title: Minocycline mitigates the gliogenic effects of proinflammatory cytokines on neural stem cells.
abstract: Mobilizing endogenous neural stem cells (NSCs) in the adult brain is designed to enhance the brain's regenerative capacity after cerebral lesions, e.g., as a result of stroke. Cerebral ischemia elicits neuroinflammatory processes affecting NSCs in multiple ways, the precise mechanisms of which currently remain elusive. An inhibitory effect of minocycline on microglia activation, a hallmark of postischemic neuroinflammation, has already been demonstrated in clinical trials, showing minocycline to be safe and potentially effective in ischemic stroke. Here we investigate the direct effects of minocycline and of proinflammatory cytokines on the differentiation potential of NSCs in vitro and in vivo. Primary fetal rat NSCs were treated with minocycline plus a combination of the proinflammatory cytokines tumor necrosis factor-α, interleukin 1β, and interleukin 6. The differentiation fate of NSCs was assessed immunocytochemically. To investigate the effects of minocycline and inflammation in vivo, minocycline or lipopolysaccharides were injected intraperitoneally into adult rats, with subsequent immunohistochemistry. Minocycline alone did not affect the differentiation potential of NSCs in vivo or in vitro. In contrast, proinflammatory cytokines accelerated the differentiation of NSCs, promoting an astrocytic fate while inhibiting neurogenesis in vitro and in vivo. It is interesting to note that minocycline counteracted this cytokine-induced rapid astrocytic differentiation and restored the neurogenic and oligodendrogliogenic potential of NSCs. Data suggest that minocycline antagonizes the rapid glial differentiation induced by proinflammatory cytokines following cerebral ischemia but without having a direct effect on the differentiation potential of NSCs. Thus, minocycline constitutes a promising drug for stroke research, counteracting the detrimental effects of postischemic neuroinflammation in multiple ways.
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sabine Ulrike
authors.initials: SU
authors.lastname: Vay
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blaschke
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany.
authors.forename: Gereon Rudolf
authors.initials: GR
authors.lastname: Fink
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeter
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany.
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Rueger
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004338:Drug Combinations; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000941:Antigens; D016207:Cytokines; D004338:Drug Combinations; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D008911:Minocycline; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D055748:SOXB1 Transcription Factors; D014404:Tubulin; D000099216:Chondroitin Sulfate Proteoglycan 4; C527784:Sox2 protein, rat
keywords: glial differentiation; lipopolysaccharide; neuroinflammation; neuronal differentiation; stroke