White Matter Damage After Stroke And The Effect Of Matrix Metalloproteinases In Type-two Diabetic Mice

Neurology Research, Henry Ford Hospital, Detroit, MI 48202, USA.
Stroke (Impact Factor: 5.72). 02/2011; 42(2):445-52. DOI: 10.1161/STROKEAHA.110.596486
Source: PubMed


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.
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.
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.
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.

Download full-text


Available from: Xu Cui,
  • Source
    • "Transplantation of BMSCs over-expressing miR-126, increases the release of angiogenic factors, improves resistance against hypoxia, and activates Notch ligand Delta-like-4, thereby enhancing functional angiogenesis in the ischemic myocardium and improves cardiac function (Huang et al., 2013a). Increased angiogenesis and improved cardiac function may be attributed to stimulation of AKT/ERK-related pathway (Chen and Zhou, 2011). Abnormal down-regulation of miR 146a has been implicated in mediating chronic inflammatory responses that interfere with wound healing in diabetic subjects (Xu et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells, and off-label use of some pharmacological agents, to promote recovery processes in the sub-acute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes, which enhance angiogenesis, arteriogenesis, neurogenesis, and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described.
    Frontiers in Human Neuroscience 06/2014; 8:382. DOI:10.3389/fnhum.2014.00382 · 3.63 Impact Factor
  • Source
    • "Diabetes upregulates MMP9 expression and activity, which may contribute to increased brain hemorrhage and BBB leakage after stroke [28]. Activation of extracellular components like MMPs can cause damage to the basal lamina, alter microvascular endothelial function and trigger disruption of the BBB thereby increasing its permeability [29], [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our previous studies have found that bone-marrow-stromal cells (BMSC) therapy improves functional recovery after stroke in non-diabetic rats while increases brain hemorrhage and induces arteriosclerosis-like changes in type-one-diabetic (T1DM) rats. Niaspan treatment of stroke increases vascular stabilization, decreases brain hemorrhage and blood-brain-barrier (BBB) leakage in T1DM rats. We therefore tested the hypothesis that combination therapy of BMSC with Niaspan attenuates the side effects of BMSC monotherapy in T1DM rats. T1DM-rats induced by streptozotocin were subjected to 2 hours of middle-cerebral-artery occlusion (MCAo) and treated with: 1) PBS; 2) BMSC (5×10(6)); 3) Niaspan (40 mg/kg) daily for 14 days; 4) BMSC (5×10(6)) +Niaspan (40 mg/kg, daily for 14 days) combination starting at 24 hours after MCAo. All rats were monitored for 14 days. Combination BMSC+Niaspan treatment of T1DM-MCAo rats did not increase brain hemorrhage, and significantly decreased BBB leakage and vascular arteriosclerosis-like changes as well as decreased Angiogenin, matrix metalloproteinase 9 (MMP9) and ED1 expression in ischemic brain and internal-carotid-artery compared to non-treatment control and BMSC monotherapy animals. Combination therapy using BMSC with Niaspan decreases BBB leakage and cerebral arteriosclerosis-like changes. These beneficial effects may be attributed to the decreased expression of Angiogenin, MMP9 and ED1.
    PLoS ONE 11/2013; 8(11):e81199. DOI:10.1371/journal.pone.0081199 · 3.23 Impact Factor
  • Source
    • "The novel finding of SB623-facilitated migration of endogenous cells via a biobridge implicates the active role of MMPs and ECMs in stroke pathology [36,37] and their increasingly recognized role as therapeutic targets for stroke [38,39]. A variety of stem cells, including those derived from umbilical cord blood, peripheral blood, and adult brain, have been demonstrated to alter levels and functions of MMPs and ECMs [40–42], which would suggest their potential to similarly serve as biobridges as seen with the present Notch-induced SB623 MSCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we report that a unique mechanism of action exerted by stem cells in the repair of the traumatically injured brain involves their ability to harness a biobridge between neurogenic niche and injured brain site. This biobridge, visualized immunohistochemically and laser captured, corresponded to an area between the neurogenic subventricular zone and the injured cortex. That the biobridge expressed high levels of extracellular matrix metalloproteinases characterized initially by a stream of transplanted stem cells, but subsequently contained only few to non-detectable grafts and overgrown by newly formed host cells, implicates a novel property of stem cells. The transplanted stem cells manifest themselves as pathways for trafficking the migration of host neurogenic cells, but once this biobridge is formed between the neurogenic site and the injured brain site, the grafted cells disappear and relinquish their task to the host neurogenic cells. Our findings reveal that long-distance migration of host cells from the neurogenic niche to the injured brain site can be achieved through transplanted stem cells serving as biobridges for initiation of endogenous repair mechanisms. This is the first report of a stem cell-paved "biobridge". Indeed, to date the two major schools of discipline in stem cell repair mechanism primarily support the concept of "cell replacement" and bystander effects of "trophic factor secretion". The present novel observations of a stem cell seducing a host cell to engage in brain repair advances basic science concepts on stem cell biology and extracellular matrix, as well as provokes translational research on propagating this stem cell-paved biobridge beyond cell replacement and trophic factor secretion for the treatment of traumatic brain injury and other neurological disorders.
    PLoS ONE 09/2013; 8(9):e74857. DOI:10.1371/journal.pone.0074857 · 3.23 Impact Factor
Show more