Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage.
Aneurysmal subarachnoid hemorrhage (SAH) is associated with numerous "delayed neurological deficits" (DNDs) that have been attributed to multiple pathophysiological mechanisms, including ischemia, microthrombosis, free radical damage, inflammation, and vascular remodeling. To date, effective prophylactic therapy for SAH-induced DNDs has been elusive, due perhaps to the multiplicity of mechanisms involved that render typical, single-agent therapy seemingly futile. We hypothesized that heparin, which has multiple underappreciated salutary effects, might be useful as a multitargeted prophylactic agent against SAH-induced DNDs. We performed a comprehensive review of the literature to evaluate the potential utility of heparin in targeting the multiple pathophysiological mechanisms that have been identified as contributing to SAH-induced DNDs. Our literature review revealed that unfractionated heparin can potentially antagonize essentially all of the pathophysiological mechanisms known to be activated following SAH. Heparin binds >100 proteins, including plasma proteins, proteins released from platelets, cytokines, and chemokines. Also, heparin complexes with oxyhemoglobin, blocks the activity of free radicals including reactive oxygen species, antagonizes endothelin-mediated vasoconstriction, smooth muscle depolarization, and inflammatory, growth and fibrogenic responses. Our review suggests that the use of prophylactic heparin following SAH may warrant formal study.
Simard
J Marc
JM
Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA. msimard@smail.umaryland.edu
Schreibman
David
D
Aldrich
E Francois
EF
Stallmeyer
Bernadette
B
Le
Brian
B
James
Robert F
RF
Beaty
Narlin
N
D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006493:Heparin / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000503:physiopathology; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
D007004:Hypoglycemic Agents; D006493:Heparin
Neurosurg Focus. 1997 Oct 15;3(4):e3
15104409
Cancer Sci. 2008 Feb;99(2):214-20
18271917
N Engl J Med. 2006 Jan 26;354(4):387-96
16436770
Adv Pharmacol. 1999;46:151-208
10332503
Neurocrit Care. 2004;1(2):235-46
16174921
J Biol Chem. 1994 Apr 1;269(13):10112-8
8144511
J Neurosurg. 2003 Aug;99(2):376-82
12924713
J Neurosurg. 1999 Jun;90(6):1105-14
10350259
Stroke. 2002 Mar;33(3):775-81
11872903
Surg Neurol. 1995 Sep;44(3):270-4
8545780
Stroke. 2003 Feb;34(2):427-33
12574555
Ann N Y Acad Sci. 2007 Dec;1122:23-34
18077562
Stroke. 1987 Nov-Dec;18(6):1169-72
3318003
Clin Auton Res. 2004 Jun;14(3):143-5
15241641
J Cereb Blood Flow Metab. 2004 Jan;24(1):75-83
14688619
J Neurosurg. 1992 Nov;77(5):740-8
1403117
J Neurosurg. 1985 May;62(5):673-9
3989590
Neurosci Lett. 2002 Jun 28;326(2):137-41
12057847
J Neurosci Res. 2009 Jan;87(1):1-11
18709660
J Cereb Blood Flow Metab. 2006 Oct;26(10):1223-33
16467784
J Cereb Blood Flow Metab. 2008 Nov;28(11):1761-70
18628782
Acta Neurochir (Wien). 2002 Dec;144(12):1305-10; discussion 1310
12478342
J Neurosci. 2005 Jan 19;25(3):723-31
15659610
Brain Behav Immun. 2008 Mar;22(3):301-11
17951027
J Neurosurg. 1992 Jan;76(1):81-90
1727173
Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1094-6
11451734
Eur J Biochem. 2000 Dec;267(24):7094-101
11106420
J Thromb Thrombolysis. 2003 Feb;15(1):11-8
14574071
Surg Neurol. 2005;64 Suppl 1:S1:2-5; discussion S1:5
15967223
Stroke. 2001 Jul;32(7):1665-72
11441217
Arch Biochem Biophys. 1994 Nov 1;314(2):315-22
7979371
Clin Neurol Neurosurg. 2004 Mar;106(2):97-103
15003298
J Neurosurg. 2004 Jun;100(6):1066-71
15200122
Thromb Res. 2008;122(6):743-52
17727922
J Neurosurg. 2000 Mar;92(3):390-400
10701524
Nat Clin Pract Neurol. 2007 May;3(5):256-63
17479073
J Vasc Surg. 1998 Mar;27(3):512-20
9546238
Circulation. 1994 Feb;89(2):770-6
8313565
Neurol Res. 2006 Oct;28(7):713-20
17164034
Neurosurgery. 1987 Apr;20(4):564-70
3587548
Pediatr Res. 2002 May;51(5):635-40
11978889
Stroke. 2002 Jul;33(7):1927-33
12105378
Neurosurg Focus. 2006 Sep 15;21(3):E2
17029341
J Neurosurg. 1996 Dec;85(6):1102-7
8929502
Life Sci. 2004 Jul 9;75(8):979-89
15193958
Neurol Res. 2009 Mar;31(2):195-9
19298761
Biomed Pharmacother. 2004 May;58(4):213-9
15183845
Neurosurgery. 2003 Jul;53(1):123-33; discussion 133-5
12823881
Curr Med Chem. 2004 Jul;11(13):1779-91
15279581
Pulm Pharmacol Ther. 2001;14(2):111-9
11273792
Ann Med. 2004;36(2):98-118
15119830
Hypertension. 2002 Feb;39(2 Pt 2):525-9
11882602
J Clin Invest. 1998 Feb 15;101(4):877-89
9466983
Neurosurg Focus. 2006 Sep 15;21(3):E8
17029347
J Vasc Res. 2005 May-Jun;42(3):183-9
15785094
Haemostasis. 1993 Mar;23 Suppl 1:212-9
8388354
Neurosurgery. 2002 Dec;51(6):1333-41; discussion 1342
12445337
Ann N Y Acad Sci. 1989;556:1-17
2660680
Clin Pharmacokinet. 1992 May;22(5):359-74
1505142
Mol Neurobiol. 2009 Aug;40(1):15-32
19365736
Biochim Biophys Acta. 1997 Dec 9;1333(3):F179-99
9426203
Neurocrit Care. 2008;8(3):404-12
18196475
Biochim Biophys Acta. 2007 Nov;1773(11):1637-44
17822789
Cytokine. 1999 Feb;11(2):157-62
10089138
Biochem Soc Trans. 2006 Jun;34(Pt 3):458-60
16709187
Hum Gene Ther. 1998 May 1;9(7):1003-11
9607412
J Cell Physiol. 1999 Feb;178(2):205-15
10048585
Circ Res. 2000 Jul 21;87(2):92-8
10903991
Blood. 2008 Aug 15;112(4):1461-71
18490516
Neurosurgery. 2007 Apr;60(4):658-67; discussion 667
17415202
Thromb Res. 1994 Jul 1;75(1):1-32
8073404
Eur J Biochem. 1977 Jun 15;76(2):339-43
19244
J Cardiovasc Pharmacol. 2007 Jan;49(1):39-45
17261962
Drug Discov Today. 2008 Mar;13(5-6):254-60
18342802
J Physiol. 2006 Jan 1;570(Pt 1):73-84
16284070
Neurosci Lett. 2003 Jul 3;344(3):193-6
12812838
Circulation. 2006 Sep 19;114(12):1293-300
16940188
Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2110-5
12920044
Stroke. 2003 Jun;34(6):1497-500
12764230
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1750-9
17557914
Drug News Perspect. 2001 Jun;14(5):261-7
12813589
Circ Res. 2006 Nov 24;99(11):1252-60
17068294
J Cell Physiol. 1997 Jul;172(1):69-78
9207927
Immunol Cell Biol. 2008 Oct;86(7):598-607
18626488
J Neurol Sci. 2000 Sep 1;178(1):17-22
11018244
Neurol Res. 2007 Oct;29(7):636-42
18173899
Acta Neurochir (Wien). 1997;139(4):319-24
9202771
Neurosurgery. 1998 Oct;43(4):863-75; discussion 875-6
9766314
Br J Haematol. 2006 Apr;133(1):62-7
16512830
Neurol Res. 2006 Jun;28(4):381-98
16759442
J Neurosci Res. 2004 Aug 15;77(4):565-72
15264226
J Neurosurg. 2005 Feb;102(2):194-201
15739544
Arch Immunol Ther Exp (Warsz). 1999;47(4):245-9
10483873
Crit Care Med. 2003 Apr;31(4):1108-12
12682480
Int J Tissue React. 1993;15(4):163-8
8188456
Surg Neurol. 1982 Jul;18(1):40-5
7112386
J Neurosurg. 1985 Apr;62(4):570-5
3973727
Cancer. 1999 Jan 15;85(2):257-72
10023691
Neurosurgery. 1989 Dec;25(6):892-8
2601819
J Cereb Blood Flow Metab. 2006 Mar;26(3):382-91
16079788
Adv Immunol. 2001;78:57-110
11432208
Stroke. 2008 Nov;39(11):3015-21
18688013
J Neurosci. 2002 Jul 1;22(13):5365-73
12097488
J Neurosurg. 1999 Jun;90(6):1091-7
10350257
Rev Neurol (Paris). 2008 Oct;164(10):815-8
18778842
Acta Chir Plast. 1997;39(1):13-6
9212486
Neurol Res. 2009 Jul;31(6):644-50
19133165
Life Sci. 2002 Mar 8;70(16):1901-8
12005175
An Acad Bras Cienc. 2005 Dec;77(4):651-64
16341442
Acta Neurochir (Wien). 1994;127(1-2):112-7
7524276
Br J Neurosurg. 1995;9(4):465-75
7576273
Croat Med J. 2006 Apr;47(2):253-63
16625690
J Neurol Neurosurg Psychiatry. 2001 Apr;70(4):534-7
11254783
Biochem Pharmacol. 1997 Dec 15;54(12):1271-80
9393669
Pharmacol Rev. 1996 Jun;48(2):327-52
8804108
Chem Biol Drug Des. 2008 Dec;72(6):455-82
19090915
Thromb Res. 1999 Dec 1;96(5):373-81
10605952
FASEB J. 2006 Sep;20(11):1936-8
16877529
Am J Physiol. 1992 Nov;263(5 Pt 2):R1035-41
1443220
Stroke. 2009 Feb;40(2):591-6
19095985
Semin Respir Crit Care Med. 2008 Feb;29(1):66-74
18302088
J Neurosurg. 2003 Dec;99(6):953-9
14705720
J Cereb Blood Flow Metab. 1999 Mar;19(3):307-20
10078883
J Cereb Blood Flow Metab. 1988 Feb;8(1):1-8
3339099
Semin Neurol. 2005 Dec;25(4):435-44
16341999
Arch Biochem Biophys. 1996 Mar 15;327(2):234-8
8619608
Stroke. 1991 Aug;22(8):971-82
1866764
Trends Pharmacol Sci. 2007 Jun;28(6):252-6
17466386
Stroke. 2001 Sep;32(9):1989-93
11546886
Burns. 2001 Jun;27(4):349-58
11348743
Am Rev Respir Dis. 1993 Jan;147(1):160-3
8420411
Aliment Pharmacol Ther. 2000 Nov;14(11):1403-9
11069310
Ann N Y Acad Sci. 2001 Dec;947:42-54; discussion 54-5
11795306
Neurol Res. 2008 Jun;30(5):444-9
18953733
Int Angiol. 1992 Oct-Dec;11(4):261-7
1338338
Stroke. 2009 Mar;40(3):994-1025
19164800
J Neurosurg Anesthesiol. 2006 Jan;18(1):68-72
16369143
Neurol Res. 2006 Oct;28(7):750-8
17164038
Crit Rev Neurosurg. 1999 Sep 24;9(5):303-318
10525849
Neurosci Lett. 2001 Sep 21;311(1):9-12
11585555
Biochim Biophys Acta. 2005 Aug 1;1751(1):110-7
16054021
Am J Physiol. 1992 Apr;262(4 Pt 1):C854-61
1566813