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Involvement of matrix metalloproteinases‐2 and ‐9 in the formation of a lacuna‐like cerebral cavity
Author(s) -
Cayabyab Francisco S.,
Gowribai Krishnamoorty,
Walz Wolfgang
Publication year - 2013
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23223
Subject(s) - lesion , minocycline , microglia , matrix metalloproteinase , pathology , cerebral cortex , immunostaining , medicine , inflammation , chemistry , immunohistochemistry , endocrinology , biochemistry , antibiotics
We used a modified pial vessel disruption (PVD) protocol with adult male Wistar rats to mimic small‐vessel stroke in the cerebral cortex. Within 3 weeks, this lesion develops into a single lacuna‐like cavity, which is fluid‐filled and encapsulated by reactive astrocytes. Minocycline treatment that commences 1 hr after lesion and continues for 6 days prevents the cavitation and causes a filling of the lesion with reactive astrocytes and no barrier. Here, we determined whether inhibition of matrix metalloproteinases‐2 and ‐9 (MMPs) mediates this minocycline action. Confocal microscopy revealed increased punctate staining of MMPs inside the lesion sites after 2 days of PVD. Astrocytes lined the lesion border but showed sparse localization inside the lesion. In contrast, increased MMP levels inside the lesion coincided with increased ED1 or OX‐42 immunostaining, suggesting that MMP elevation reflected increased secretions from microglia/macrophages. Imaging analyses also revealed that minocycline administered for 2 days before animal euthanasia, significantly decreased MMP levels within the lesion. Moreover, Western blot analysis of cortical tissue extracts showed a significant 30–40% upregulation of MMPs 2 days after lesion. Minocycline administered 2 hr before the lesion significantly inhibited both MMP‐9 and MMP‐2 levels by ∼40%. In contrast, minocycline administered 1 hr after the lesion only decreased MMP‐9 levels by ∼30%. Because MMP inhibition with batimastat injection also prevented cavity formation at 21 days, we conclude that minocycline prevented the creation of a lacuna‐like cyst in the cerebral cortex by inhibiting the MMP secretion from microglia in the affected tissue. © 2013 Wiley Periodicals, Inc.