The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis

被引:60
作者
Doeppner, Thorsten R. [1 ,2 ]
Mlynarczuk-Bialy, Izabela [3 ]
Kuckelkorn, Ulrike [4 ]
Kaltwasser, Britta [1 ,2 ]
Herz, Josephine [1 ]
Hasan, Mohammad R. [1 ]
Hermann, Dirk M. [1 ]
Baehr, Mathias [2 ,5 ]
机构
[1] Univ Duisburg Essen, Sch Med, Dept Neurol, D-45147 Essen, Germany
[2] Univ Gottingen, Dept Neurol, Sch Med, D-3400 Gottingen, Germany
[3] Med Univ Warsaw, Ctr Biostruct Res, Dept Histol & Embryol, Warsaw, Poland
[4] Charite Univ Med Berlin, Dept Biochem, Berlin, Germany
[5] DFG Res Ctr Mol Physiol Brain CMPB, Gottingen, Germany
关键词
cerebral ischaemia; thrombolytic therapy; neurogenesis; neuroregeneration; neuroprotective agents; TISSUE-PLASMINOGEN ACTIVATOR; KAPPA-B ACTIVATION; REDUCES INFARCTION; LEUKOCYTE INFILTRATION; BRAIN-INJURY; STEM-CELLS; RAT MODEL; IN-VIVO; STROKE; BORTEZOMIB;
D O I
10.1093/brain/aws269
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Only a minority of stroke patients receive thrombolytic therapy. Therefore, new therapeutic strategies focusing on neuroprotection are under review, among which, inhibition of the proteasome is attractive, as it affects multiple cellular pathways. As proteasome inhibitors like bortezomib have severe side effects, we applied the novel proteasome inhibitor BSc2118, which is putatively better tolerated, and analysed its therapeutic potential in a mouse model of cerebral ischaemia. Stroke was induced in male C57BL/6 mice using the intraluminal middle cerebral artery occlusion model. BSc2118 was intrastriatally injected 12 h post-stroke in mice that had received normal saline or recombinant tissue-plasminogen activator injections during early reperfusion. Brain injury, behavioural tests, western blotting, MMP9 zymography and analysis of angioneurogenesis were performed for up to 3 months post-stroke. Single injections of BSc2118 induced long-term neuroprotection, reduced functional impairment, stabilized blood-brain barrier through decreased MMP9 activity and enhanced angioneurogenesis when given no later than 12 h post-stroke. On the contrary, recombinant tissue-plasminogen activator enhanced brain injury, which was reversed by BSc2118. Protein expression of the transcription factor HIF1A was significantly increased in saline-treated and recombinant tissue-plasminogen activator-treated mice after BSc2118 application. In contrast, knock-down of HIF1A using small interfering RNA constructs or application of the HIF1A inhibitor YC1 (now known as RNA-binding motif, single-stranded-interacting protein 1 (RBMS1)) reversed BSc2118-induced neuroprotection. Noteworthy, loss of neuroprotection after combined treatment with BSc2118 and YC1 in recombinant tissue-plasminogen activator-treated animals was in the same order as in saline-treated mice, i.e. reduction of recombinant tissue-plasminogen activator toxicity through BSc2118 did not solely depend on HIF1A. Thus, the proteasome inhibitor BSc2118 is a promising new candidate for stroke therapy, which may in addition alleviate recombinant tissue-plasminogen activator-induced brain toxicity.
引用
收藏
页码:3282 / 3297
页数:16
相关论文
共 51 条
[1]   Neuronal replacement from endogenous precursors in the adult brain after stroke [J].
Arvidsson, A ;
Collin, T ;
Kirik, D ;
Kokaia, Z ;
Lindvall, O .
NATURE MEDICINE, 2002, 8 (09) :963-970
[2]   Effect of the proteasome inhibitor MLN519 on the expression of inflammatory molecules following middle cerebral artery occlusion and reperfusion in the rat [J].
Berti, R ;
Williams, AJ ;
Velarde, LC ;
Moffett, JR ;
Elliott, PJ ;
Adams, J ;
Yao, C ;
Dave, JR ;
Tortella, FC .
NEUROTOXICITY RESEARCH, 2003, 5 (07) :505-514
[3]   Tripeptide mimetics inhibit the 20 S proteasome by covalent bonding to the active threonines [J].
Braun, HA ;
Umbreen, S ;
Groll, M ;
Kuckelkorn, U ;
Mlynarczuk, I ;
Wigand, ME ;
Drung, I ;
Kloetzel, PM ;
Schmidt, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (31) :28394-28401
[4]   Neuroprotection achieved with a novel proteasome inhibitor which blocks NF-κB activation [J].
Buchan, AM ;
Li, H ;
Blackburn, B .
NEUROREPORT, 2000, 11 (02) :427-430
[5]   DIVERSE ROLES OF MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES IN NEUROINFLAMMATION AND CEREBRAL ISCHEMIA [J].
Candelario-Jalil, E. ;
Yang, Y. ;
Rosenberg, G. A. .
NEUROSCIENCE, 2009, 158 (03) :983-994
[6]  
Chavez JC, 2002, J NEUROSCI, V22, P8922
[7]  
Chiba Yoshiyuki, 2008, Kobe J Med Sci, V54, pE136
[8]   Recombinant tissue plasminogen activator induces blood-brain barrier breakdown by a matrix metalloproteinase-9-independent pathway after transient focal cerebral ischemia in mouse [J].
Copin, Jean-Christophe ;
Bengualid, Daniel Jimenez ;
Da Silva, Rafaela F. ;
Kargiotis, Odysseas ;
Schaller, Karl ;
Gasche, Yvan .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2011, 34 (07) :1085-1092
[9]   Enhanced poly (ADP-Ribose) polymerase-1 activation contributes to recombinant tissue plasminogen activator-induced aggravation of ischemic brain injury in vivo [J].
Crome, Olaf ;
Doeppner, Thorsten R. ;
Schwarting, Soenke ;
Mueller, Barbara ;
Baehr, Mathias ;
Weise, Jens .
JOURNAL OF NEUROSCIENCE RESEARCH, 2007, 85 (08) :1734-1743
[10]   Roles for HIF-1α in neural stem cell function and the regenerative response to stroke [J].
Cunningham, Lee Anna ;
Candelario, Kate ;
Li, Lu .
BEHAVIOURAL BRAIN RESEARCH, 2012, 227 (02) :410-417