Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat.
Intracerebral hemorrhage (ICH) results from rupture of a blood vessel in the brain. After ICH, the blood-brain barrier (BBB) surrounding the hematoma is disrupted, leading to cerebral edema. In both animals and humans, edema coincides with inflammation, which is characterized by production of pro-inflammatory cytokines, activation of resident brain microglia and migration of peripheral immune cells into the brain. Accordingly, inflammation is an attractive target for reducing edema following ICH. In the present study, BBB damage was assessed by quantifying intact microvessels surrounding the hematoma, monitoring extravasation of IgG and measuring brain water content 3 days after ICH induced by collagenase injection into the rat striatum. In the injured brain, the water content increased in both ipsilateral and contralateral hemispheres compared with the normal brain. Quantitative real-time RT-PCR revealed an up-regulation of inflammatory genes associated with BBB damage; IL1beta, TNFalpha and most notably, MMP-12. Immunostaining showed MMP-12 in damaged microvessels and their subsequent loss from tissue surrounding the hematoma. MMP-12 was also observed for the first time in neurons. Dual-antibody labeling demonstrated that neutrophils were the predominant source of TNFalpha protein. Intraperitoneal injection of the tetracycline derivative, minocycline, beginning 6 h after ICH ameliorated the damage by reducing microvessel loss, extravasation of plasma proteins and edema; decreasing TNFalpha and MMP-12 expression; and reducing the numbers of TNFalpha-positive cells and neutrophils in the brain. Thus, minocycline, administered at a clinically relevant time, appears to target the inflammatory processes involved in edema development after ICH.
Wasserman
Jason K
JK
Toronto Western Research Institute, University Health Network, Toronto Ontario, Canada M5T 2S8.
Schlichter
Lyanne C
LC
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000473:pathology*; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008911:Minocycline / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D024141:Collagen Type IV; D016207:Cytokines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D008911:Minocycline