@phdthesis{Dinca2007,
  author    = {Ivona Venera Dinca},
  title     = {Age-related efficacy of indomethacin treatment in ischemic stroke with emphasis on inflammatory mediators, angiogenesis and functional recovery},
  journal    = {Die Effizienz der Behandlung mit Indometacin nach einem isch{\"a}mischen Schlaganfall, in Abh{\"a}ngigkeit vom Alter und unter besonderer Beachtung von inflammatorischen Mediatoren, Angiogenese und funktioneller Erholung},
  url       = {https://nbn-resolving.org/urn:nbn:de:gbv:9-000377-8},
  year      = {2007},
  abstract  = {Abstract: Ischemic stroke is an aging disease and causes high mortality or long-term disability. The reduced neurological recovery in aging is possibly associated with impairment of angiogenesis and non-specific enhancement of inflammatory reaction. To check this hypotheses, those events were compared within young and elder animals brain at day 14 following focal ischemic stroke. Moreover, it is of importance to investigate also the potential therapies of indomethacin for prolonging the therapeutic window using aged animal models. The focus of present study was on neurobiological and neurological differences between young and old rats modulated by indomethacin daily treatment beginning at four hours post-ischemic episode. The effectiveness of indomethacin treatment in young and elder rats was probed using immunohistochemistry, oligonucleotide microarray, Real Time PCR and neurological evaluation. Our results provide insight of several age-independent positive consequences of Cox non-specific inhibition by indomethacin including increased NeuN positive surviving neurons, reduced infarct volume and enhanced neuroprotective response of innate immune system evidenced by increased Iba1 and Anx3 immunoreactivities in moderately activated microglia in periinfarction. From gene level we observed in both age groups downregulation of Mdk and Cxcl1 chemokines, and Id3 transcription factor which might modulate inflammatory response and facilitate repair. Other several findings showed age-dependent drug effect. Indomethacin had reduced efficacy in aged ischemic brain. From a total of 34 genes differential regulated, we observed 43\% in young and only 28\% of genes in aged have tendency toward age-matched sham expression level. In aged rats, indomethacin is ineffective in inhibiting phagocytic activity which is probably due to no expression changes of several cytokines like Tnf{\´a} and Cxcl4. Also, at protein level we observed no change of lysosomal ED1 immunoreactivity under treatment. On the other hand aging is characterized by no expression changes of Plau, Timp1, Timp2 and Col18a1 after treatment resulting in no improvement of angiogenesis. In young rats, conversely, drug administration decreased phagocytic activity by downregulating several cytotoxic cytokines such as Tnf{\´a} and Cxcl4. Moreover, the observable decrease of proteases like MMP10, Plau and MMP inhibitor Timp2 employed in matrix remodeling together with downregulation of Col18a1 expression after treatment might sustain angiogenesis in young rat ischemic brain. Indomethacin improves the motor-sensory performance in ischemic stroke rats as compared with age-matched untreated animals. Young rats fully recovered while aged showed important recuperation but did not achieve the preoperative level. In view of all this, indomethacin treatment might be consider as adjuvant therapy following ischemic stroke, even if aging blunts the positive effect of indomethacin on altered angiogenic-related gene expression. Because of the small number of rats, the results obtained from this study show only a tendency to significance and that further studies with more animals need to be statistically validated before firmly conclusions can be drawn. KEY WORDS: indomethacin; aging; microglia; angiogenesis; gene expression; microarray; neurological recovery; reversible middle cerebral artery occlusion.},
  language  = {en}
}