Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases.
Blood-brain barrier (BBB) breakdown after stroke is linked to the up-regulation of metalloproteinases (MMPs) and inflammation. This study examines the effects of progesterone (PROG) and its neuroactive metabolite allopregnanolone (ALLO) on BBB integrity following permanent middle cerebral artery occlusion (pMCAO). Rats underwent pMCAO by electro-coagulation and received intraperitoneal injections of PROG (8 mg/kg), ALLO (8 mg/kg) or vehicle at 1 h post-occlusion and then subcutaneous injections (8 mg/kg) at 6, 24, and 48 h. MMP activation and expression were analyzed by Western blot, immunohistochemistry and gelatin zymography 72 h post-pMCAO. Occludin1, claudin5, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) were analyzed at 72 h post-pMCAO with Western blots. BBB permeability was measured by Evans blue extravasation and infarct size was evaluated by cresyl violet at 72 h after pMCAO. Ischemic injury significantly (p<0.05) increased the expression of MMP-9, MMP-2, TNF-α and IL-6, and reduced the levels of occludin1 and claudin5. These changes were followed by increased infarct size (% contralateral hemisphere) and Evans blue extravasation into the brain indicating compromise of the BBB. PROG and ALLO attenuated BBB disruption and infarct size following pMCAO by reducing MMPs and the inflammatory response and by preventing the degradation of occludin1 and claudin5. We conclude that PROG and ALLO can help to protect BBB disruption following pMCAO.
Ishrat
Tauheed
T
Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Sayeed
Iqbal
I
Atif
Fahim
F
Hua
Fang
F
Stein
Donald G
DG
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology*; D015153:Blotting, Western; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology*; D062507:Claudin-5; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000096:biosynthesis; D020768:Middle Cerebral Artery / Q000473:pathology; D062793:Occludin; D010539:Permeability; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D062507:Claudin-5; C491510:Cldn5 protein, rat; D015850:Interleukin-6; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D011280:Pregnanolone; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
Expert Opin Investig Drugs. 2005 Apr;14(4):393-409
15882116
Biochem Biophys Res Commun. 2009 Dec 18;390(3):678-83
19825364
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3774-8
7731982
Restor Neurol Neurosci. 2007;25(2):151-9
17726274
J Cereb Blood Flow Metab. 2007 Apr;27(4):697-709
16850029
Brain Res. 1996 Sep 30;735(1):101-7
8905174
J Neuroimmunol. 1996 Jan;64(1):37-43
8598388
Ernst Schering Res Found Workshop. 2004;(47):1-16
15032051
J Cereb Blood Flow Metab. 2005 Apr;25(4):460-7
15674236
Trends Neurosci. 1999 Sep;22(9):391-7
10441299
Neurosci Lett. 2007 Apr 24;417(1):1-5
17386975
J Neurosci. 2007 Feb 14;27(7):1511-8
17301159
Nat Med. 1998 Feb;4(2):228-31
9461198
Expert Opin Investig Drugs. 2010 Jul;19(7):847-57
20486864
Inflamm Res. 2009 Sep;58(9):619-24
19333725
Brain Res. 2009 Mar 31;1263:165-73
19368823
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H558-68
15764676
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1977-82
19174516
Stroke. 2000 Dec;31(12):3034-40
11108768
Prog Brain Res. 2009;175:219-37
19660659
Ann Emerg Med. 2006 Apr;47(4):381-9
16546625
Cell Mol Life Sci. 2006 Mar;63(6):709-22
16465451
J Neurotrauma. 2001 Sep;18(9):901-9
11565602
Brain Res Rev. 2008 Mar;57(2):386-97
17826842
Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2
17011666
Circulation. 2002 Aug 6;106(6):740-5
12163437
Mol Cell Neurosci. 2001 Nov;18(5):443-57
11922137
Neuron. 1993 Sep;11(3):523-30
8398145
Nat Med. 2007 Oct;13(10):1173-5
17828272
Neurosci Lett. 2007 Sep 25;425(2):94-8
17826908
Circulation. 2003 Feb 4;107(4):598-603
12566373
Nat Med. 2004 Jul;10(7):704-11
15208706
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13532-6
16938871
Neuron. 2008 Jan 24;57(2):178-201
18215617
J Neurosci. 2007 Apr 18;27(16):4403-12
17442825
Exp Neurol. 2006 Apr;198(2):469-78
16445913
Stroke. 1985 Mar-Apr;16(2):268-73
3975965
J Clin Invest. 2003 Nov;112(10):1533-40
14617754
J Neurosci. 2008 Sep 17;28(38):9451-62
18799677
Brain Res. 2005 Nov 16;1062(1-2):171-4
16256079
Biochem Soc Trans. 2007 Nov;35(Pt 5):1163-5
17956302
Endocrinology. 1993 Sep;133(3):1003-9
8365352
PLoS One. 2008 Aug 22;3(8):e3037
18725947
J Neurosurg. 2000 May;92(5):848-52
10794300
Stroke. 1985 Jan-Feb;16(1):101-9
3966252
Neurol Res. 2008 Oct;30(8):783-93
18826804
J Neurol Sci. 1999 Dec 1;171(1):24-30
10567046
BMC Neurosci. 2006 Jul 17;7:56
16846501
Curr Alzheimer Res. 2006 Jul;3(3):185-90
16842093
Neurobiol Dis. 2004 Jun;16(1):1-13
15207256
Neuroscientist. 2009 Aug;15(4):324-32
19359672
Neurosurg Focus. 2007 May 15;22(5):E4
17613235
Thromb Haemost. 2004 Mar;91(3):457-64
14983220
Blood. 2000 Jul 15;96(2):569-76
10887120
Prog Neurobiol. 2003 Sep;71(1):3-29
14611864
J Cereb Blood Flow Metab. 2004 Jul;24(7):805-13
15241189
J Cereb Blood Flow Metab. 2008 Nov;28(11):1786-94
18628783
J Clin Neurosci. 2006 Jan;13(1):1-8
16410192
Acta Neurochir Suppl (Wien). 1990;51:256-8
2089910
Stroke. 1998 Oct;29(10):2189-95
9756602
J Neurotrauma. 2005 Jan;22(1):106-18
15665606
Stroke. 2002 Mar;33(3):831-6
11872911
J Steroid Biochem Mol Biol. 1996 Jan;56(1-6 Spec No):209-19
8603042
Brain Res Rev. 2008 Mar;57(2):398-409
17931704
Adv Neurol. 1990;52:327-33
2396529
Neuroscience. 2009 Feb 6;158(3):1049-61
18789376
J Neurosci. 2001 Oct 1;21(19):7724-32
11567062
Shock. 1997 Nov;8(5):341-8
9361344
Brain Res. 2009 Feb 27;1257:94-101
19135987