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

Content Provider	Europe PMC
Author	Jaeger, Hanna M. Pehlke, Jens R. Kaltwasser, Britta Kilic, Ertugrul Bähr, Mathias Hermann, Dirk M. Doeppner, Thorsten R.
Copyright Year	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.
Journal	Oncotarget
Volume Number	6
PubMed Central reference number	PMC4546449
Issue Number	16
PubMed reference number	26050199
e-ISSN	19492553
DOI	10.18632/oncotarget.4226
Language	English
Publisher	Impact Journals LLC
Publisher Date	2015-06-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2015 Jaeger et al.
Subject Keyword	pathology excitotoxicity focal cerebral ischemia neuroprotection N-methyl-D-aspartate-receptors (NMDAR)
Content Type	Text
Resource Type	Article
Subject	Oncology