Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage.
OBJECTIVE
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 microL MIF (500 micromol/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.
Wang
Jian
J
Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.
Tsirka
Stella E
SE
D000818:Animals; D001930:Brain Injuries / Q000517:prevention & control*; D002421:Caudate Nucleus / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000150:complications; D017364:Collagenases / Q000009:adverse effects; D004487:Edema / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000209:etiology / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D014405:Tuftsin / Q000627:therapeutic use*
D008263:Macrophage Migration-Inhibitory Factors; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D017364:Collagenases; D014405:Tuftsin