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

Abstract

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.

• Authors: Thorsten R Doeppner, Izabela Mlynarczuk-Bialy, Ulrike Kuckelkorn, Britta Kaltwasser, Josephine Herz, Mohammad R Hasan, Dirk M Hermann, Mathias Bähr
• Journal: Brain : a journal of neurology (Brain) Vol. 135 Issue Pt 11 Pg. 3282-97 (Nov 2012) ISSN: 1460-2156 [Electronic] England
• PMID: 23169919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• BSc2118
• Butanes
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neuroprotective Agents
• Oligopeptides
• Proteasome Inhibitors
• Recombinant Proteins
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Blood-Brain Barrier (drug effects)
• Brain Ischemia (drug therapy, metabolism, physiopathology)
• Butanes (administration & dosage, antagonists & inhibitors, pharmacology, therapeutic use, toxicity)
• Disease Models, Animal
• Drug Interactions
• Gene Knockdown Techniques
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Microinjections
• Neurogenesis (drug effects)
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Oligopeptides (administration & dosage, antagonists & inhibitors, pharmacology, therapeutic use, toxicity)
• Proteasome Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Recombinant Proteins (administration & dosage, adverse effects)
• Recovery of Function (drug effects)
• Thrombolytic Therapy
• Tissue Plasminogen Activator (administration & dosage, adverse effects, antagonists & inhibitors)