Increased cerebral matrix metalloprotease-9 activity is associated with
compromised recovery in the diabetic db/db mouse following a stroke.
Authors Kumari R, Willing LB, Patel SD, Baskerville KA, Simpson IA
Submitted By Ian Simpson on 12/10/2012
Status Published
Journal Journal of neurochemistry
Year 2011
Date Published 12/1/2011
Volume : Pages 119 : 1029 - 1040
PubMed Reference 21923664
Abstract Diabetes is a major risk factor of stroke and is associated with increased
frequency of stroke and a poorer prognosis for recovery. In earlier studies we
have utilized type 2 diabetic mouse models of stroke and demonstrated that
diabetic db/db and ob/ob mice experience larger infarct volumes and impaired
recovery associated with greater infiltration of macrophage following
hypoxic-ischemic (H/I) insult than their heterozygous non-diabetic db/+ and ob/+
littermates. To obtain a better understanding of the pathogenesis of the
impaired recovery, we have investigated the role of matrix metalloproteases and
their endogenous inhibitors in the breakdown of the blood-brain barrier (BBB)
following H/I. Diabetic db/db mice showed a significant and more rapid increase
in matrix metalloprotease (MMP)-9 mRNA, protein and gelatinolytic activity
compared with db/+, which resulted in an increased degradation of occludin and
collagen IV and subsequently, an increased BBB permeability and greater
infiltration of neutrophils into the infarct area. The expression of the MMPs,
especially in the db/+ mice, is preceded by an elevated expression of their
endogenous tissue inhibitors of metalloproteases (TIMPs) 1, 2, and 3, whereas in
the db/db mice, a lower expression of the TIMPs is associated with greater MMP 3
and 9 expression. These results suggest that an imbalance in the MMPs/TIMPs
cascade in the diabetic mouse, particularly MMP-9, results in a greater
neutrophil invasion, a compromised BBB and consequently a greater insult.

Investigators with authorship
Ian SimpsonPenn State University