myelin-basic-protein and Carotid-Stenosis

Endothelial progenitor cells (EPCs) have been extensively investigated as a therapeutic approach for repairing the vascular system in cerebrovascular diseases. Beyond vascular regeneration per se, EPCs may also release factors that affect the entire neurovascular unit. Here, we aim to study the effects of the EPC secretome on oligovascular remodeling in a mouse model of white matter injury after prolonged cerebral hypoperfusion.. The secretome of mouse EPCs was analyzed with a proteome array. In vitro, the effects of the EPC secretome and its factor angiogenin were assessed on primary oligodendrocyte precursor cells and mature human cerebral microvascular endothelial cells (hCMED/D3). In vivo, mice were subjected to permanent bilateral common carotid artery stenosis, then treated with EPC secretome at 24 hours and at 1 week, and cognitive outcome was evaluated with the Y maze test together with oligodendrocyte precursor cell proliferation/differentiation and vascular density in white matter at 4 weeks.. Multiple growth factors, cytokines, and proteases were identified in the EPC secretome, including angiogenin. In vitro, the EPC secretome significantly enhanced endothelial and oligodendrocyte precursor cell proliferation and potentiated oligodendrocyte precursor cell maturation. Angiogenin was proved to be a key factor since pharmacological blockade of angiogenin signaling negated the positive effects of the EPC secretome. In vivo, treatment with the EPC secretome increased vascular density, myelin, and mature oligodendrocytes in white matter and rescued cognitive function in the mouse hypoperfusion model.. Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling.

Topics: Angiogenesis Inducing Agents; Animals; Brain Ischemia; Carotid Stenosis; Cell Proliferation; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Endothelial Progenitor Cells; Glutathione S-Transferase pi; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Mice; Myelin Basic Protein; Oligodendrocyte Precursor Cells; Peptide Hydrolases; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Platelet-Derived Growth Factor alpha; Ribonuclease, Pancreatic; Vascular Remodeling; White Matter

Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion.. Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury.. Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration.. White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.

Topics: Animals; Behavior, Animal; Brain Ischemia; Carotid Stenosis; Chronic Disease; Cilostazol; Cognition; Dementia, Vascular; Diffusion Tensor Imaging; Disease Models, Animal; Hippocampus; Inflammation; Leukoencephalopathies; Myelin Basic Protein; Neuroprotective Agents; Neuropsychological Tests; Oligodendroglia; Ranvier's Nodes; Rats; Rats, Wistar; Tetrazoles; White Matter

We sought to investigate the role of the adenosine A1 receptors (A1ARs) in white matter lesions under chronic cerebral hypoperfusion (CCH) and explore the potential repair mechanisms by activation of the receptors. A right unilateral common carotid artery occlusion (rUCCAO) method was used to construct a CCH model. 2-chloro-N6-cyclopentyladenosine (CCPA), a specific agonist of A1ARs, was used to explore the biological mechanisms of repair in white matter lesions under CCH. The expression of mammalian target of rapamycin (mTOR), phosphorylation of mTOR (P-mTOR), myelin basic protein (MBP, a marker of white matter myelination) were detected by Western-blot. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokine interleukin-10 (IL-10) levels were determined by ELISA. Compared with the control groups on week 2, 4 and 6, in CCPA-treated groups, the ratio of P-mTOR/mTOR, expression of MBP and IL-10 increased markedly, while the expression of TNF-α reduced at week 6. In conclusion, A1ARs appears to reduce inflammation in white matter via the mTOR signaling pathway in the rUCCAO mice. Therefore, A1ARs may serve as a therapeutic target during the repair of white matter lesions under CCH.

Topics: Animals; Brain; Carotid Artery, Common; Carotid Stenosis; Inflammation; Interleukin-10; Leukoencephalopathies; Ligation; Male; Mice, Inbred C57BL; Myelin Basic Protein; Phosphorylation; Receptor, Adenosine A1; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Bilateral carotid artery occlusion (2-vessel occlusion, 2VO) in rats is a classic and frequently used approach to develop an animal model of chronic cerebral hypoperfusion. However, this method results in substantial mortality in rats.. We investigated whether a modified 2VO procedure, which induces bilateral carotid artery stenosis via ligation of each bilateral common carotid artery (CCA) with a 32 gauge (G) needle followed by needle removal, could produce a chronic cerebral hypoperfusion rat model with an increased survival rate. Sprague-Dawley (SD) rats were treated with the standard or modified 2VO procedure, and changes in cerebral blood flow (CBF) and survival rates were determined. On day 28, cognitive function was assessed with the Morris Water Maze (MWM) test, and neuronal survival and degeneration within the hippocampal CA1 area were measured. Damage to the white matter (WM) within the corpus striatum was assessed via Luxol fast blue (LFB) staining and analyses analyzing the levels of the myelin basic protein (MBP) protein levels.. The modified 2VO procedure induced similar cognitive impairments, hippocampal lesions and WM damage compared with the standard 2VO procedure in rats; however, it had an increased survival rate. Comparison with existing methods This novel method can be used to quickly and effectively establish a chronic cerebral hypoperfusion rat model with common materials and an improved survival rate.. Bilateral carotid artery stenosis using a 32 G needle is a useful and reliable method to develop a rat model of chronic cerebral hypoperfusion with increased survival.

Topics: Animals; Apoptosis; CA1 Region, Hippocampal; Carotid Artery, Common; Carotid Stenosis; Chronic Disease; Corpus Striatum; Disease Models, Animal; Functional Laterality; Ligation; Male; Maze Learning; Myelin Basic Protein; Needles; Neurons; Neurosurgical Procedures; Rats, Sprague-Dawley; White Matter

The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.. Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1β, and interleukin-6 were examined.. MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo.. These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

Topics: Analysis of Variance; Animals; Cardiotonic Agents; Carotid Stenosis; Cyclooxygenase 2; Dipterocarpaceae; Drugs, Chinese Herbal; Hippocampus; Interleukin-1beta; Interleukin-6; Male; MAP Kinase Signaling System; Microglia; Mitogen-Activated Protein Kinases; Myelin Basic Protein; p38 Mitogen-Activated Protein Kinases; Panax notoginseng; Phosphorylation; Rats; Rats, Wistar; Salvia miltiorrhiza