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12 LIF as a Therapeutic Target for Ischemic Stroke

12 LIF as a Therapeutic Target for Ischemic Stroke

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The Function of Cytokines in Ischemic Stroke



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activated by LIF (i.e., Akt signaling) as means of circumventing potential issues

with safety and dosing. Since LIF can be released by several cell types following

injury [77, 82, 83], it will be crucial to characterize the sources of endogenous LIF

signaling. Once the temporal and cell-specific responses are uncovered with regard

to LIF signaling, there will be more therapeutic options to mimic the endogenous

protection afforded by this cytokine.



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Part IV



White Matter Injury and Repair in Stroke



Ischemic Injury to White Matter: An AgeDependent Process

Sylvain Brunet, Chinthasagar Bastian, and Selva Baltan



Abbreviations

AMPA/KA

CKA

CNS

GS

KB-R

MON

NCX

NMDAR

OGD

RNS

ROS

WM



AMPA/kainate

7-Chlorokynurenic acid

Central nervous system

Glutamate synthetase

2-[2-[4(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate

Mouse optic nerve

Na+–Ca2+ exchanger

NMDA-type receptors

Oxygen glucose deprivation

Reactive nitrogen species

Reactive oxygen species

White matter



S. Brunet, B.Sc., Ph.D. • S. Baltan, M.D., Ph.D. (*)

Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case

Western Reserve University, 9500 Euclid Avenue (NB21), Cleveland, OH 44195, USA

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation,

9500 Euclid Avenue (NB30), Cleveland, OH 44195, USA

e-mail: brunets@ccf.org; baltans@ccf.org

C. Bastian, M.B.B.S., Ph.D.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation,

9500 Euclid Avenue (NB30), Cleveland, OH 44195, USA

e-mail: bastiac@ccf.org

© Springer International Publishing Switzerland 2016

J. Chen et al. (eds.), Non-Neuronal Mechanisms of Brain Damage

and Repair After Stroke, Springer Series in Translational Stroke Research,

DOI 10.1007/978-3-319-32337-4_16



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Introduction



In the United States, someone experiences a stroke every 40 s [1]. Axonal injury and

dysfunction are responsible for most of the disability observed after a stroke [2] and

aging is one of the most significant risk factors for stroke. The human brain comprises equal proportions of gray matter and white matter (WM) and WM is injured

in most strokes [2]. However, most research efforts have traditionally been dedicated

to protecting the gray matter. While effective in rodents, this approach has failed to

translate to humans. Many reasons may underlie this failure, but major differences

between humans and rodents include the greater proportion of WM in the human

brain and the lack of significant WM involvement following middle cerebral artery

occlusion in rodents, which is one of the most widely used animal models of stroke.

Thus, over the past several years we and others have focused on examining how WM

responds to ischemic injury, with an emphasis on the impact of aging [3–5].



2



WM Is Sensitive to Ischemic Injury



WM axons are dependent on a constant supply of oxygen and glucose to transmit

signals. Central nervous system (CNS) WM electrical function is remarkably tolerant to anoxia [6], while there is regional heterogeneity in the ability to function and

survive anoxia [7]. On the other hand, young adult WM is susceptible to ischemia

induced by combined oxygen and glucose deprivation (OGD, Fig. 1). Mechanisms

underlying ischemic WM injury proved to be unpredictably complex (Fig. 2) [8–

16]. WM is composed of axons, oligodendrocytes, microglia, and astrocytes [2, 17].

Axons are myelinated by oligodendrocytes and exhibit patterns/gaps called nodes

of Ranvier. Astrocytes support axons metabolically and restore the extracellular

ionic environment following axonal activity. Microglia is partly responsible for

immune surveillance. Thus, WM is composed of a complex cellular environment in

which glial cell–cell interactions intricately maintain axon function. During ischemia, WM cellular elements are individually under attack but remain interactive

with each other in intricate mechanisms that are currently under investigation.



3



Mechanisms of WM Ischemic Injury



It is now well-established that ischemia in WM sequentially activates three different

injury pathways: the ionic, the excitotoxic, and the oxidative stress injury pathways.

The ionic pathway attacks axons by collapsing their ionic homeostasis, which is

initiated by the failure of the Na+–K+ pump, cell membrane depolarization, Na+

channel activation, reversal of the Na+/Ca2+ exchanger, and Ca2+ channel activation,

resulting in the accumulation of intracellular Na+ and Ca2+ (Fig. 2, yellow) [18–23].

This increased intracellular Na+ leads to the reversal of the Na+-glutamate transporter and the release of glutamate from astrocytes [16].



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Fig. 1 WM is susceptible to ischemic injury. Axon function is quantified as the area under the

compound action potential (CAP), normalized to control area, and plotted against time. Under normal conditions, CAP area is stable for long periods of time (brown). A 60 min period of OGD gradually depresses CAP area until conduction along axons is completely lost (gray). Restoring oxygen

and glucose leads to ~25 % axon function recovery. Sample traces from control (a), OGD (b), and

recovery (c) periods are shown above the graph (Reproduced in part from Baltan (2014) [18])



Subsequently, the excitotoxic pathway is initiated by an increase in extracellular

glutamate (Fig. 2, green). The excitotoxic pathway mainly targets oligodendrocytes

by overactivating AMPA/KA receptors [11, 14, 16, 24–27] (redox) [28], which

leads to increases in intracellular Na+ and Ca2+ and the activation of downstream

toxic intracellular pathways to mediate WM injury.

In parallel with the excitotoxic pathway, increased extracellular glutamate also leads

to the activation of the oxidative stress pathway (Fig. 2, blue). The oxidative pathway

damages WM components due to the formation of reactive oxygen species (ROS), which

arises because the increased extracellular glutamate competes with cysteine at the glutamate-cysteine pump [29], depleting intracellular cysteine to reduce glutathione levels

[30] and to cause mitochondrial dysfunction. In addition, the increase in intracellular Ca2+

activates NOS to produce nitric oxide [31, 32], which readily reacts with ROS to produce

reactive nitrogen species (RNS). ROS and RNS can then attack multiple cellular elements

(phospholipids, proteins, DNA, RNA) to mediate injury.

The ionic pathway triggers the injury process, which subsequently reverses the

glutamate transporter; however, it is the accumulation of glutamate that dictates the

threshold for irreversible injury. Therefore, if the injury is short and only involves



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Fig. 2 Ischemia activates three pathways to mediate WM injury. Ischemia leads to the activation

of the ionic pathway, which then leads to the sequential activation of the excitotoxic and oxidative

stress pathways, which converge to cause irreversible injury to WM during ischemia. Note that

glutamate release due to reversed Na+-dependent transport dictates the irreversible nature of the

injury. ROS reactive oxygen species (Reproduced in part from Baltan (2009) [2])



the ionic pathway, then the ischemic injury is completely reversible. Unlike gray

matter, this sequential order of events is necessary for the injury to develop, such

that bypassing the ionic pathway and applying exogenous glutamate (or glutamate

analogues) fails to cause WM injury [16].



4



Mouse Optic Nerve: An Ideal Model to Investigate WM



The mouse optic nerve (MON) is ideal for ischemic studies of WM. The optic nerve,

the second cranial nerve, is a purely myelinated central nervous system WM tract

and is sensitive to ischemia and to the aging process [33, 34]. In addition, tissue



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331



Fig. 3 The MON model is ideal for monitoring WM electrical function and cellular architecture.

(a) Use of suction electrodes allows all axons to be stimulated and a CAP to be recorded. Cartoon

of mouse optic nerve between two suction electrodes, where the left suction electrode stimulates

and the right suction electrode records the CAP. Axons are represented in yellow, oligodendrocytes

are in green, and astrocytes are in red. I current. (b) Using cell-specific antibodies, WM axons are

labeled with SMI-31 for neurofilament (green), GFAP for astrocytes (magenta), and APC for

mature oligodendrocyte cell bodies (green). Sytox (+) glial nuclei are in blue. Scale bar = 50 μm for

SMI-31 and GFAP, 10 μm for APC (Reproduced in part from Baltan (2014) [18])



isolation does not require extensive surgical interventions; therefore there is negligible surgical injury, its small diameter allows sufficient glucose diffusion [6, 35],

there are no neurons or synapses to contribute indirectly to the ischemic injury, and

electrical function can be monitored by recording evoked compound action potentials (CAPs). MONs are stable both structurally and electrically for long durations

(18 h) and glial cells and axons retain their native relationships to one another within

a three-dimensional spatial organization (Fig. 3a). Furthermore, the cellular components can reliably be identified using immunohistochemistry (Fig. 3b), glutamate

release can be measured by HPLC [36], proteins of interest can be quantified by

Western blot analysis [3], and intravitreal injections provide a path for axonal



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12 LIF as a Therapeutic Target for Ischemic Stroke

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