title: Effects of minocycline on endogenous neural stem cells after experimental stroke.
abstract: Minocycline has been reported to reduce infarct size after focal cerebral ischemia, due to an attenuation of microglia activation and prevention of secondary damage from stroke-induced neuroinflammation. We here investigated the effects of minocycline on endogenous neural stem cells (NSCs) in vitro and in a rat stroke model. Primary cultures of fetal rat NSCs were exposed to minocycline to characterize its effects on cell survival and proliferation. To assess these effects in vivo, permanent cerebral ischemia was induced in adult rats, treated systemically with minocycline or placebo. Imaging 7 days after ischemia comprised (i) Magnetic Resonance Imaging (MRI), assessing the extent of infarcts, (ii) Positron Emission Tomography (PET) with [(11)C]PK11195, characterizing neuroinflammation, and (iii) PET with 3'-deoxy-3'-[(18)F]fluoro-L-thymidine ([(18)F]FLT), detecting proliferating endogenous NSCs. Immunohistochemistry was used to verify ischemic damage and characterize cellular inflammatory and repair processes in more detail. In vitro, specific concentrations of minocycline significantly increased NSC numbers without increasing their proliferation, indicating a positive effect of minocycline on NSC survival. In vivo, endogenous NSC activation in the subventricular zone (SVZ) measured by [(18)F]FLT PET correlated well with infarct volumes. Similar to in vitro findings, minocycline led to a specific increase in endogenous NSC activity in both the SVZ as well as the hippocampus. [(11)C]PK11195 PET detected neuroinflammation in the infarct core as well as in peri-infarct regions, with both its extent and location independent of the infarct size. The data did not reveal an effect of minocycline on stroke-induced neuroinflammation. We show that multimodal PET imaging can be used to characterize and quantify complex cellular processes occurring after stroke, as well as their modulation by therapeutic agents. We found minocycline, previously implied in attenuating microglial activation, to have positive effects on endogenous NSC survival. These findings hold promise for the development of novel treatments in stroke therapy.
authors.affiliation: Department of Neurology, University Hospital of Cologne, Germany. adele.rueger@uk-koeln.de
authors.forename: M A
authors.initials: MA
authors.lastname: Rueger
authors.forename: S
authors.initials: S
authors.lastname: Muesken
authors.forename: M
authors.initials: M
authors.lastname: Walberer
authors.forename: S U
authors.initials: SU
authors.lastname: Jantzen
authors.forename: K
authors.initials: K
authors.lastname: Schnakenburg
authors.forename: H
authors.initials: H
authors.lastname: Backes
authors.forename: R
authors.initials: R
authors.lastname: Graf
authors.forename: B
authors.initials: B
authors.lastname: Neumaier
authors.forename: M
authors.initials: M
authors.lastname: Hoehn
authors.forename: G R
authors.initials: GR
authors.lastname: Fink
authors.forename: M
authors.initials: M
authors.lastname: Schroeter
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D001931:Brain Mapping; D001973:Bromodeoxyuridine / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004660:Encephalitis / Q000209:etiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007546:Isoquinolines / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000187:drug effects*; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D039481:CD11b Antigen; D002247:Carbon Isotopes; D015224:Dideoxynucleosides; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D007546:Isoquinolines; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D014404:Tubulin; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D008911:Minocycline; D001973:Bromodeoxyuridine; C002854:alovudine; C037850:PK 11195