Oncotarget

Research Papers: Pathology:

The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis

Hanna M. Jaeger, Jens R. Pehlke, Britta Kaltwasser, Ertugrul Kilic, Mathias Bähr, Dirk M. Hermann and Thorsten R. Doeppner _

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Oncotarget. 2015; 6:14033-14044. https://doi.org/10.18632/oncotarget.4226

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Abstract

Hanna M. Jaeger1, Jens R. Pehlke2, Britta Kaltwasser1, Ertugrul Kilic3, Mathias Bähr4, Dirk M. Hermann1 and Thorsten R. Doeppner1,3

1 University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany

2 LWL-Klinik Muenster, Department of Addiction Disorders, Muenster, Germany

3 Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey

4 University of Goettingen Medical School, Department of Neurology, Goettingen, Germany

Correspondence to:

Thorsten R. Doeppner, email:

Keywords: pathology, excitotoxicity, focal cerebral ischemia, neuroprotection, N-methyl-D-aspartate-receptors (NMDAR)

Received: March 31, 2015 Accepted: May 13, 2015 Published: May 22, 2015

Abstract

N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling.Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84.Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and-activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-κB activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished.In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy.


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