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  • Küçük Resim
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    Conditioned medium derived from neural progenitor cells induces long-term post-ischemic neuroprotection, sustained neurological recovery, neurogenesis, and angiogenesis
    (Springer, 2017) Doeppner, Thorsten R.; Traut, Viktorija; Heidenreich, Alexander; Kaltwasser, Britta; Bosche, Bert; Bahr, Mathias; Hermann, Dirk M.
    Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48 h when delivered up to 12 h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48 h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28 days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.
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    Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation
    (Wiley, 2021) Haupt, Matteo; Zheng, Xuan; Kuang, Yaoyun; Lieschke, Simone; Janssen, Lisa; Bosche, Bert; Jin, Fengyan; Hein, Katharina; Kılıç, Ertuğrul; Venkataramani, Vivek; Hermann, Dirk M.; Bahr, Mathias; Doeppner, Thorsten R.
    Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed, whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li-EVs) in comparison with EVs enriched from native MSCs. Indeed, Li-EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV-treated cells. Using a stroke mouse model, intravenous delivery of Li-EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV-treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li-EVs displayed significantly increased levels of miR-1906, which has been shown to be a new regulator of toll-like receptor 4 (TLR4) signaling. Li-EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase-2 expression, all of which culminating in reduced levels of poststroke cerebral inflammation. Conclusively, the present study for the first time demonstrates an enhanced therapeutic potential of Li-EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection an enhanced neurological recovery.
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    Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia
    (Academic Press, 2015) Hermann, Dirk Matthias; Zechariah, Anil; Kaltwasser, Britta; Bosche, Bert; Çağlayan, Ahmet Burak; Kılıç, Ertuğrul; Doeppner, Thorsten Roland
    According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50 mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy.