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

作者: Hanna M. Jaeger , Jens R. Pehlke , Britta Kaltwasser , Ertugrul Kilic , Mathias Bähr

DOI: 10.18632/ONCOTARGET.4226

关键词: StrokeCalpainAntagonistNeuroprotectionMedicineFlupirtineAnalgesicExcitotoxicityPharmacologyTolerability

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

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