title: Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice.
abstract: Loss of plasma membrane integrity is a feature of acute cellular injury/death in vitro and in vivo. Plasmalemma-resealing agents are protective in acute central nervous system injury models, but their ability to reseal cell membranes in vivo has not been reported. Using a mouse controlled cortical impact (CCI) model, we found that propidium iodide-positive (PI+) cells pulse labeled at 6, 24, or 48 hours maintained a degenerative phenotype and disappeared from the injured brain by 7 days, suggesting that plasmalemma permeability is a biomarker of fatal cellular injury after CCI. Intravenous or intracerebroventricular administration of Kollidon VA64, poloxamer P188, or polyethylene glycol 8000 resealed injured cell membranes in vivo (P<0.05 versus vehicle or poloxamer P407). Kollidon VA64 (1 mmol/L, 500 μL) administered intravenously to mice 1  hour after CCI significantly reduced acute cellular degeneration, chronic brain tissue damage, brain edema, blood-brain barrier damage, and postinjury motor deficits (all P<0.05 versus vehicle). However, VA64 did not rescue pulse-labeled PI+ cells from eventual demise. We conclude that PI permeability within 48 hours of CCI is a biomarker of eventual cell death/loss. Kollidon VA64 reduces secondary damage after CCI by mechanisms other than or in addition to resealing permeable cells.
authors.affiliation: Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Lamin H
authors.initials: LH
authors.lastname: Mbye
authors.forename: Eyup
authors.initials: E
authors.lastname: Keles
authors.forename: Luyang
authors.initials: L
authors.lastname: Tao
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhang
authors.forename: Joonyong
authors.initials: J
authors.lastname: Chung
authors.forename: Mykol
authors.initials: M
authors.lastname: Larvie
authors.forename: Rajani
authors.initials: R
authors.lastname: Koppula
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whalen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000473:pathology; D002463:Cell Membrane Permeability; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D014753:Vinyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate)
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