Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) causes morbidity and mortality and commonly follows the reperfusion after an ischemic event. Tissue plasminogen activator (tPA), a fibrinolytic serine protease, is routinely given for the treatment of stroke. However, tPA also can promote neuronal death, suggesting that caution should be exercised when using it. Furthermore, tPA upon brain injury mediates microglial activation and modulates neuronal survival. To investigate the role of tPA and microglia during brain hemorrhage, we induced experimentally ICH by intracerebral injection of collagenase. Seven days after the introduction of ICH, it persisted in tPA-deficient (tPA(-/-)) mice but is drastically reduced in size in wild-type mice. Three weeks after ICH, there are still red blood cells in tPA(-/-) but not in wild-type animals. Activated microglia persist around the injury site. When microglial activation is inhibited by tuftsin fragment 1-3 macrophage/microglial inhibitory factor (MIF), the stroke injury volume is significantly reduced, and the neurobehavioral deficits exhibited by the mice are improved. Our results suggest that endogenous tPA assists in the clearance of intracerebral hemorrhage, presumably by affecting microglial activation, and MIF could be a valuable neuroprotective agent for the treatment of ICH.
Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.
Jian
J
Wang
Andrew D
AD
Rogove
Anna E
AE
Tsirka
Stella E
SE
Tsirka
D000818:Animals; D001921:Brain / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000473:pathology*; D017364:Collagenases / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007276:Injections, Intraventricular; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000172:deficiency* / Q000235:genetics; D014405:Tuftsin / Q000494:pharmacology*
D010959:Tissue Plasminogen Activator; D017364:Collagenases; D020782:Matrix Metalloproteinases; D014405:Tuftsin