The pharmacokinetics and pharmacodynamics of Kollidon VA64 dissociate its protective effects from membrane resealing after controlled cortical impact in mice.
Membrane-resealing agents such as poloxamer P188 improve the outcome in experimental brain injury paradigms; however, whether membrane resealing is a key mechanism for protection has not been shown in vivo. We previously reported that Kollidon VA64, a polymeric membrane-resealing agent, reduces cell membrane permeability and improves brain edema, brain tissue damage, and functional outcome after controlled cortical impact in mice, without rescuing resealed cells from death. To reconcile these disparate findings, we used a dual-pulse labeling protocol to determine membrane-resealing kinetics by VA64/P188 in vivo. Membrane resealing after controlled cortical impact in mice by intravenous or intracerebroventricular VA64 and poloxamer P188 was transient, with most cells becoming repermeabilized within 2 hours, even with multiple-dose paradigms that maintained high VA64 blood levels. Moreover, VA64 reduced cytotoxic brain edema in a water intoxication model devoid of plasmalemma permeability (P<0.05 versus P188, VA30, mannitol, and vehicle). We conclude that VA64 reduces cytotoxic and traumatic brain edema independent of membrane resealing. The results suggest that classic membrane-resealing agents such as poloxamer P188, and the newly discovered VA64, exert protective effects in central nervous system injury paradigms by mechanisms other than or in addition to maintaining permeable cell membranes sealed.
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Benjamin F
BF
Miller
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Eyup
E
Keles
Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA.
Lee
L
Tien
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Jimmy
J
Zhang
Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA.
David
D
Kaplan
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [3] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Eng H
EH
Lo
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Michael J
MJ
Whalen
D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014753:Vinyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D018696:Neuroprotective Agents; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate)