Elsevier

Neuroscience Letters

Volume 565, 17 April 2014, Pages 47-52
Neuroscience Letters

Mini review
Astrocytic therapies for neuronal repair in stroke

https://doi.org/10.1016/j.neulet.2013.10.055Get rights and content

Highlights

  • Astrocytes are an under-investigated area of therapeutics for stroke recovery.

  • Changes in astrocytes may help or hurt neurons acutely after stroke.

  • Astrocytic responses promote or inhibit neural repair long-term.

  • Targets and times of astrocyte-directed intervention in stroke are discussed.

Abstract

Stroke is a leading cause of disability and death worldwide. Much of the work on improving stroke recovery has focused on preventing neuronal loss; however, these approaches have repeatedly failed in clinical trials. Conversely, relatively little is known about the mechanisms of repair and recovery after stroke. Stroke causes an initial process of local scar formation that confines the damage, and a later and limited process of tissue repair that involves the formation of new connections and new blood vessels. Astrocytes are central to both scar formation and to tissue repair after stroke. Astrocytes regulate the synapses and blood vessels within their cellular projections, or domain, and both respond to and release neuroimmune molecules in response to damage. Despite this central role in brain function, astrocytes have been largely neglected in the pursuit of effective stroke therapeutics. Here, we will review the changes astrocytes undergo in response to stroke, both beneficial and detrimental, and discuss possible points of intervention to promote recovery.

Introduction

Stroke is a leading cause of disability and death worldwide, affecting almost 800,000 people every year in the United States alone [14]. Eighty-seven percent of strokes are ischemic, in which blood flow to the brain is reduced; the remaining 13% are hemorrhagic, in which a vessel ruptures and blood accumulates in the brain. Because of its higher prevalence and the widespread availability of validated animal models, most research efforts have focused on ischemic stroke; this review will take the same approach. Many neurons die within a few hours after stroke; therefore, considerable effort has been devoted to the development of drugs that would confer neuroprotection when delivered shortly after stroke. While this strategy has shown promise in animal models, it has failed in clinical trials [38]. One possible explanation for this failure is that neuronal survival alone may be insufficient to promote recovery. Therefore, in recent years there has been an increased focus on the roles of astrocytes in stroke.

Astrocytes play a number of key roles in a properly functioning nervous system. Astrocytes are crucial in coordinating changes in vascular tone in response to neuronal activity; removing excess glutamate from the synaptic cleft, limiting transmitter spillover and preventing excitotoxicity; aiding in the formation and integrity of the blood–brain barrier (BBB); promoting synaptogenesis; and responding to and releasing pro- and anti-inflammatory molecules [42]. In stroke, all of these activities are affected. Here, we will review the changes astrocytes undergo after stroke, the beneficial and detrimental consequences these changes have for recovery, and the ways in which astrocytic responses may be modulated to promote repair and recovery. Because treatments administered before or at the time of ischemia are impractical for clinical translation, we will focus on systems in which post-ischemic modulation shows promise.

The studies described here encompass several stroke models [11]. In cell culture, stroke is modeled through oxygen/glucose deprivation (OGD). The primary model used in vivo is middle cerebral artery occlusion (MCAO) in rodents, which produces focal ischemia. MCAO can be transient (tMCAO, generally ranging from 30 min to several hours), or permanent (pMCAO). Another common model is photothrombotic stroke: a photosensitive dye is injected intraperitoneally, followed by localized stereotaxic illumination through the skull. This causes photooxidation within blood vessels, resulting in localized damage. Other models include microsphere injection, which causes a number of small infarcts throughout the brain, and four-vessel occlusion, in which the vertebral arteries are electrocauterized and the carotid arteries are temporarily clamped, producing global ischemia [34]. Astrocytic responses play crucial roles in all of these models, as discussed below. While we will not discuss hemorrhagic stroke here, due to its less prevalent and less studied nature, several recent papers have begun to explore the role of astrocytes in hemorrhagic stroke models [29], [43].

Section snippets

Reactive astrocytosis

Reactive astrocytosis refers to the changes astrocytes undergo in response to injury or disease. It is a complex and gradated process, ranging from minor changes in gene expression to cell hypertrophy to astrocyte proliferation and scar formation [41]. The process begins almost immediately after injury. While minor forms of reactive astrocytosis can resolve over time, more severe changes, such as scar formation, can be permanent. The extent to which reactive astrocytosis is beneficial vs.

Excitotoxicity

One early potential points of intervention in stroke is reduction of excitotoxicity in the peri-infarct region. The peri-infarct region is the tissue immediately adjacent to the infarct core that can be incorporated into the core over time but also has potential to recover. The extent to which the peri-infarct region withstands further damage likely influences stroke severity and recovery potential [52]. One way in which ischemic damage spreads throughout neuronal tissue is via excitotoxicity,

Astrocyte proliferation

One sign of severe reactive astrocytosis is astrocyte proliferation [41]. With time, these astrocytes can help form a scar around the infarct, sealing off the site and preventing the spread of damaging molecules to intact tissue; however, this scar can also limit the extent of axonal outgrowth and regeneration. The beneficial or detrimental effects of astrocyte proliferation remain a subject of active study. In some cases astrocyte proliferation has been shown to be protective. Newly-born

Neuroinflammation

Astrocytes both respond to and produce immune molecules like cytokines and chemokines, of both pro- and anti-inflammatory natures [6]. Of the genes increased by fourfold or more in reactive astrocytes one day after tMCAO, a quarter of them are involved in immune response [49]. Interestingly, astrocytic dopamine receptors play a key role in the control of neuroinflammation [40]. Activation of the astrocytic dopamine D2 receptor (DRD2) suppresses neuroinflammation in injury by inducing production

Angiogenesis and BBB repair

Astrocytes may also mediate stroke recovery through increased angiogenesis and BBB repair. The BBB is disrupted for up to two weeks after stroke [1]; while stroke induces formation of new vessels, many are leaky and do not persist long-term [48]. Astrocytic secretion of Sonic hedgehog (Shh) promotes BBB formation and integrity in vivo, in both development and adulthood [5], while Shh release from cultured astrocytes mediates angiogenesis after OGD [19]. Shh induces upregulation of astrocytic

Synaptogenesis and axonal sprouting

Astrocytes are also important in the formation of the new synapses that are necessary for stroke recovery. In addition to the role of thrombospodin-4 in astrocyte proliferation and vessel stability after stroke [9], other Thbs proteins are involved in neural repair processes. Astrocytic secretion of Thbs 1 and 2 promotes synaptogenesis [12], and is upregulated after pMCAO in mice. Additionally, Thbs-1/2 knockouts show defects in post-stroke synaptogenesis and axonal sprouting, indicating that

Astrocyte transplantation

To explore the role of astrocyte-specific transplants in ischemia, Jiang et al. [20] differentiated human ESCs into astrocytes using two different progenitor populations, Olig2+ versus Olig2− neural progenitor cells, and transplanted them into rats that had undergone four-vessel occlusion to produce global cerebral ischemia six hours previously. Transplantation with either group decreases neuronal loss and improves behavioral recovery; however, the Olig2+-astrocytes are more efficacious than

Conclusions

Astrocytes undergo a number of changes in response to stroke, affecting virtually all astrocytic functions. Many of these changes are beneficial and improve recovery, including the release of angiogenic molecules and upregulation of growth factors and other synaptogenic proteins. However, other astrocytic changes are clearly detrimental to recovery, including increased excitotoxicity via the downregulation of GLT-1 and the release of ephrin-A5 to inhibit axonal outgrowth (Fig. 1). Still other

Acknowledgement

This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

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