Combination treatment of experimental stroke with Niaspan and Simvastatin, reduces axonal damage and improves functional outcome.
In this study we examined the effect of combination treatment of experimental stroke with Niaspan, a prolonged-release formulation of Niacin (vitamin B3), and Simvastatin, a cholesterol-lowering drug, on functional outcome, axonal damage, axonal density and the of Iba-1 immunoreactive microglia expression in the ischemic brain of rats. Adult male rats were subjected to 2 h middle cerebral artery occlusion (MCAo) and treated with or without Niaspan alone, Simvastatin alone and combination Niaspan and Simvastatin starting 24 h after MCAo and daily for 14 days. Neurological functional tests were performed. Axonal damage and density were evaluated by Amyloid Precursor Protein (APP) and Bielschowsky silver, respectively. Nogo66 Receptor (NgR) expression and immunoreactive microglia (Iba-1) were also measured in the ischemic brain. Niaspan and Simvastatin monotherapy and combination treatment significantly promote functional outcome after stroke (p<0.05) compared to MCAo control animals. Combination treatment with Niaspan and Simvastatin induces additive but not synergetic effects when compared to Niaspan or Simvastatin monotherapy groups. Combination treatment significantly decreased APP expression and increased Bielschowsky silver expression. NGR and Iba-1 expression were significantly decreased in the ischemic brain. These data suggest that treatment of experimental stroke with combination of Niaspan and Simvastatin significantly improves functional outcome, reduces axonal damage and increases axonal density. Decreased expression of the NGR and reduced activated microglia may contribute to functional recovery after stroke.
Shehadah
Amjad
A
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI, 48202, USA.
Chen
Jieli
J
Cui
Xu
X
Roberts
Cynthia
C
Lu
Mei
M
Chopp
Michael
M
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D058851:GPI-Linked Proteins; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009185:Myelin Proteins; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009525:Niacin / Q000627:therapeutic use*; D000070816:Nogo Receptor 1; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome
C100745:Aif1 protein, rat; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D003692:Delayed-Action Preparations; D058851:GPI-Linked Proteins; D008840:Microfilament Proteins; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C486581:Rtn4r protein, rat; D009525:Niacin; D019821:Simvastatin
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9
12824464
Stroke. 2001 Apr;32(4):1005-11
11283404
Neuroscience. 2006 Aug 25;141(2):737-744
16730914
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4160-5
11259645
Exp Neurol. 2003 Sep;183(1):25-33
12957485
Neuron. 2002 Oct 24;36(3):345-8
12408839
Am J Cardiovasc Drugs. 2008;8(2):69-81
18422390
Neurosci Lett. 2007 May 7;417(3):255-60
17382469
Expert Opin Ther Targets. 2009 Dec;13(12):1387-98
19922299
Stroke. 2005 Oct;36(10):2220-5
16166574
Neuroreport. 2000 Apr 7;11(5):963-7
10790864
Nat Neurosci. 2004 Jul;7(7):736-44
15184901
J Cell Sci. 1999 Nov;112 ( Pt 22):4007-16
10547361
Neuron. 2002 Jul 18;35(2):283-90
12160746
Ann Neurol. 2003 Jun;53(6):743-51
12783420
J Cereb Blood Flow Metab. 2002 Sep;22(9):1080-9
12218413
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500
10557349
Circulation. 2004 Dec 7;110(23):3512-7
15537681
J Neurocytol. 2002 Feb;31(2):93-120
12815233
Dev Neurobiol. 2007 Aug;67(9):1148-65
17514713
Brain Res. 1997 Jan 9;744(2):189-98
9027378
Nature. 2003 Apr 17;422(6933):688-94
12700753
J Cereb Blood Flow Metab. 1990 Mar;10(2):290-3
1689322
Stroke. 1998 Sep;29(9):1972-80; discussion 1980-1
9731626
Acta Neuropathol. 1996 Dec;92(6):608-13
8960319
J Neurosci. 2009 May 13;29(19):6285-95
19439606
J Neuroimmunol. 2007 Mar;184(1-2):53-68
17188755
Mol Cell Neurosci. 2005 May;29(1):26-39
15866044
Int J Clin Pract. 2004 Jul;58(7):706-13
15311728
Arterioscler Thromb Vasc Biol. 2001 Aug;21(8):1327-32
11498461
Am J Cardiol. 2008 Apr 17;101(8A):3B-8B
18375239
Nature. 2002 Jun 27;417(6892):941-4
12068310
J Neurosci. 2004 Jul 7;24(27):6209-17
15240813
Acta Neuropathol. 1994;87(1):55-62
8140894
J Cereb Blood Flow Metab. 2005 Feb;25(2):281-90
15678129
Am J Cardiol. 2008 May 15;101(10):1428-36
18471454
Atherosclerosis. 1998 Jun;138(2):271-80
9690910
Brain Res. 1991 Nov 1;563(1-2):334-8
1786548
J Cereb Blood Flow Metab. 2004 Feb;24(2):133-50
14747740
J Cereb Blood Flow Metab. 2009 May;29(5):911-20
19223914
J Neurotrauma. 2001 Jan;18(1):1-9
11200244
Health Technol Assess. 2007 Apr;11(14):1-160, iii-iv
17408535
Brain Res Mol Brain Res. 1998 Jun 1;57(1):1-9
9630473
Vasc Health Risk Manag. 2008;4(5):1001-9
19183748
J Neurotrauma. 2004 Jun;21(6):754-74
15253803
Ann Neurol. 2007 Jul;62(1):49-58
17557352
J Neurosci. 2008 Feb 27;28(9):2221-30
18305255
Neuroreport. 1993 Feb;4(2):211-4
8453062
J Neurosci Methods. 2003 Sep 30;128(1-2):183-90
12948561
JAMA. 2000 Sep 13;284(10):1263-70
10979113
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15769-74
9861045
Expert Rev Cardiovasc Ther. 2008 Nov;6(10):1303-10
19018682
Stroke. 2001 Nov;32(11):2682-8
11692034
Lancet. 1994 Oct 15;344(8929):1055-6
7523810
Circ Res. 2003 Apr 4;92(6):692-9
12609969