The effect of type 2 diabetes on CD36 expression and the uptake of oxLDL: Diabetes affects CD36 and oxLDL uptake.

We investigated whether type 2 diabetes mellitus (T2DM), a risk factor of stroke, affects the level of scavenger receptor CD36 and the uptake of its ligand, oxidized LDL (oxLDL); and whether pioglitazone, a drug that enhances CD36, promotes oxLDL uptake. Compared to normoglycemic db/+ mice, adult db/db mice showed a pronounced reduction in surface CD36 expression on myeloid cells from the blood, brain, and bone marrow as detected by flow cytometry, which correlated with elevated plasma soluble-CD36 as determined by ELISA. Increased CD36 expression was found in brain macrophages and microglia of both genotypes 7 days after ischemic stroke. In juvenile db/db mice, prior to obesity and hyperglycemia, only a mild reduction of surface CD36 was found in blood neutrophils, while all other myeloid cells showed no difference relative to the db/+ strain. In vivo, oral pioglitazone treatment for four weeks increased CD36 levels on myeloid cells in db/db mice. In vitro, uptake of oxLDL by bone marrow derived macrophages (BMDMs) of db/db mice was reduced relative to db/+ mice in normal glucose medium. OxLDL uptake inversely correlated with glucose levels in the medium in db/+ BMDMs. Furthermore, pioglitazone restored oxLDL uptake by BMDMs from db/db mice cultured in high glucose. Our data suggest that T2DM is associated with reduced CD36 on adult myeloid cells, and pioglitazone enhances CD36 expression in db/db cells. T2DM or high glucose reduces oxLDL uptake while pioglitazone enhances oxLDL uptake. Our findings provide new insight into the mechanism by which pioglitazone may be beneficial in the treatment of insulin resistance.

Training of the impaired forelimb after traumatic brain injury enhances hippocampal neurogenesis in the Emx1 null mice lacking a corpus callosum.

Unilateral brain injury is known to disrupt the balance between the two cortices, as evidenced by an abnormally high interhemispheric inhibitory drive from motor cortex M1intact to M1lesioned transmitted transcallosally. Our previous work has shown that the deletion of homeobox gene Emx1 not only led to the agenesis of the corpus callosum (cc), but also to reduced hippocampal neurogenesis. The current study sought to determine whether lacking the cc affected the recovery of forelimb function and hippocampal plasticity following training of the affected limb in mice with unilateral traumatic brain injuries (TBI). One week after TBI, produced by a controlled cortical impact to impair the preferred limb, Emx1 wild type (WT) and knock out (KO) mice were subjected to the single-pellet reaching task with the affected limb for 4 weeks. Both TBI and Emx1 deletion had overall adverse effects on the successful rate of reaching. However, TBI significantly affected reaching performance only in the WT mice and not in the KO mice. Both TBI and Emx1 gene deletion also negatively affected hippocampal neurogenesis, demonstrated by a reduction in doublecortin (DCX)-expressing immature neurons, while limb training enhanced DCX expression. However, limb training increased DCX cells in KO mice only in the TBI-treated group, whereas it induced neurogenesis in both WT mice groups regardless of the treatment. Our finding also suggests that limb training enhances neuroplasticity after brain injury at functionally remote regions including the hippocampus, which may have implications for promoting overall recovery of function after TBI.

Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice.

BACKGROUND AND PURPOSE: The presence of collaterals is associated with a reduced risk of stroke and transient ischemic attack in patients with steno-occlusive carotid artery disease. Although metabolic syndrome negatively impacts collateral status, it is unclear whether and to what extent type 2 diabetes mellitus affects cerebral collateral flow regulation during hypoperfusion. METHODS: We examined the spatial and temporal changes of the leptomeningeal collateral flow and the flow dynamics of the penetrating arterioles in the distal middle cerebral artery and anterior cerebral artery branches over 2 weeks after unilateral common carotid artery occlusion (CCAO) using optical coherent tomography in db/+ and db/db mice. We also assessed the temporal adaptation of the circle of Willis after CCAO by measuring circle of Willis vessel diameters. RESULTS: After unilateral CCAO, db/db mice exhibited diminished leptomeningeal collateral flow compensation compared with db/+ mice, which coincided with a reduced dilation of distal anterior cerebral artery branches, leading to reduced flow not only in pial vessels but also in penetrating arterioles bordering the distal middle cerebral artery and anterior cerebral artery. However, no apparent cell death was detected in either strain of mice during the first week after CCAO. db/db mice also experienced a more severe early reduction in the vessel diameters of several ipsilateral main feeding arteries in the circle of Willis, in addition to a delayed post-CCAO adaptive response by 1 to 2 weeks, compared with db/+ mice. CONCLUSIONS: Type 2 diabetes mellitus is an additional risk factor for hemodynamic compromise during cerebral hypoperfusion, which may increase the severity and the risk of stroke or transient ischemic attack.

Impaired leptomeningeal collateral flow contributes to the poor outcome following experimental stroke in the Type 2 diabetic mice.

Collateral status is an independent predictor of stroke outcome. However, the spatiotemporal manner in which collateral flow maintains cerebral perfusion during cerebral ischemia is poorly understood. Diabetes exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, and it continued to grow over the course of 1 week. In contrast, an impairment of collateral recruitment was evident in the Type 2 diabetic db/db mice, which coincided with a worse stroke outcome compared with their normoglycemic counterpart db/+, despite their equally well-collateralized leptomeningeal anastomoses. Similar to the wild-type mice, both db/+ and db/db mice underwent collateral growth 7 d after MCA stroke, although db/db mice still exhibited significantly reduced retrograde flow into the MCA territory chronically. Acutely induced hyperglycemia in the db/+ mice did not impair collateral flow after stroke, suggesting that the state of hyperglycemia alone was not sufficient to impact collateral flow. Human albumin was efficacious in improving collateral flow and outcome after stroke in the db/db mice, enabling perfusion to proximal MCA territory that was usually not reached by retrograde flow from anterior cerebral artery without treatment. Our results suggest that the impaired collateral status contributes to the exacerbated ischemic injury in mice with Type 2 diabetes, and modulation of collateral flow has beneficial effects on stroke outcome among these subjects.