http://link.springer.com/article/10.1007/s12035-015-9533-3
- Thorsten R. Doeppner
- , Britta Kaltwasser
- , Ulrike Kuckelkorn
- , Petra Henkelein
- , Eva Bretschneider
- , Ertugrul Kilic
- , Dirk M. Hermann
Abstract
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.
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