Cerebral White Matter Is Highly Vulnerable to Ischemia

Pantoni, Leonardo; García, Julio Herrero; Gutiérrez, Jorge

doi:10.1161/01.str.27.9.1641

Cited by 563 publications

(428 citation statements)

References 28 publications

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“…Although ischemic lesions and damage have been observed using MRI techniques, direct measurement of tissue pO 2 in the WM has not been explored and the effects that ischemia exerts on WM have been seldom studied. [28][29][30] Using the unique capability of EPR oximetry combined with LiPc to measure localized interstitial pO 2 in living animals, we were able to assess cerebral pO 2 in the WM of rats in vivo, for the first time, over a longitudinal study.…”

Section: Discussionmentioning

confidence: 99%

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Weaver

Jalal

Yang

et al. 2014

J Cereb Blood Flow Metab

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Small vessel disease is associated with white-matter (WM) magnetic resonance imaging (MRI) hyperintensities (WMHs) in patients with vascular cognitive impairment (VCI) and subsequent damage to the WM. Although WM is vulnerable to hypoxic-ischemic injury and O 2 is critical in brain physiology, tissue O 2 level in the WM has not been measured and explored in vivo. We hypothesized that spontaneously hypertensive stroke-prone rat (SHR/SP) fed a Japanese permissive diet (JPD) and subjected to unilateral carotid artery occlusion (UCAO), a model to study VCI, would lead to reduced tissue oxygen (pO 2 ) in the deep WM. We tested this hypothesis by monitoring WM tissue pO 2 using in vivo electron paramagnetic resonance (EPR) oximetry in SHR/SP rats over weeks before and after JPD/UCAO. The SHR/SP rats experienced an increase in WM pO 2 from 9 to 12 weeks with a maximal 32% increase at week 12, followed by a dramatic decrease in WM pO 2 to near hypoxic conditions during weeks 13 to 16 after JPD/UCAO. The decreased WM pO 2 was accompanied with WM damage and hemorrhages surrounding microvessels. Our findings suggest that changes in WM pO 2 may contribute to WM damage in SHR/SP rat model, and that EPR oximetry can monitor brain pO 2 in the WM of small animals. Keywords: brain oxygen; EPR oximetry; vascular cognitive impairment; white matter INTRODUCTION Brain cells poorly tolerate hypoxia, and even short periods of low oxygen (O 2 ) can initiate molecular pathways that are lethal to cells in both the gray and white matter (WM). Deep WM is a common site of hypoxic/ischemic injury in the elderly where it is associated with cognitive decline, gait disturbances, and focal ischemia leading to vascular cognitive impairment (VCI). Magnetic resonance imaging (MRI) reveals white-matter hyperintensities (WMHs) in the elderly located in the periventricular and subcortical regions, and considered to be due to strokes and secondary small vessel disease. An alternative mechanism is that the deep WM is vulnerable to hypoxia for a variety of reasons. Studies in humans suggest that there is impairment in the ability of the deep WM to respond to increased demand by raising cerebral blood flow or O 2 . 1 Although glutamate mediated excitotoxicity, inflammatory cytokines, and protease activation result in oligodendrocyte death in acute ischemic injury, the pathophysiology of WM injury in chronic vascular disease has not been fully explored. 2 Small vessel disease is associated with WMHs in patients with VCI; damage to small vessels causes an inflammatory response with disruption in the blood-brain barrier (BBB) associated with expression of matrix metalloproteinases (MMPs) and subsequent damage to the WM. Vascular dementia patients show expression of MMPs in regions of loss of myelin. [3][4][5]

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Section: Discussionmentioning

confidence: 99%

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Weaver

Jalal

Yang

et al. 2014

J Cereb Blood Flow Metab

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“…In general, oligodendrocyte damage, including swelling and vacuolization, occurs after the BBB breakdown, and then, changes in axon/myelin structures are observed due to the fragmentation of myelin. [45][46][47] On the contrary, the number of OPCs increases in the ischemic penumbra after MCAO, which leads to the proliferation of immature (nonmyelinated) oligodendrocytes. 46,48,49 The responses of oligodendrocyte lineage cells after ischemia may be affected by comorbidities, such as hypertension or diabetes.…”

Section: Rat/mouse Model Of Middle Cerebral Artery Occlusionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

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“…Oligodendrocyte damage is central to loss of function in ischemic white matter injury and is thought to result from glutamate-mediated excitotoxicity (Pantoni et al, 1996;Tekkok and Goldberg, 2001;Dewar et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Functional glutamate transport in rodent optic nerve axons and glia

Arranz

Hussein

Alix

et al. 2008

Glia

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Glutamate uptake and potential release via Na + -dependent glutamate transporters is crucial to CNS function and to various forms of injury. Evidence for glutamatemediated damage of oligodendroglia somata and processes in white matter suggests that glutamate regulation in white matter is of particular clinical importance. The expression of glutamate transporters was examined in developing mouse and mature mouse and rat white matter using immuno-histochemistry and immuno-electron microscopy. EAAC1 was the major glutamate transporter detected in oligodendroglia cell membranes in both neonatal and mature optic nerve while GLT1 was the most heavily expressed transporter in the membranes of astrocytes. Both EAAC1 and GLAST were also seen in adult astrocytes but there was little membrane expression of either in the neonate. GLAST, EAAC1 and GLT1 were expressed in neonatal axons with significant amount of GLT1 present in the axolemma, while in mature axons EAAC1 was abundant at the node of Ranvier. Functional glutamate transport was probed in developing mouse optic nerve revealing Na + -dependent, TBOA-blockable uptake of D-aspartate in astrocytes, axons and oligodendrocytes. The data show that in addition to oligodendroglia and astrocytes, axons represent a significant potential sink and source for extracellular glutamate in white matter.

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Cerebral White Matter Is Highly Vulnerable to Ischemia

Cited by 563 publications

References 28 publications

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Functional glutamate transport in rodent optic nerve axons and glia

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