In view of its profound effect on cell survival and function, the modulation of the
ubiquitin-
proteasome-system has recently been shown to promote neurological recovery and brain remodeling after focal
cerebral ischemia. Hitherto, local intracerebral delivery strategies were used, which can hardly be translated to human patients. We herein analyzed effects of systemic intraperitoneal delivery of the
proteasome inhibitor BSc2118 on neurological recovery,
brain injury, peripheral and cerebral immune responses, neurovascular integrity, as well as cerebral neurogenesis and angiogenesis in a mouse model of transient intraluminal
middle cerebral artery occlusion. Systemic delivery of
BSc2118 induced acute neuroprotection reflected by reduced
infarct volume when delivered up to 9 h post-
stroke. The latter was associated with reduced
brain edema and stabilization of blood-brain-barrier integrity, albeit cerebral
proteasome activity was only mildly reduced. Neuronal survival persisted in the post-
acute stroke phase up to 28 days post-
stroke and was associated with improved neurological recovery when the
proteasome inhibitor was continuously delivered over 7 days. Systemic
proteasome inhibition prevented
stroke-induced acute
leukocytosis in peripheral blood and reversed the subsequent immunosuppression, namely, the reduction of blood lymphocyte and granulocyte counts. On the contrary, post-ischemic
brain inflammation, cerebral HIF-1α abundance, cell proliferation, neurogenesis, and angiogenesis were not influenced by the
proteasome inhibitor. The modulation of peripheral immune responses might thus represent an attractive target for the clinical translation of
proteasome inhibitors.