Oxidative stress and matrix metalloproteinases (MMPs) contribute to hemorrhagic transformation after ischemic stroke and brain injury after intracerebral hemorrhage (ICH). The goal of this study was to develop a new model of spontaneous ICH, based on the hypothesis that acute, superimposed on chronic, hypertension produces ICH. We hypothesized that increases in angiotensin II (AngII)-mediated oxidative stress and activation of MMPs are associated with, and may precede, spontaneous ICH during hypertension. In C57BL/6 mice, chronic hypertension was produced with AngII infusion and an inhibitor of nitric oxide synthase. During chronic hypertension, mice with acute hypertension from injections of AngII developed ICH. Oxidative stress and MMP levels increased in the brain even before developing ICH. Active MMPs colocalized with a marker of oxidative stress, especially on cerebral vessels that appeared to lead toward regions with ICH. Incidence of ICH and levels of oxidative stress and MMP-9 were greater in mice with acute hypertension produced by AngII than by norepinephrine. In summary, we have developed an experimental model of ICH during hypertension that may facilitate studies in genetically altered mice. We speculate that acute hypertension, especially when induced by AngII, may be critical in spontaneous ICH during chronic hypertension, possibly through oxidative stress and MMP-9.

uperoxide and other reactive oxygen species (ROS) are increased in arteries in several major cardiovascular diseases. 1,2 This finding led to one of the most intriguing hypotheses in contemporary vascular biology: ROS play a critical role in pathophysiology of atherosclerosis, stroke, hypertension, and other cardiovascular diseases.In the past, the concept that ROS, including oxygen radicals, may affect the heart and blood vessels focused on (1) generation of ROS by leukocytes, and (2) vascular damage during ischemia/reperfusion. Leukocytes release ROS at a high concentration, which kills bacteria, and thereby may produce vascular damage. In addition, reperfusion of blood after ischemia generates ROS, and reperfusion may thereby damage reperfused tissues, including heart, brain, and liver.It is now clear that ROS play a far more important role than previously recognized, in normal signaling 3 and physiological mechanisms, as well as in pathophysiology. Low levels of ROS play an important role in normal cellular signaling pathways, 4 and modulate growth and apoptosis of endothelium, and of vascular and cardiac muscle. These changes are important during development, and also during adaptive changes that lead to hypertrophy and remodeling.High levels of ROS are generated in many disease states, including atherosclerosis and hypertension, and contribute to endothelial dysfunction, and to risk of cardiovascular consequences. It is now widely accepted that excessive superoxide inactivates nitric oxide (NO) and contributes to endothelial dysfunction (eg, Arimura et al 5 ), which is a risk factor for cardiovascular disease. A more recent hypothesis is that superoxide dismutases (SODs) may augment endothelium-mediated vasodilatation, by generation of hydrogen peroxide, 6 as well as by dismutation of superoxide. In some vascular beds, hydrogen peroxide appears to be an endothelium-derived relaxing factor. The interaction of ROS, antioxidants and endothelium is complex and important.This review will focus on the role of ROS (especially superoxide) in cardiovascular diseases. Mechanisms of Oxidative StressTwo mechanisms that may lead to increases in superoxide in cardiovascular diseases are increased generation or decreased dismutation (or inactivation) of superoxide. The usual mechanism for increases in superoxide in cardiovascular disease is by increased generation. Many enzymes (including NAD(P)H oxidase, xanthine oxidase, cyclooxygenase, "uncoupled" NO synthases [NOS]) can generate superoxide and may contribute to increases in superoxide in cardiovascular diseases. 7 Leukocytes, in inflammatory states, also may contribute to increases in superoxide.Although decreased dismutation or inactivation of superoxide may produce high levels of superoxide, this mechanism appears to be a less common cause for oxidative stress in disease states than increased generation of superoxide. In fact, oxidative stress typically stimulates antioxidant mechanisms, including SODs, so oxidative stress usually is associated with a compensator...

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In dementia with Lewy bodies (DLB), the Lewy bodies (LBs) are an essential substrate. Although LB pathology has gained increasing attention as one of the major causes of dementia, little is known about the exact prevalence of LB pathology in the general population. In addition, the pathology of Alzheimer-type dementia (ATD) is frequently associated with DLB. To investigate the prevalence of LB pathology in a community-based population and to evaluate the relationship between LB and ATD pathology, we performed an analysis of 102 consecutive autopsy cases. The survey extended over 2.5 years and autopsy rate was 70.5%. LB pathology was detected using alpha-synuclein immunohistochemistry and was assessed based on consensus guidelines for DLB. ATD pathology was evaluated by both CERAD and NIA-RI criteria. Twenty-nine subjects were clinically demented. LB pathology was present in 23 (22.5%) of 102 cases, and in 12 (41.4%) of the demented subjects. The LB score was not significantly different between DLB cases and non-demented subjects with LB pathology (nd-LB), while the Braak stages were significantly different between the two groups. Prevalence of LB pathology constantly increased with age. DLB cases accompanying severe ATD pathology showed more rapid increase of LB scores than did DLB cases without severe ATD pathology. Moreover, DLB cases with severe ATD pathology had poorer prognoses than those without severe ATD pathology. Our results suggested that aging and severe ATD pathology have a strong effect on the evolution of LB pathology.

Background and Purpose-Recent studies show that successful endovascular thrombectomy 6 to 12 hours after stroke onset enhances functional outcomes 3 months later. In this study, we investigated the effects of reperfusion after ischemia on repair processes in the ischemic areas, as well as on functional recovery, using mouse stroke models. Methods-We examined time-dependent histological changes and functional recovery after transient middle cerebral artery occlusion of different durations, including permanent middle cerebral artery occlusion, using the CB-17 (CB-17/lcr-+/+Jcl) mouse strain, which has poor pial collateral blood flow. Results-Large microtubule-associated protein 2-negative areas of neuronal death were produced in mice subjected to ≥60 minutes of ischemia followed by reperfusion on day 1, while restricted microtubule-associated protein 2-negative regions were observed in mice subjected to a 45-minute period of ischemia. A substantial reduction in microtubule-associated protein 2-negative areas was observed on day 7 in mice given early reperfusion and was associated with better functional recovery. Klüver-Barrera staining demonstrated that white matter injury on day 1 was significantly lesser in mice with reperfusion. Immunohistochemistry and electron microscopy revealed that a greater number of endothelial cells were present in the infarct areas in mice with earlier reperfusion and were associated with a more rapid recruitment of plateletderived growth factor receptor β-positive pericytes and subsequent intrainfarct fibrosis. Early reperfusion also resulted in a greater accumulation of glial fibrillary acidic protein-positive astrocytes in peri-infarct areas. Peri-infarct astrogliosis was attenuated in platelet-derived growth factor receptor β heterozygous knockout mice. Conclusions-Early reperfusion after ischemia enhances the survival of endothelial cells and pericytes within ischemic areas even after the infarct is established, resulting in efficient intrainfarct fibrosis and peri-infarct astrogliosis. These effects might be associated with efficient peri-infarct reorganization and functional recovery. in peri-infarct areas in experimental researches, although this remains controversial. 21,22 Furthermore, it is experimentally suggested that efficient fibrotic formation within areas of infarct may promote peri-infarct astrogliosis. 23 Thus, if these repair processes are associated with functional recovery, apparent infarct volumes at early phases may not be suitable for predicting functional outcome.To date, few papers have focused on the effects of reperfusion on poststroke repair processes in both animals and human. In the present study, we hypothesized that early reperfusion might elicit efficient tissue repair, such as intrainfarct fibrosis and peri-infarct astrogliosis, and lead to functional recovery even if it does not prevent neuronal death within the ischemic areas. To examine the precise effects of ischemia-reperfusion in the MCA, we performed tMCAO of various durations, as well as perm...

These findings suggest that insulin resistance is independently associated with poor functional outcome after acute ischemic stroke apart from the risk of short-term stroke recurrence or mortality.

Pericytes are mural cells abundantly present in cerebral microvessels and play important roles, including the formation and maintenance of the blood-brain barrier. Nox4 is a major source of reactive oxygen species in cardiovascular cells and modulate cellular functions, particularly under pathological conditions. In the present study, we found that the expression of Nox4 was markedly induced in microvascular cells, including pericytes, in peri-infarct areas after middle cerebral artery occlusion stroke models in mice. The upregulation of Nox4 was greater in a permanent middle cerebral artery occlusion model compared with an ischemia/reperfusion transient middle cerebral artery occlusion model. We performed permanent middle cerebral artery occlusion on mice with Nox4 overexpression in pericytes (Tg-Nox4). Infarct volume was significantly greater with enhanced reactive oxygen species production and blood-brain barrier breakdown in peri-infarct areas in Tg-Nox4, compared with littermate controls. In cultured brain pericytes, Nox4 was significantly upregulated by hypoxia and was promptly downregulated by reoxygenation. Phosphorylation of NFkB and production of matrix metalloproteinase 9 were significantly increased in both cultured pericytes overexpressing Nox4 and in periinfarct areas in Tg-Nox4. Collectively, Nox4 is upregulated in pericytes in peri-infarct areas after acute brain ischemia and may enhance blood-brain barrier breakdown through activation of NFkB and matrix metalloproteinase 9, thereby causing enlargement of infarct volume.

Visual Abstract Significance StatementPericyte-mediated fibrotic tissue repair is a major histological change within the infarct area during the subacute phase after ischemic stroke. Whether fibrotic repair is beneficial or detrimental to post-stroke functional recovery is highly debated. Here, we demonstrate that inhibition of fibrotic repair in mice by heterozygous deletion of platelet-derived growth factor receptor b (PDGFRb ) (Pdgfrb 1/-) significantly attenuates functional recovery after ischemic stroke. Pericyte-derived PDGFRb -positive cells within the infarct area produced trophic factors that activated astrocytes, thereby enhancing peri-infarct astrogliosis. Furthermore, astrocytes, conditioned with PDGF-BB-stimulated pericyte culture medium, promoted oligodendrocyte (OL) differentiation and a myelinating response. Peri-infarct oligodendrogenesis and re-myelination within areas of astrogliosis was significantly attenuated in Pdgfrb 1/mice. Pericyte-mediated tissue repair is beneficial for post-stroke functional recovery and is a potential therapeutic target.March/April 2020, 7(2) ENEURO.0474-19.2020 1-20Research Article: Theory/New Concepts tioned medium (PCM), particularly when treated with platelet-derived growth factor subunit B (PDGFB) homodimer (PDGF-BB; PCM/PDGF-BB), activated STAT3 and enhanced the proliferation and activity of cultured astrocytes. Although peri-infarct proliferation of oligodendrocyte (OL) precursor cells (OPCs) was induced promptly after pMCAO regardless of intrainfarct repair, OPC differentiation and remyelination were significantly attenuated in Pdgfrb 1/mice. Consistently, astrocyte-CM (ACM) promoted OPC differentiation and myelination, which were enhanced remarkably by adding PCM/PDGF-BB to the medium. Post-stroke functional recovery correlated well with the extent and process of intrainfarct repair and peri-infarct oligodendrogenesis. Overall, pericyte-mediated intrainfarct fibrotic repair through PDGFRb may promote functional recovery through enhancement of peri-infarct oligodendrogenesis as well as astrogliosis after acute ischemic stroke.