The earliest report I have of MMP-9 being useful for stroke was way back in 2005. And 11 years later we still have no translational use for it. We keep doing studies but never seem to get anywhere useful with it. A great stroke leader would get something accomplished.
In 2005, the scientist(Mr Gu) had previously played the role of
lead author on a study published in the Journal of Neuroscience that
had revealed MMP-9 could be a promising area that therapeutic medicines
for stroke patients could target.
- 1Discipline of Anatomy and Pathology,
Adelaide Centre for Neuroscience Research, School of Medicine, The
University of Adelaide, Adelaide, SA, Australia
- 2Department of Neurology, MIND Institute, University of California at Davis Medical Center, Sacramento, CA, USA
Numerous studies have documented increases in matrix
metalloproteinases (MMPs), specifically MMP-9 levels following stroke,
with such perturbations associated with disruption of the blood brain
barrier (BBB), increased risk of hemorrhagic complications, and worsened
outcome. Despite this, controversy remains as to which cells release
MMP-9 at the normal and pathological BBB, with even less clarity in the
context of stroke. This may be further complicated by the influence of
tissue plasminogen activator (tPA) treatment. The aim of the present
review is to examine the relationship between neutrophils, MMP-9 and tPA
following ischemic stroke to elucidate which cells are responsible for
the increases in MMP-9 and resultant barrier changes and hemorrhage
observed following stroke.
Introduction
Over the last decade the matrix metalloproteinases
(MMPs) have been widely investigated for their role in disruption of the
blood-brain barrier (BBB), particularly the extracellular matrix (ECM),
following stroke (
Romanic et al., 1998;
Rosenberg et al., 1998;
Fujimura et al., 1999;
Gasche et al., 1999;
Gidday et al., 2005) and other cerebral pathologies such as traumatic brain injury (
Planas et al., 2001) and neoplasm (
Lukes et al., 1999;
Turba et al., 2007).
MMPs are a family of zinc and calcium-dependent endopeptidases that are
capable of degrading all components of the ECM including laminin,
collagen and fibronectin, amongst many other targets (
Van den Steen et al., 2002). At least 23 MMPs have been identified to date (
Sternlicht and Werb, 2001),
with MMP-2 and MMP-9 the most widely studied in stroke. In particular,
MMP-9 has been implicated, not only in the pathogenesis of BBB breakdown
and subsequent vasogenic edema formation following stroke (
Fujimura et al., 1999;
Gasche et al., 1999;
Rosenberg and Yang, 2007), but also in hemorrhagic transformation (HT) in the setting of tissue plasminogen activator (tPA) therapy (
Lapchak et al., 2000;
Wang et al., 2009).
Cerebral edema and HT of the infarct are significant problems in
clinical stroke, which are associated with poor outcome and contribute
to the morbidity and mortality of this condition (
Hacke et al., 1996;
Fiorelli et al., 1999). Elucidating the mechanisms of such deleterious events is the key to developing targeted, more effective clinical therapies.
Numerous clinical and experimental studies have confirmed an increase in serum MMP-9 following stroke (
Clark et al., 1997;
Romanic et al., 1998;
Yushchenko et al., 2000;
Montaner et al., 2003a;
Ning et al., 2006).
However, the cellular source of this MMP-9 remains controversial.
Although it is generally accepted that MMP-9 is increased following
stroke, there is debate as to which cells are responsible, whether it be
resident brain cells, cells of the vasculature or circulating immune
cells, such as neutrophils. However, the aim of the present review was
to explore the potential relationship between neutrophil-derived MMP-9
and complications such as BBB disruption and HT following stroke to
elucidate the cellular source of MMP-9 in ischemic stroke.
Renée J. Turner
Frank R. Sharp
