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Contents
9(1): Pp. 10 - 19
Marie-Francoise Ritz, Caspar Grond-Ginsbach, Stefan Engelter and Philippe Lyrer
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Cerebral small vessel disease (SVD) is an important cause of stroke, cognitive decline and vascular dementia (VaD). It is associated with diffuse white matter abnormalities and small deep cerebral ischemic infarcts. The molecular mechanisms involved in the development and progression of SVD are unclear. As hypertension is a major risk factor for developing SVD, Spontaneously Hypertensive Rats (SHR) are considered an appropriate experimental model for SVD. Prior work suggested an imbalance between the number of blood microvessels and astrocytes at the level of the neurovascular unit in 2-month-old SHR, leading to neuronal hypoxia in the brain of 9-month-old animals. To identify genes and pathways involved in the development of SVD, we compared the gene expression profile in the cortex of 2 and 9-month-old of SHR with age-matched normotensive Wistar Kyoto (WKY) rats using microarray-based technology. The results revealed significant differences in expression of genes involved in energy and lipid metabolisms, mitochondrial functions, oxidative stress and ischemic responses between both groups. These results strongly suggest that SHR suffer from chronic hypoxia, and therefore are unable to tolerate ischemia-like conditions, and are more vulnerable to highenergy needs than WKY. This molecular analysis gives new insights about pathways accounting for the development of SVD.
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6(4): Pp. 279 - 287
Marie-Françoise Ritz, Felix Fluri, Stefan T. Engelter, Nicole Schaeren-Wiemers and Philippe A. Lyrer
[Open Access Plus] |
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Cerebral small vessel disease (SVD) is a major contributor to dementia in the elderly, and hypertension represents a major cause for developing the disease. However, little is known about its development and progression. Modifications of large cerebral arteries due hypertension are thought to participate to the development of small ischemic infarcts, but the status of the small vessels before the establishment of hypertension is not well defined. Using spontaneously hypertensive rats (SHR) and stroke-prone SHR (SP-SHR) as a models for SVD, we analysed the effect of hypertension on the microvasculature in the cortex and putamen, and on its relationship with astrocytes in animals aged 2 to 9 months. Compared with the normotensive Wistar-Kyoto rats (WKY), the densities of the collagen type IV-positive capillaries were significantly higher in both brain areas of young SHR and SP-SHR. In contrast, the expression of the astrocytic marker GFAP was significantly lower in these animals, whereas astrogliosis was observed after 6 months in their cortex only. To investigate if chronic hypoxia occurs due to the lower number of astrocytes in young SHR and SPSHR, we evaluated the levels of HIF-1.. in both brain regions. The accumulation of HIF-1.. was not observed at the youngest ages, but was apparent in neurons of 9-month-old SHR and SP-SHR. Our results indicate that the brains of young SHR and SP-SHR rats show evidence of cellular imbalance between microvessels and astrocytes at the neurovascular unit that may lead to their higher vulnerability to hypoxic events at older ages.
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6(3): Pp. 204 - 212
Paolo Zamboni, Giuseppe Consorti, Roberto Galeotti, Sergio Gianesini, Erica Menegatti, Giovanna Tacconi and Francesco Carinci
[Open Access Plus] |
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A new nosologic vascular pattern that is defined by chronic cerebrospinal venous insufficiency (CCSVI) has been strongly associated with multiple sclerosis. The picture is characterized by significant obstacles of the main extracranial cerebrospinal veins, the jugular and the azygous system, and by the opening of substitute circles. The significance of collateral circle is still neglected. To the contrary, substitute circles are alternative pathways or vicarious venous shunts, which permit the drainage and prevent intracranial hypertension. In accordance with the pattern of obstruction, even the intracranial and the intrarachidian veins can also become substitute circles, they permit redirection of the deviated flow, piping the blood towards available venous segments outside the central nervous system. We review the complex gross and radiological anatomy of collateral circulation found activated by the means of EchoColor-Doppler and selective venography in the event of CCSVI, focusing particularly on the suboccipital cavernous sinus (SCS), the condylar venous system, the pterygoid plexus, the thyroid veins, and the emiazygous-lumbar venous anastomosis with the left renal vein.
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5(4): Pp. 260 - 265
Erica Menegatti and Paolo Zamboni
[Open Access Plus] |
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Physiologic functioning of the cerebrovenous system is indispensable for maintaining normal brain function. However, in contrast to the cerebroarterial system, the cerebral venous return is not routinely investigated. Combined high-resolution echo-colour-Doppler (ECD) and transcranial colour coded Doppler sonography (TCCS) represents an ideal method to investigate the haemodynamics of cerebral venous return. TCCS-ECD is noninvasive, repeatable, costeffective and permits to investigate the cerebral venous outflow in its dependence upon changes in posture and the alternating pressure gradients of the thoracic pump. Several authors reported normal parameters concerning related aspects of cerebral venous return. However, there is no ECD-TCCS standardization of what can be considered a normal venous return. The authors have summarized the current knowledge of the Doppler haemodynamics of the cerebrovenous system and propose a list of reproducible clinical parameters for its sonographic evaluation. In future, the development of this diagnostic technique could be of singular interest in iron-related inflammatory and neurodegenerative disorders like multiple sclerosis.
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5(2): Pp. 118 - 124
Lixian Jiang, Mary Newman, Samuel Saporta, Ning Chen, Cyndy Sanberg, Paul R. Sanberg and Alison E. Willing
[Open Access Plus] |
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Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein (MIP-1α) are implicated in monocyte infiltration into the central nervous system (CNS) under pathological conditions. We previously showed that in vivo human umbilical cord blood cells (HUCB) migrate toward brain injury after middle cerebral artery occlusion (MCAO). We hypothesized that MCP-1 and MIP-1α may participate in the recruitment of HUCB towards the injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and 24 hours later the production of MCP-1 and MIP-1α in the brain was examined with immunohistochemistry, ELISA, and western blotting. The chemotactic effect of MCP-1 and MIP-1α, and the expression of MCP-1 receptor CCR2 and MIP-1α receptor CCR1, CCR5 on the surface of HUCB were also examined. MCP-1 and MIP-1α expression were significantly increased in the ischemic hemisphere of brain, and significantly promoted HUCB cell migration compared to the contralateral side. This cell migration was neutralized with polyclonal antibodies against MCP-1 or MIP-1α. Also chemokine receptors were constitutively expressed on the surface of HUCB cells. The data suggested that the increased chemokines in the ischemic area can bind cell surface receptors on HUCB, and induce cell infiltration of systemically delivered HUCB cells into the CNS in vivo.
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4(4): Pp. 274 - 279
Zhongmin Xiang, Sunil Thomas and Giulio Pasinetti
[Open Access Plus] |
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Cyclooxygenase-2 (COX-2) is up-regulated during ischemia. However, the role of COX-2 in neuronal injury is still unclear. In this study we tested whether neuronal overexpression of human COX-2 in a transgenic mouse model potentiates neuronal injury after global ischemic insult. Further, we tested whether the neuronal injury could be ameliorated by intra-ischemic mild hypothermia (33- 34°C) alone or in combination with diet treatment of rofecoxib, a COX-2 specific inhibitor. Global ischemia with intra-ischemic normothermia (36-37°C) resulted in significantly higher neuronal damage in the CA1 region of hippocampus of transgenic mice than in wild type controls, confirming a deleterious role of COX-2 in ischemic neuronal damage. Hypothermia significantly reduced neuronal damage in both transgenic mice and wild type controls to the same extent, suggesting that the aggravating effect of COX-2 could be largely eliminated by hypothermia. When hypothermia was combined with rofecoxib treatment, neuronal damage was further reduced in response to global ischemia. The results suggest that COX-2 inhibition by prophylactic treatment with rofecoxib coupled with hypothermia at the time of acute stroke insult could be an effective therapeutic approach in early stages of stroke treatment in high risk patients.
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4(4): Pp. 252 - 258
Paolo Zamboni, Erica Menegatti, Ilaria Bartolomei, Roberto Galeotti, Anna Maria Malagoni, Giovanna Tacconi and Fabrizio Salvi
[Open Access Plus] |
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In multiple sclerosis (MS) plaques are known to be venocentric; in addition, MS lesions and peripheral venous disorders share a number of key features. To date, however, despite the anatomical relationship between MS lesions and the venous system, no information on the intracranial venous haemodynamics of MS is available. Eighty-nine consecutive MS patients (58 relapsing-remitting, 31 secondary progressive) matched with 60 controls underwent transcranial color-coded duplex sonography (TCCS). We assessed, in supine as well as in sitting positions, the direction of flow at the activation of the thoracic pump in the deep middle cerebral veins (dMCVs), and in the transverse sinus (TS). In the dMCVs, we also measured peak systolic velocity (PSV), peak diastolic velocity (PDV), as well as the resistance index (RI). Reflux/bidirectional flow rate was significantly higher in the MS population determining also significant differences in PDV, characterized by negative values (16.2±1 cm/sec in controls vs. -1.3 ±2.6 cm/sec in MS, respectively, p < 0.0001). Consequently, RI was dramatically increased in the MS group, affecting impedance of cerebral venous drainage (0.48±0.04 in controls vs. 1.1 ±0.08 in MS, respectively p < 0.0001). Therefore, the detection of reflux directed toward the subcortical grey matter was significantly associated to highest disability scores (p < 0.0001). Our study of MS patients demonstrated significant haemodynamic alterations detected in veins anatomically related to plaque disposition. Our findings should contribute towards understanding the role of altered venous flow and tissue drainage in the MS inflammatory chain, as well as in the neurodegenerative process.
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3(4): Pp. 307 - 325
Fuad Lechin and Bertha van der Dijs
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Both clinical and experimental studies dealing with patients affected by idiopathic or essential hypertension (EH) are devoted to the great deal of physiological, pharmacological and pathological as well as therapeutical issues of EH. However, most articles devoted to EH do not refer to the central nervous system mechanisms underlying this disease and the channels which allow that these mechanisms are funneled to the peripheral autonomic nervous system and trigger this cardiovascular disorder. In the present review article we attempted to reach this target devoted to the central nervous system circuitry involved in the cardiovascular pathophysiology. We postulated that EH depends on the predominance of the binomial A5 noradrenergic (NA) nucleus + median raphe serotonergic (5-HT) nucleus over the (A6)-NA + dorsal raphe- 5HT nuclei. This hypothesis receives additional support from our results obtained throughout the neuropharmacological therapy of this type of neurophysiological disorder. Our therapeutical strategy is addressed to enhance the activity of the (A6)-NA + dorsal raphe-5HT binomial circuitry.
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