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FK506 protects against various immune responses and secondary degeneration following cerebral ischemia

Item Type:Article
Title:FK506 protects against various immune responses and secondary degeneration following cerebral ischemia
Creators Name:Brecht, S. and Waetzig, V. and Hidding, U. and Hanisch, U.K. and Walther, M. and Herdegen, T. and Neiss, W.F.
Abstract:The immunosuppressant FK506 (1 mg/kg, i.p.) reduces the infarct size following 90 min occlusion of the middle cerebral artery (MCAo) in adult rat brain. Here we have investigated the effect of FK506 on cerebral immune cells that are considered to contribute to neurodegeneration. FK506 substantially attenuated the response of resident and peripheral immune cells following transient ischemia. Between 24 hr and 5 days after MCAo, FK506 reduced the T-cell infiltration in the infarct area as well as the presence of activated and/or phagocytic OX-18, OX-42, GSA-IB4, Iba1, and ED1 positive microglia/macrophages. FK506 also lowered the protein levels of TNFalpha and IL-2 in ischemic brain areas. Repetitive application of FK506 over 20 days attenuated the activation of microglia in the substantia nigra (SN), an area of secondary degeneration. Importantly, FK506 conferred also lasting protection of the neurons of SN; these neurons degenerate by withdrawal of neurotrophic factors from the striatum that undergoes necrotic death as part of the ischemic core. To understand the molecular basis of FK506 effects in cerebral immune cells, we determined in primary postnatal day 0/1 (P0/P1) microglia (i) the expression of the FK506 binding proteins FKBP12, FKBP52, and FKPB65 and (ii) that FK506 (1-100 ng/mL) lowered the number of resting or lipopolysaccharide stimulated microglia as well as we induced the lipopolysaccharide release of TNFalpha in a dose-dependent manner. In summary, FK506 confers rescue of brain tissue following cerebral ischemia not only by neuronal protection, but also by suppression of microglial activation and peripheral immune responses.
Keywords:FKBP, JNK, Microglia, TNFalpha, Substantia Nigra, Immune Cells, Ischemia, Animals, Rats
Source:Anatomical Record
Page Range:1993-2001
Date:December 2009
Official Publication:https://doi.org/10.1002/ar.20994
PubMed:View item in PubMed

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