Abstract 13053: Annexin-A1 Bioactive Peptide Provides Neuroprotection by Attenuating Microglial Activation Following Cardiac Surgery in Rats
Background: Neuroinflammation induced by cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) plays critical roles in perioperative cerebral injury, and is mediated in part by microglial activation. We hypothesized that a biologically active Annexin-A1 peptide (ANXA1sp), a known effector in the resolution of inflammation, is neuroprotective during experimental cardiac surgery by attenuating microglial activation and subsequent inflammatory responses to cerebral ischemia-reperfusion (IR).
Methods: In vivo IR: Male rats underwent 60 min DHCA at 18°C and received either vehicle or ANXA1sp (2 mg/kg, iv) followed by timed reperfusion ranging from 3h to 7 days (n=5 to 11/group/timepoint). In vitro simulated IR: BV2 microglial cells were treated with ANXA1sp (10 μM) for 1 h, subjected to 2 h oxygen-glucose deprivation followed by reoxygenation from 3-24h (n=3/group). Neuronal apoptosis (TUNEL), necrosis (acid fuchsin-celestine blue), microglial activation (Iba1 expression), NF-kB activity, cytokine production and leukocyte extravasation (MPO, ELISA) were assessed in tissue or cell culture, as appropriate.
Results: ANXA1sp treated animals showed improved neurological scores and shorter latency on Morris water maze at 3 and 7 days postreperfusion, and reduced cortical and hippocampal neuronal apoptosis and necrosis at 24h and 7 days postreperfusion (P≤0.05). This was associated with attenuation of microglial activation (Figure, A), inhibition of early cerebral NF-kB p65 phosphorylation, nuclear translocation, and DNA-binding activity (Figure, B), and suppression of downstream TNFα, IL-1β, IL-6 and MPO (p≤0.05), which were replicated in vitro.
Conclusions: ANXA1 peptidomimetics are a novel target for perioperative neuroprotection in cardiac surgery, by attenuating IR-associated microglial activation and neuroinflammation in part through NF-kB mediated signaling mechanisms.
- © 2013 by American Heart Association, Inc.