Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood–Brain–Barrier Integrity
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.
KeywordsCerebral ischemia Stroke Proteasome Neuroprotection Neuroregeneration Inflammation
This study was supported by grants from the German Research Council (DFG, No. HE3173/2-2 and No. HE3173/3-1 to DMH) and a grant from the Scientific and Technological Research Council of Turkey (TUBITAK, No. 2221 to TRD).
Compliance with Ethical Standards
All studies were performed according to local government authorities.
Conflict of Interest
The authors declare that they have no competing interests.
- 9.Berti R, Williams AJ, Velarde LC, Moffett JR, Elliott PJ, Adams J, Yao C, Dave JR et al (2003) Effect of the proteasome inhibitor MLN519 on the expression of inflammatory molecules following middle cerebral artery occlusion and reperfusion in the rat. Neurotox Res 5(7):505–514CrossRefPubMedGoogle Scholar
- 13.Williams AJ, Hale SL, Moffett JR, Dave JR, Elliott PJ, Adams J, Tortella FC (2003) Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via antiinflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration. J Cereb Blood Flow Metab 23(1):75–87CrossRefPubMedGoogle Scholar
- 15.Zhang L, Zhang ZG, Zhang RL, Lu M, Adams J, Elliott PJ, Chopp M (2001) Postischemic (6-hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke 32(12):2926–2931CrossRefPubMedGoogle Scholar
- 20.Mlynarczuk-Bialy I, Doeppner TR, Golab J, Nowis D, Wilczynski GM, Parobczak K, Wigand ME, Hajdamowicz M et al (2014) Biodistribution and efficacy studies of the proteasome inhibitor BSc2118 in a mouse melanoma model. Transl Oncol 7(5):570–579. doi: 10.1016/j.tranon.2014.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Doeppner TR, Mlynarczuk-Bialy I, Kuckelkorn U, Kaltwasser B, Herz J, Hasan MR, Hermann DM, Bahr M (2012) The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis. Brain 135(Pt 11):3282–3297. doi: 10.1093/brain/aws269 CrossRefPubMedGoogle Scholar
- 24.Doeppner TR, Kaltwasser B, ElAli A, Zechariah A, Hermann DM, Bahr M (2011) Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation. J Cereb Blood Flow Metab 31(5):1251–1262. doi: 10.1038/jcbfm.2010.211 CrossRefPubMedGoogle Scholar
- 25.Doeppner TR, Kaltwasser B, Teli MK, Bretschneider E, Bahr M, Hermann DM (2014) Effects of acute versus post-acute systemic delivery of neural progenitor cells on neurological recovery and brain remodeling after focal cerebral ischemia in mice. Cell Death Dis 5, e1386. doi: 10.1038/cddis.2014.359 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Herz J, Hagen SI, Bergmuller E, Sabellek P, Gothert JR, Buer J, Hansen W, Hermann DM et al (2014) Exacerbation of ischemic brain injury in hypercholesterolemic mice is associated with pronounced changes in peripheral and cerebral immune responses. Neurobiol Dis 62:456–468. doi: 10.1016/j.nbd.2013.10.022 CrossRefPubMedGoogle Scholar