OBJECTIVE: Traumatic brain injury (TBI) has been shown to induce a significant change in polyamine metabolism. Polyamines and polyamine-dependent calcium influx play an important role in mediating the effects of excitotoxic amino acids at the N-methyl-D-aspartate (NMDA) receptor site. We studied the effects of ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, on brain edema formation, blood-brain barrier breakdown, and volume of injury after TBI. METHODS: Experimental TBI was induced in Sprague-Dawley rats by a controlled cortical impact device, functioning at a velocity of 3 m/s to produce a 2-mm deformation. Ifenprodil or saline (10 mg/kg) was injected intraperitoneally immediately after the cortical impact injury and then every 90 minutes until 6 hours after TBI. Blood-brain barrier breakdown was evaluated quantitatively 6 hours after injury by fluorometric assay of Evans blue extravasation. Brain water content, an indicator of brain edema, was measured with the wet-dry method 24 hours after TBI. Injury volume was quantitated from the brain slices stained with 2% cresyl violet solution 7 days after TBI. RESULTS: Blood-brain barrier breakdown was significantly lower in the traumatic cortex of the ifenprodil-treated group than in the saline-treated group (84.4 +/- 26.8 microg/g versus 161.8 +/- 27 microg/g, respectively, P < 0.05). Brain edema was significantly reduced in the cortex of the ifenprodil-treated group relative to that in the saline-treated group (80.9 +/- 0.5% versus 82.4 +/- 0.6% respectively, P < 0.05). Ifenprodil treatment reduced injury volume significantly (14.9 +/- 8.1 mm3 versus 24.4 +/- 6.7 mm3, P < 0.05). CONCLUSION: The polyamine-site NMDA receptor antagonist ifenprodil affords significant neuroprotection in a controlled cortical impact brain injury model and may hold promise for the discovery and treatment of the mechanism of delayed neurological deficits after TBI.
OBJECTIVE:Traumatic brain injury (TBI) has been shown to induce a significant change in polyamine metabolism. Polyamines and polyamine-dependent calcium influx play an important role in mediating the effects of excitotoxic amino acids at the N-methyl-D-aspartate (NMDA) receptor site. We studied the effects of ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, on brain edema formation, blood-brain barrier breakdown, and volume of injury after TBI. METHODS: Experimental TBI was induced in Sprague-Dawley rats by a controlled cortical impact device, functioning at a velocity of 3 m/s to produce a 2-mm deformation. Ifenprodil or saline (10 mg/kg) was injected intraperitoneally immediately after the cortical impact injury and then every 90 minutes until 6 hours after TBI. Blood-brain barrier breakdown was evaluated quantitatively 6 hours after injury by fluorometric assay of Evans blue extravasation. Brain water content, an indicator of brain edema, was measured with the wet-dry method 24 hours after TBI. Injury volume was quantitated from the brain slices stained with 2% cresyl violet solution 7 days after TBI. RESULTS:Blood-brain barrier breakdown was significantly lower in the traumatic cortex of the ifenprodil-treated group than in the saline-treated group (84.4 +/- 26.8 microg/g versus 161.8 +/- 27 microg/g, respectively, P < 0.05). Brain edema was significantly reduced in the cortex of the ifenprodil-treated group relative to that in the saline-treated group (80.9 +/- 0.5% versus 82.4 +/- 0.6% respectively, P < 0.05). Ifenprodil treatment reduced injury volume significantly (14.9 +/- 8.1 mm3 versus 24.4 +/- 6.7 mm3, P < 0.05). CONCLUSION: The polyamine-site NMDA receptor antagonist ifenprodil affords significant neuroprotection in a controlled cortical impact brain injury model and may hold promise for the discovery and treatment of the mechanism of delayed neurological deficits after TBI.
Authors: Pallab Singh; Shachee Doshi; Jennifer M Spaethling; Adam J Hockenberry; Tapan P Patel; Donna M Geddes-Klein; David R Lynch; David F Meaney Journal: J Biol Chem Date: 2011-12-16 Impact factor: 5.157
Authors: Daniel Woo; Guido J Falcone; William J Devan; W Mark Brown; Alessandro Biffi; Timothy D Howard; Christopher D Anderson; H Bart Brouwers; Valerie Valant; Thomas W K Battey; Farid Radmanesh; Miriam R Raffeld; Sylvia Baedorf-Kassis; Ranjan Deka; Jessica G Woo; Lisa J Martin; Mary Haverbusch; Charles J Moomaw; Guangyun Sun; Joseph P Broderick; Matthew L Flaherty; Sharyl R Martini; Dawn O Kleindorfer; Brett Kissela; Mary E Comeau; Jeremiasz M Jagiella; Helena Schmidt; Paul Freudenberger; Alexander Pichler; Christian Enzinger; Björn M Hansen; Bo Norrving; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Jaume Roquer; Peter Kraft; Alison M Ayres; Kristin Schwab; Jacob L McCauley; Joanna Pera; Andrzej Urbanik; Natalia S Rost; Joshua N Goldstein; Anand Viswanathan; Eva-Maria Stögerer; David L Tirschwell; Magdy Selim; Devin L Brown; Scott L Silliman; Bradford B Worrall; James F Meschia; Chelsea S Kidwell; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Rainer Malik; Martin Dichgans; Steven M Greenberg; Peter M Rothwell; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Carl D Langefeld; Jonathan Rosand Journal: Am J Hum Genet Date: 2014-03-20 Impact factor: 11.025
Authors: Kamyar Zahedi; Francis Huttinger; Ryan Morrison; Tracy Murray-Stewart; Robert A Casero; Kenneth I Strauss Journal: J Neurotrauma Date: 2010-03 Impact factor: 5.269