title: Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue.
abstract: Persons with spinal cord injury (SCI) are in need of effective therapeutics. Estrogen (E2), as a steroid hormone, is a highly pleiotropic agent; with anti-inflammatory, anti-apoptotic, and neurotrophic properties, it is ideal for use in treatment of patients with SCI. Safety concerns around the use of high doses of E2 have limited clinical application, however. To address these concerns, low doses of E2 (25 μg and 2.5 μg) were focally delivered to the injured spinal cord using nanoparticles. A per-acute model (6 h after injury) was used to assess nanoparticle release of E2 into damaged spinal cord tissue; in addition, E2 was evaluated as a rapid anti-inflammatory. To assess inflammation, 27-plex cytokine/chemokine arrays were conducted in plasma, cerebrospinal fluid (CSF), and spinal cord tissue. A particular focus was placed on IL-6, GRO-KC, and MCP-1 as these have been identified from CSF in human studies as potential biomarkers in SCI. S100β, an additional proposed biomarker, was also assessed in spinal cord tissue only. Tissue concentrations of E2 were double those found in the plasma, indicating focal release. E2 showed rapid anti-inflammatory effects, significantly reducing interleukin (IL)-6, GRO-KC, MCP-1, and S100β in one or all compartments. Numerous additional targets of rapid E2 modulation were identified including: leptin, MIP-1α, IL-4, IL-2, IL-10, IFNγ, tumor necrosis factor-α, etc. These data further elucidate the rapid anti-inflammatory effects E2 exerts in an acute rat SCI model, have identified additional targets of estrogen efficacy, and suggest nanoparticle delivered estrogen may provide a safe and efficacious treatment option in persons with acute SCI.
authors.affiliation: 1 Department of Neurology and Neurosurgery, Medical University of South Carolina , Charleston, South Carolina.
authors.forename: April
authors.initials: A
authors.lastname: Cox
authors.affiliation: 1 Department of Neurology and Neurosurgery, Medical University of South Carolina , Charleston, South Carolina.
authors.forename: Abhay
authors.initials: A
authors.lastname: Varma
authors.affiliation: 2 Department of Bioengineering, Clemson University , Clemson, South Carolina.
authors.forename: John
authors.initials: J
authors.lastname: Barry
authors.affiliation: 2 Department of Bioengineering, Clemson University , Clemson, South Carolina.
authors.forename: Alexey
authors.initials: A
authors.lastname: Vertegel
authors.affiliation: 1 Department of Neurology and Neurosurgery, Medical University of South Carolina , Charleston, South Carolina.|3 Ralph H. Johnson VA Medical Center , Charleston, South Carolina.
authors.forename: Naren
authors.initials: N
authors.lastname: Banik
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D053758:Nanoparticles; D051381:Rats; D017207:Rats, Sprague-Dawley; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D064568:S100 Calcium Binding Protein beta Subunit; C579158:S100b protein, rat; D004958:Estradiol
keywords: CSF; GRO-KC; IL-6; MCP-1; S100β; estrogen; nanoparticle; spinal cord injury
references.citation: J Neurotrauma. 2012 Aug 10;29(12):2209-19
references.pmid: 22435710
references.citation: Curr Pharm Des. 2005;11(10):1211-22
references.pmid: 15853678
references.citation: Cochrane Database Syst Rev. 2012;1:CD001046
references.pmid: 22258943
references.citation: Neurochem Res. 2013 Aug;38(8):1734-41
references.pmid: 23690229
references.citation: Spinal Cord. 2014 Jun;52(6):428-33
references.pmid: 24710150
references.citation: Spine (Phila Pa 1976). 2014 May 20;39(12):971-7
references.pmid: 24583739
references.citation: Nanotechnology. 2010 Jul 2;21(26):265103
references.pmid: 20534889
references.citation: Spine (Phila Pa 1976). 2010 Oct 1;35(21 Suppl):S263-70
references.pmid: 20881470
references.citation: J Rehabil Res Dev. 2003 Jul-Aug;40(4 Suppl 1):81-91
references.pmid: 15077652
references.citation: Arch Phys Med Rehabil. 2015 Apr;96(4):633-44
references.pmid: 25461821
references.citation: Brain Res. 2008 Apr 8;1203:177-88
references.pmid: 18316064
references.citation: J Neurosurg. 2013 Aug;119(2):353-61
references.pmid: 23724987
references.citation: Brain Res. 2012 Jun 21;1461:76-86
references.pmid: 22572084
references.citation: J Neurosci Res. 1998 Aug 1;53(3):368-76
references.pmid: 9698165
references.citation: Neurochem Res. 2011 Oct;36(10):1809-16
references.pmid: 21611834
references.citation: Scand J Clin Lab Invest. 2008;68(8):806-13
references.pmid: 18622802
references.citation: Int J Biol Sci. 2012;8(9):1254-66
references.pmid: 23136554
references.citation: Exp Neurol. 2014 Sep;259:28-37
references.pmid: 24440641
references.citation: Neurochem Int. 2000 Apr;36(4-5):417-25
references.pmid: 10733009
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1127-35
references.pmid: 20434525
references.citation: Shock. 2008 Mar;29(3):362-71
references.pmid: 17704735
references.citation: Eur Rev Med Pharmacol Sci. 2013 Jul;17(14):1869-73
references.pmid: 23877849
references.citation: J Neurosci. 2013 Jun 26;33(26):10924-33
references.pmid: 23804112
references.citation: Ann N Y Acad Sci. 2010 Jun;1199:90-4
references.pmid: 20633113
references.citation: Saudi J Biol Sci. 2014 Jul;21(3):232-7
references.pmid: 24955008
references.citation: Neurosurgery. 2005 Feb;56(2):391-7; discussion 391-7
references.pmid: 15670387
references.citation: Steroids. 2009 Jul;74(7):555-61
references.pmid: 19428444
references.citation: J Clin Neurosci. 2008 May;15(5):541-4
references.pmid: 18343116
references.citation: Cent Nerv Syst Trauma. 1987;4(3):149-59
references.pmid: 3442814
references.citation: J Neurotrauma. 2005 Mar;22(3):345-52
references.pmid: 15785230
references.citation: Methods Mol Biol. 2011;726:325-38
references.pmid: 21424459
references.citation: Pediatr Emerg Care. 2012 Nov;28(11):1238-45; quiz 1246-8
references.pmid: 23128657
references.citation: J Neurosci Res. 2012 Apr;90(4):782-90
references.pmid: 22420033
references.citation: Endocrinology. 2012 Aug;153(8):3815-27
references.pmid: 22700771
references.citation: Metab Brain Dis. 2015 Apr;30(2):473-82
references.pmid: 24833553
references.citation: J Neurotrauma. 2010 Mar;27(3):611-26
references.pmid: 20001688
references.citation: Neurochem Res. 2004 Nov;29(11):2007-14
references.pmid: 15662835
references.citation: Genome Biol. 2004;5(9):R66
references.pmid: 15345050
references.citation: J Neurotrauma. 2011 Jun;28(6):1035-49
references.pmid: 21355819
references.citation: J Neuroendocrinol. 2012 Jan;24(1):62-70
references.pmid: 21592237
references.citation: JAMA. 2002 Jul 17;288(3):321-33
references.pmid: 12117397
references.citation: J Neuroinflammation. 2012;9:157
references.pmid: 22747981
references.citation: Contraception. 2002 Mar;65(3):187-96
references.pmid: 11929640
references.citation: Spinal Cord. 2013 Jan;51(1):2-9
references.pmid: 23165505
references.citation: Nanotechnology. 2011 Dec 16;22(50):505103
references.pmid: 22107797
references.citation: J Neurotrauma. 2013 Sep 1;30(17):1531-41
references.pmid: 23659385
references.citation: Brain Res. 2009 Jun 18;1276:159-70
references.pmid: 19389388
references.citation: Ann N Y Acad Sci. 2003 Dec;1007:89-100
references.pmid: 14993043
references.citation: World Neurosurg. 2015 May;83(5):867-78
references.pmid: 23524031
references.citation: J Neurosci. 2009 Nov 4;29(44):13823-36
references.pmid: 19889994
references.citation: Biochim Biophys Acta. 1999 Jul 8;1450(3):191-231
references.pmid: 10395934
references.citation: Intensive Care Med. 2012 Jan;38(1):137-44
references.pmid: 22124768
references.citation: Scand J Plast Reconstr Surg Hand Surg. 2001 Dec;35(4):355-9
references.pmid: 11878171
references.citation: J Comp Neurol. 2012 Aug 15;520(12):2630-46
references.pmid: 22684936
references.citation: Brain Res. 2014 May 2;1561:11-22
references.pmid: 24637260
references.citation: J Neurotrauma. 2014 Sep 15;31(18):1561-9
references.pmid: 24786364
references.citation: J Neurotrauma. 2010 Apr;27(4):669-82
references.pmid: 20038240
references.citation: JAMA. 2011 Apr 6;305(13):1305-14
references.pmid: 21467283
references.citation: Injury. 2005 Jul;36 Suppl 2:B113-22
references.pmid: 15993112
references.citation: J Neuroinflammation. 2014;11:150
references.pmid: 25163400
references.citation: Biochim Biophys Acta. 2009 Jun;1793(6):1008-22
references.pmid: 19110011
references.citation: J Neurosci Res. 2010 Jun;88(8):1738-50
references.pmid: 20091771
references.citation: Neuroscience. 2013 May 15;238:209-17
references.pmid: 23485590
references.citation: J Cereb Blood Flow Metab. 1997 Mar;17(3):280-9
references.pmid: 9119901
references.citation: J Interferon Cytokine Res. 2009 Jun;29(6):313-26
references.pmid: 19441883
references.citation: J Neurotrauma. 2004 Mar;21(3):293-306
references.pmid: 15115604
references.citation: Clin Pharmacol Ther. 2008 May;83(5):761-9
references.pmid: 17957183