title: Dose- and time-dependent neuroprotective effects of Pycnogenol following traumatic brain injury.
abstract: After traumatic brain injury (TBI), both primary and secondary injury cascades are initiated, leading to neuronal death and cognitive dysfunction. We have previously shown that the combinational bioflavonoid, Pycnogenol (PYC), alters some secondary injury cascades and protects synaptic proteins when administered immediately following trauma. The purpose of the present study was to explore further the beneficial effects of PYC and to test whether it can be used in a more clinically relevant fashion. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate/severe cortical contusion. Subjects received a single intravenous (i.v.) injection of PYC (1, 5, or 10 mg/kg) or vehicle, with treatment initiated at 15 min, 2 h, or 4 h post injury. All rats were killed at 96 h post TBI. Both the cortex and hippocampus ipsilateral and contralateral to the injury were evaluated for possible changes in oxidative stress (thiobarbituric acid reactive species; TBARS) and both pre- and post-synaptic proteins (synapsin-I, synaptophysin, drebrin, post synaptic density protein-95, and synapse associated protein-97). Following TBI, TBARS were significantly increased in both the injured cortex and ipsilateral hippocampus. Regardless of the dose and delay in treatment, PYC treatment significantly lowered TBARS. PYC treatment significantly protected both the cortex and hippocampus from injury-related declines in pre- and post-synaptic proteins. These results demonstrate that a single i.v. treatment of PYC is neuroprotective after TBI with a therapeutic window of at least 4 h post trauma. The natural bioflavonoid PYC may provide a possible therapeutic intervention in neurotrauma.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536-0230, USA.
authors.forename: Mubeen A
authors.initials: MA
authors.lastname: Ansari
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Roberts
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scheff
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000008:administration & dosage*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D028223:Pinus; D010936:Plant Extracts; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
chemical_list: D005419:Flavonoids; D018696:Neuroprotective Agents; D010936:Plant Extracts; D017392:Thiobarbituric Acid Reactive Substances; C024070:pycnogenols
references.citation: J Neurotrauma. 2010 May;27(5):939-50
references.pmid: 20175672
references.citation: Mol Cell Neurosci. 2007 Apr;34(4):571-7
references.pmid: 17289399
references.citation: Curr Drug Metab. 2009 Mar;10(3):256-71
references.pmid: 19442088
references.citation: J Neurochem. 2007 Nov;103(4):1523-9
references.pmid: 17725578
references.citation: Br J Pharmacol. 2008 Dec;155(8):1279-96
references.pmid: 18776918
references.citation: J Neurotrauma. 1997 Jan;14(1):23-34
references.pmid: 9048308
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5117-22
references.pmid: 15044697
references.citation: Neuroscience. 2005;136(4):971-89
references.pmid: 16242846
references.citation: Free Radic Biol Med. 2008 Aug 15;45(4):443-52
references.pmid: 18501200
references.citation: J Neurochem. 2007 Nov;103(4):1355-67
references.pmid: 17961201
references.citation: J Neurosurg. 1996 Sep;85(3):476-81
references.pmid: 8751635
references.citation: Mol Cell Biochem. 2007 Jan;294(1-2):137-44
references.pmid: 16924419
references.citation: JPEN J Parenter Enteral Nutr. 2011 Sep;35(5):556-9
references.pmid: 21881010
references.citation: J Neurotrauma. 2005 Jul;22(7):719-32
references.pmid: 16004576
references.citation: J Neurosci Res. 2002 Mar 1;67(5):646-63
references.pmid: 11891777
references.citation: Phytother Res. 2010 Jun;24 Suppl 2:S220-4
references.pmid: 20127879
references.citation: Respir Physiol Neurobiol. 2012 Jun 15;182(1):1-8
references.pmid: 22366865
references.citation: J Psychopharmacol. 2008 Jul;22(5):553-62
references.pmid: 18701642
references.citation: Genes Nutr. 2007 Dec;2(3):257-73
references.pmid: 18850181
references.citation: Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68
references.pmid: 11996210
references.citation: Neuromolecular Med. 2011 Dec;13(4):300-9
references.pmid: 22038400
references.citation: Neuroscience. 2009 Jul 21;161(4):1037-44
references.pmid: 19393301
references.citation: Exp Neurol. 2013 Jan;239:183-91
references.pmid: 23059456
references.citation: Ann N Y Acad Sci. 2001 Apr;928:141-56
references.pmid: 11795505
references.citation: Phytomedicine. 2009 Dec;16(12):1101-4
references.pmid: 19577447
references.citation: J Neurotrauma. 2008 May;25(5):513-26
references.pmid: 18533843
references.citation: Mol Neurobiol. 2001 Aug-Dec;24(1-3):169-81
references.pmid: 11831551
references.citation: Lab Invest. 1996 Feb;74(2):315-42
references.pmid: 8780153
references.citation: Neurobiol Dis. 2002 Apr;9(3):294-304
references.pmid: 11950275
references.citation: Exp Neurol. 2006 Feb;197(2):309-17
references.pmid: 16364299
references.citation: Pharmacol Res. 2012 Jan;65(1):66-73
references.pmid: 21875668
references.citation: Brain Res. 1991 Dec 13;567(1):1-10
references.pmid: 1667742
references.citation: Cell Mol Life Sci. 2000 Sep;57(10):1471-81
references.pmid: 11078024
references.citation: J Neurotrauma. 2010 Jun;27(6):1091-9
references.pmid: 20560755
references.citation: PLoS One. 2012;7(1):e30294
references.pmid: 22272328
references.citation: Neurotherapeutics. 2010 Jan;7(1):51-61
references.pmid: 20129497
references.citation: J Neurotrauma. 1997 Jun;14(6):385-98
references.pmid: 9219853
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8333-8
references.pmid: 15923260
references.citation: J Agric Food Chem. 2012 Feb 29;60(8):1937-44
references.pmid: 22300539
references.citation: Biochem J. 2001 Sep 15;358(Pt 3):547-57
references.pmid: 11535118
references.citation: J Neurotrauma. 2005 Dec;22(12):1475-84
references.pmid: 16379584
references.citation: J Neurotrauma. 2009 Jun;26(6):925-39
references.pmid: 19331514
references.citation: Brain Res. 1995 Mar 20;674(2):196-204
references.pmid: 7540925
references.citation: J Neurochem. 2007 Apr;101(1):168-81
references.pmid: 17394464
references.citation: J Med Food. 2011 Apr;14(4):325-33
references.pmid: 21443429
references.citation: J Neurotrauma. 2004 Jan;21(1):9-20
references.pmid: 14987461
references.citation: J Neurosci Res. 2007 Aug 1;85(10):2216-23
references.pmid: 17510982
references.citation: Gen Pharmacol. 1999 Mar;32(3):279-86
references.pmid: 10211581
references.citation: Free Radic Biol Med. 2004 Apr 1;36(7):838-49
references.pmid: 15019969
references.citation: Free Radic Biol Med. 2008 Dec 1;45(11):1510-9
references.pmid: 18822368
references.citation: J Neurosci Res. 2006 Oct;84(5):1091-7
references.pmid: 16862565
references.citation: FASEB J. 1995 Jun;9(9):726-35
references.pmid: 7601337
references.citation: Biochem Pharmacol. 2005 Jan 15;69(2):339-45
references.pmid: 15627486
references.citation: Eur J Neurosci. 2000 Jun;12(6):1949-60
references.pmid: 10886336
references.citation: J Neurooncol. 2011 Jan;101(1):15-24
references.pmid: 20467782
references.citation: Neuroscience. 2010 Sep 1;169(3):1046-62
references.pmid: 20678995
references.citation: J Cereb Blood Flow Metab. 2006 Nov;26(11):1407-18
references.pmid: 16538231
references.citation: J Neurochem. 2010 May;113(3):637-48
references.pmid: 20132469
references.citation: Autophagy. 2010 Apr;6(3):366-77
references.pmid: 20168088
references.citation: Free Radic Biol Med. 2006 Jul 1;41(1):77-85
references.pmid: 16781455
references.citation: J Cereb Blood Flow Metab. 2006 Dec;26(12):1479-89
references.pmid: 16538228