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Increased cerebral matrix metalloprotease‐9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke
Author(s) -
Kumari Rashmi,
Willing Lisa B,
Patel Shyama D,
Baskerville Karen A.,
Simpson Ian A.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07487.x
Subject(s) - matrix metalloproteinase , endocrinology , medicine , occludin , blood–brain barrier , diabetes mellitus , pathogenesis , endogeny , infiltration (hvac) , inflammation , stroke (engine) , chemistry , tight junction , central nervous system , biochemistry , mechanical engineering , physics , engineering , thermodynamics
J. Neurochem. (2011) 119 , 1029–1040. 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.