Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain.
Proteolytic disruption of the extracellular matrix with opening of the blood-brain barrier (BBB) because of matrix metalloproteinases (MMPs) occurs in reperfusion injury after stroke. Matrix metalloproteinase inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described, which provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the Magnetic resonance imaging (MRI) method for treatment studies and the long-term effects on recovery. Magnetic resonance imaging studies were performed in control (N=6) and drug-treated (N=8) groups on a dedicated 4.7-T MRI scanner. Adult Wistar-Kyoto underwent a 2-h middle cerebral artery occlusion followed by an MRI study after 3 h of reperfusion, which consisted of T2- and diffusion-weighted techniques. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-gadolinium-diethylenetriaminepentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 mins. The same animal was imaged again at 48 h for lesion size estimation. Data was postprocessed pixel-wise to generate apparent diffusion coefficient and permeability coefficient maps. Treatment with BB-1101 significantly reduced BBB permeability at 3 h, but failed to reduce lesion size at 48 h. Behavioral studies showed impairment in recovery in treated rats. Magnetic resonance imaging allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurologic status of treated animals. Although these preliminary results suggest that BB-1101 is useful in reducing early BBB leakage owing to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery.
Sood
Rohit R
RR
Department of Neurology, University of New Mexico, Albuquerque, New Mexico 87131, USA. rsood@salud.unm.edu
Taheri
Saeid
S
Candelario-Jalil
Eduardo
E
Estrada
Eduardo Y
EY
Rosenberg
Gary A
GA
D000818:Animals; D001593:Benzyl Compounds; D001812:Blood-Brain Barrier / Q000187:drug effects*; D003907:Dexamethasone / Q000627:therapeutic use*; D004338:Drug Combinations; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010431:Pentoxifylline / Q000627:therapeutic use*; D010539:Permeability / Q000187:drug effects; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D020127:Recovery of Function; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D013386:Succinates
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013386:Succinates; D003907:Dexamethasone; D010431:Pentoxifylline
Magn Reson Med. 2000 Jun;43(6):837-44
10861878
J Cereb Blood Flow Metab. 2007 Apr;27(4):697-709
16850029
Nat Rev Neurosci. 2001 Jul;2(7):502-11
11433375
Magn Reson Med. 2003 Aug;50(2):283-92
12876704
Stroke. 2003 Aug;34(8):2025-30
12855824
J Cereb Blood Flow Metab. 2004 Sep;24(9):945-63
15356416
J Cereb Blood Flow Metab. 1983 Mar;3(1):8-32
6822623
Neurology. 1984 Mar;34(3):315-20
6546610
Acta Neuropathol. 1985;68(2):122-9
3907257
Stroke. 1993 Mar;24(3):465-8
8446984
J Cereb Blood Flow Metab. 1995 Nov;15(6):1002-11
7593332
J Mol Med (Berl). 1997 May;75(5):341-7
9181475
Nat Med. 1998 Feb;4(2):228-31
9461198
Stroke. 1998 May;29(5):1020-30
9596253
Am J Physiol. 1998 May;274(5 Pt 2):R1203-11
9644031
Stroke. 1998 Oct;29(10):2189-95
9756602
Ann Neurol. 1998 Oct;44(4):592-600
9778257
J Cereb Blood Flow Metab. 1998 Nov;18(11):1163-72
9809504
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H558-68
15764676
AJNR Am J Neuroradiol. 2006 Jan;27(1):51-4
16418355
J Neurosci. 2006 Mar 29;26(13):3491-5
16571756
Nat Med. 2006 Apr;12(4):441-5
16565723
J Neurosci. 2006 May 31;26(22):5996-6003
16738242
Exp Neurol. 2006 Jul;200(1):38-49
16624294
Magn Reson Imaging. 2006 Oct;24(8):1039-49
16997074
J Magn Reson Imaging. 2007 Jan;25(1):39-47
17173307
J Cereb Blood Flow Metab. 2000 Oct;20(10):1474-82
11043910