1. ¹Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA
2. ²Department of Neurology, The BRaIN Center, University of New Mexico, Albuquerque, New Mexico, USA
3. ³Department of Neuroscience, University of New Mexico, Albuquerque, New Mexico, USA
4. ⁴Department of Cell Biology and Physiology, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA

Correspondence: Dr RR Sood, Department of Neurology, University of New Mexico, MRI core, BRaIN Center, Yale Blvd, Room # 1112, Domenici Hall, Albuquerque, NM 87131, USA. E-mail:rsood@salud.unm.edu

Received 2 April 2007; Revised 31 May 2007; Accepted 11 June 2007; Published online 15 August 2007.

Abstract

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.