title: The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis.
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.
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Jaeger
authors.affiliation: LWL-Klinik Muenster, Department of Addiction Disorders, Muenster, Germany.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Pehlke
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.affiliation: University of Goettingen Medical School, Department of Neurology, Goettingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.|Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D020820:Dyskinesias / Q000188:drug therapy; D002546:Ischemic Attack, Transient / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects*; D000066829:Neuroprotection; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D000631:Aminopyridines; D000700:Analgesics; D043925:Angiogenesis Inducing Agents; D016194:Receptors, N-Methyl-D-Aspartate; C034161:flupirtine
keywords: N-methyl-D-aspartate-receptors (NMDAR); Pathology Section; excitotoxicity; focal cerebral ischemia; neuroprotection; pathology