Effect of minocycline on inflammation-induced damage to the blood-brain barrier and white matter during development.
Damage to white matter in some premature infants exposed to intrauterine infections is thought to involve disruption of the blood-brain barrier. We have examined the effect of minocycline, an agent reported to reduce brain damage resulting from inflammation, on inflammation-induced disruption of the blood-brain barrier and damage to white matter. Post-natal marsupial opossums (Monodelphis domestica) were studied as most brain development in this species occurs after birth. Single intraperitoneal lipopolysaccharide (LPS) injection (0.2 mg/kg) with or without minocycline (45 mg/kg) at post-natal day (P)35 caused short-lasting barrier breakdown to plasma proteins but not to (14)C-sucrose. By P44, blood-brain barrier integrity was intact but a reduced volume of white matter was present. At P44 after prolonged inflammation (5 x 0.2 mg/kg LPS at 48 h intervals), proteins from blood were observed within brain white matter and permeability to (14)C-sucrose in the hindbrain increased by 31%. The volume of the external capsule and the proportion of myelin were 70 and 57%, respectively, of those in control animals. Minocycline administered during prolonged inflammation restored blood-brain barrier integrity but not LPS-induced damage to white matter. These data suggest that long-term changes in blood-brain barrier permeability occur only after a prolonged period of inflammation during development; however, damage to white matter can result from even a short-lasting breakdown of the barrier. Manipulation of the inflammatory response may have implications for prevention of some developmentally induced neurological conditions.
Stolp
H B
HB
Department of Pharmacology, University of Melbourne, Parkville 3010, Australia. hbstolp@unimelb.edu.au
Ek
C J
CJ
Johansson
P A
PA
Dziegielewska
K M
KM
Potter
A M
AM
Habgood
M D
MD
Saunders
N R
NR
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability; D002452:Cell Count; D004334:Drug Administration Schedule; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000235:genetics; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D017628:Microglia / Q000473:pathology; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology*; D048309:Monodelphis; D009186:Myelin Sheath / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013395:Sucrose / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013395:Sucrose; D008911:Minocycline