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A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke
Jieli Chen1, Xu Cui, Alex Zacharek
1Neurology Research, Henry Ford Hospital, Detroit, MI 48202, USA. jieli@neuro.hfh.edu
Background And Purpose:
Diabetes mellitus leads to a higher risk of ischemic stroke and worse outcome compared to the general population. However, there have been few studies on white matter (WM) damage after stroke in diabetes mellitus. We therefore investigated WM damage after stroke in mice with diabetes mellitus.
Methods:
BKS.Cg-m(+/+)Lepr(db)/J (db/db) type 2 diabetes mellitus mice and db(+) non-diabetes mellitus mice were subjected to middle cerebral artery occlusion. Functional outcome, immunostaining, zymography, Western blot, and polymerase chain reaction were used.
Results:
After stroke, mice with diabetes mellitus exhibited significantly increased lesion volume and brain hemorrhagic and neurological deficits compared to mice without diabetes mellitus. Bielshowsky silver, luxol fast blue, amyloid precursor protein, and NG2 expression were significantly decreased, indicating WM damage, and matrix metalloproteinase (MMP)-9 activity was significantly increased in the ischemic brain of mice with diabetes mellitus. Subanalysis of similar lesions in mice with and without diabetes mellitus demonstrated mice with diabetes mellitus had significantly increased WM damage than in mice without diabetes mellitus (P<0.05). To investigate the mechanism underlying diabetes mellitus-induced WM damage, oxygen-glucose deprivation-stressed premature oligodendrocyte and primary cortical neuron cultures were used. High glucose increased MMP-2, MMP-9, cleaved caspase-3 levels, and apoptosis, as well as decreased cell survival and dendrite outgrowth in cultured primary cortical neuron. High glucose increased MMP-9, cleaved caspase-3 level, and apoptosis, and decreased cell proliferation and cell survival in cultured oligodendrocytes. Inhibition of MMP by GM6001 treatment significantly decreased high glucose-induced cell death and apoptosis in cultured primary cortical neuron and oligodendrocytes but did not alter dendrite outgrowth in primary cortical neuron.
Conclusions:
Mice with diabetes mellitus have increased brain hemorrhage and show more severely injured WM than mice without diabetes mellitus after stroke. MMP-9 upregulated in mice with diabetes mellitus may exacerbate WM damage after stroke in mice with diabetes mellitus.
Insights
Diabetes mellitus exacerbates stroke outcomes, causing more severe white matter damage and brain hemorrhage in mice. Increased matrix metalloproteinase-9 (MMP-9) activity appears to worsen this white matter injury after stroke.
Area of Science:
- Neuroscience
- Endocrinology
- Pathology
Background:
- Diabetes mellitus is a known risk factor for ischemic stroke, leading to poorer patient outcomes.
- Limited research exists on the specific impact of diabetes on white matter (WM) damage post-stroke.
Purpose of the Study:
- To investigate the extent and mechanisms of white matter damage in mice with diabetes mellitus following stroke.
Main Methods:
- Utilized type 2 diabetes mellitus mice (db/db) and non-diabetic controls, subjected to middle cerebral artery occlusion (MCAO).
- Assessed functional outcomes, performed immunostaining, zymography, Western blot, and PCR.
- Employed in vitro cultures of oligodendrocytes and cortical neurons under high glucose conditions.
Main Results:
- Diabetic mice showed larger lesion volumes, increased brain hemorrhage, and worsened neurological deficits post-stroke.
- Significant reductions in WM markers (Bielshowsky silver, luxol fast blue, APP, NG2) and elevated matrix metalloproteinase-9 (MMP-9) activity were observed in diabetic stroke brains.
- In vitro, high glucose increased apoptosis and MMP levels in neurons and oligodendrocytes, while MMP inhibition reduced cell death.
Conclusions:
- Diabetes mellitus significantly increases brain hemorrhage and exacerbates white matter injury after stroke in mice.
- Upregulation of MMP-9 in diabetic conditions may be a key factor contributing to more severe white matter damage post-stroke.
