) and in vivo (tMCAO model of stroke in the mouse, CCI model of brain trauma) we assess the effects of stroke and trauma like conditions on glucocorticoid responsivity of brain endothelial cells. Results: Our study identifies excessive proteasomal glucocorticoid receptor degradation as an important mechanism causing pharmacological insensitivity of brain microvascular endothelial cells to glucocorticoids under hypoxic/ ischemic conditions. In vitro and in vivo, restoration of glucocorticoid sensitivity was achieved by inhibition of the proteasomal pathway by proteasome inhibitors (e.g. bortezomib) accompanied by treatment with a specific glucocorticoid (e.g. dexamethasome). Proof of principle has successfully been achieved in mice subjected to transient middle cerebral artery occlusion and to controlled cortical impact (CCI, model for traumatic brain injury). The novel combination treatment significantly reduced brain edema and infarct volumes (P < 0.05), while the respective monotherapies were ineffective. Conclusions and Discussion: The novel combination therapy effectively and significantly reduces edema formation and moreover significantly ameliorated neurological performance in mouse models of stroke and brain trauma. Several glucocorticoids have been tested and a selection of most effective glucocorticoids has been made.The combined approach, application of proteasome inhibitors and a glucocorticoid, offers new avenues for the treatment of brain edema following ischemic stroke, ischemia-reperfusion after resuscitation, traumatic brain injury and other neurological disorders.