Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage

Background and Purpose-Microglial activation may contribute to the pathogenesis of the brain injury in intracerebral hemorrhage (ICH). We have reported that the tripeptide macrophage/microglial inhibitory factor (MIF), Thr-Lys-Pro, inhibits microglial activation and results in functional improvement when given before the onset of hemorrhage. In this study, we investigate the protection and efficacy of treatment when MIF is administered 2 hours after collagenase injection. Methods-ICH was induced by injecting bacterial collagenase into the caudate nucleus; 100 μL MIF (500 μmol/L) was delivered via a micro-osmotic pump. Infusion of MIF or saline (control) was initiated 2 hours after collagenase injection and continued for 24 or 72 hours. Microglial activation and macrophage infiltration were assessed by 5-D-4 and F4/80 immunofluorescence, respectively. Production of reactive oxygen species was visualized by in situ detection of ethidium. Degenerating neurons were assessed by Fluoro-Jade B staining. Neurological deficits, brain injury volumes, and brain edema were assessed at 24 and 72 hours after MIF/saline treatment. Results-MIF can inhibit microglial activation and macrophage infiltration, attenuate the numbers of ethidium-positive cells compared with the saline-treated control mice, reduce the injury volume, edema, and degenerating neurons, and improve the neurological functional outcome. Conclusions-Activated microglia/macrophages are important contributors to brain injury after ICH. MIF could be a valuable neuroprotective agent for the treatment of ICH, if treatment is initiated soon after the onset of hemorrhage.