Author/Authors :
Huber, Vincent J University of Niigata - Niigata, Japan , Igarashi, Hironaka University of Niigata - Niigata, Japan , Ueki, Satoshi University of Niigata - Niigata, Japan , Terumitsu-Tsujita, Mika National Center of Neurology and Psychiatry - Tokyo, Japan , Nito, Chikako Department of Neurological Science - Graduate School of Medicine - Nippon Medical School - Tokyo, Japan , Ohno, Ken University of Niigata - Niigata, Japan , Suzuki, Yuji University of Niigata - Niigata, Japan , Itoh, Kosuke University of Niigata - Niigata, Japan , Kwee, Ingrid L Department of Neurology - University of California Davis - Davis, USA , Nakada, Tsutomu University of Niigata - Niigata, Japan
Abstract :
Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following
ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of
thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution
of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo
using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sucient sensitivity for the
specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess
those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and
without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-
administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity,
which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019
administration can be used to assess potential therapeutic strategies for ischemic stroke.
