Models That Matter: White Matter Stroke Models

Abstract

Summary Stroke is a devastating neurological disease with limited functional recovery. Stroke affects all cellular elements of the brain and impacts areas traditionally classified as both gray matter and white matter. In fact, stroke in subcortical white matter regions of the brain accounts for approximately 30% of all stroke subtypes, and white matter injury is a component of most classes of stroke damage. However, most basic scientific information in stroke cell death and neural repair relates principally to neuronal cell death and repair. Despite an emerging biological understanding of white matter development, adult function, and reorganization in inflammatory diseases, such as multiple sclerosis, little is known of the specific molecular and cellular events in white matter ischemia. This limitation stems in part from the difficulty in generating animal models of white matter stroke. This review will discuss recent progress in studies of animal models of white matter stroke, and the emerging principles of cell death and repair in oligodendrocytes, axons, and astrocytes in white matter ischemic injury.Key Words Ischemia . oligodendrocyte . oligodendrocyte progenitor cell . mouse . rat . axoglial unit . endothelin Clinical Aspects of White Matter StrokeSubcortical white matter stroke constitutes 15 to 25% of all stroke subtypes [1,2]. These lesions encompass small infarcts in deep penetrating vessels in the brain [3][4][5]. In traditional stroke subtyping, subcortical or white matter stroke includes infarcts in the white matter deep to the cortex in humans, and also small basal ganglia, thalamus, and brainstem strokes or "lacunar" infarctions. Recent studies indicate distinct clinicopathological entities between subcortical white matter versus brainstem, thalamic, or basal ganglia lacunar infarctions. Subcortical white matter infarctions are more closely related to microvascular stroke risk factors, such as hypertension and diabetes, and appear to involve a spectrum, especially as seen in magnetic resonance imaging (MRI), of ischemic white matter hyperintensities to small necrotic cavities [4]. Pathologically, white matter strokes progress and enlarge: repeat MRI imaging shows that new white matter strokes develop within pre-existing lesions and also are associated with adjacent lesions in 71% of cases [4]. Interestingly, this tissue progression from recent MRI studies resembles the original description of the pathology of lacunar infarcts from Dechambre in 1838 of a central lesion of "softening," which is then absorbed to produce the necrotic cavity [6]. This current and historical perspective indicates that the specific ischemic focus in white matter is distinct from that of large vessel disease, and is a progressive focal lesion.Subcortical white matter stroke has devastating clinical consequences. This was first cohesively presented by Pierre Marie, who described the accumulation of small clinical strokes into a progressive state, an état lacunaire, of motor slowing and global intellectual deterioration [7...

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

“…1 E-G), and bloodbrain barrier (BBB) breakdown (Fig. 1B) in processes that are shared between the mouse and the human condition (13)(14)(15)(16). Because white matter ischemic lesions progress in humans (17), we assessed progenitor responses after white matter stroke in a stepwise approach.…”

Lasting Pure-Motor Deficits after Focal Posterior Internal Capsule White-Matter Infarcts in Rats

“…32 For these reasons, the model is better suited to investigate recovery in chronic stages, as well as ischemic white-matter injury progression and repair after the hyperacute stage (e.g., 412 hours), which differs from gray matter given the predominantly oligodendrocyte and axon injury rather than neuronal cell bodies. 9 Functional outcome is a primary end point after stroke, but repair and recovery after white-matter stroke are still poorly understood due to a lack of experimental models that yield reproducible and lasting functional deficits. Therefore, our model represents a critical improvement to facilitate preclinical investigations of novel therapeutic interventions targeting recovery after white-matter injury.…”

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…In vitro data indicate that neurons are the most sensitive to oxygen/glucose deprivation, followed by endothelial cells, astrocytes, and microglia [8]. As with neurons, glutamate signaling may play a role in oligodendrocyte cell death after stroke, through both N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtypes of the glutamate receptor [9]. In rodent stroke models, oligodendrocytes survive longer than neurons [10].…”