Mini reviewAstrocytic therapies for neuronal repair in stroke
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.
References (52)
- et al.
Neuroprotection from stroke in the absence of MHCI or PirB
Neuron
(2012) - et al.
Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse
Exp. Neurol.
(2012) - et al.
Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats
Neurochem. Int.
(2011) - et al.
Riluzole elevates GLT-1 activity and levels in striatal astrocytes
Neurochem. Int.
(2012) Rodent models of focal stroke: size, mechanism, and purpose
NeuroRx
(2005)- et al.
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Cell
(2005) - et al.
Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke
Exp. Neurol.
(2013) - et al.
Targeting Eph receptors with peptides and small molecules: progress and challenges
Semin. Cell Dev. Biol.
(2012) - et al.
Investigational therapies for ischemic stroke: neuroprotection and neurorecovery
Neurotherapeutics
(2011) - et al.
Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study
Lancet
(2001)
Molecular dissection of reactive astrogliosis and glial scar formation
Trends Neurosci.
Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia
Exp. Neurol.
Effects of dexmedetomidine on the release of glial cell line-derived neurotrophic factor from rat astrocyte cells
Neurochem. Int.
Thrombospondin-based antiangiogenic therapy
Microvasc. Res.
Behavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia
Exp. Neurol.
Targeting astrocytes for stroke therapy
Neurotherapeutics
Dynamic analysis of the blood–brain barrier disruption in experimental stroke using time domain in vivo fluorescence imaging
Mol. Imaging
Role, indications and controversies of levodopa administration in chronic stroke patients
Eur. J. Phys. Rehabil. Med.
Perlecan domain V modulates astrogliosis in vitro and after focal cerebral ischemia through multiple receptors and increased nerve growth factor release
Glia
The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence
Science
Astrocytes: targets for neuroprotection in stroke
Cent. Nerv. Syst. Agents Med. Chem.
Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4
Nature
The neurorestorative benefit of GW3965 treatment of stroke in mice
Stroke
Heart disease and stroke statistics – 2013 update: a report from the American Heart Association
Circulation
Membrane lipid rafts and their role in axon guidance
Adv. Exp. Med. Biol.
Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke
PLoS ONE
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