Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro

Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 03/2010; 5(3):e9532. DOI: 10.1371/journal.pone.0009532
Source: PubMed


Astrocytes exert a wide variety of functions in health and disease and respond to a wide range of signaling pathways, including members of the Janus-kinase signal transducers and activators of transcription (Jak-STAT) family. We have recently shown that STAT3 is an important regulator of astrocyte reactivity after spinal cord injury in vivo[1].
Here, we used both a conditional gene deletion strategy that targets the deletion of STAT3 selectively to astrocytes (STAT3-CKO), and a pharmacological inhibitor of JAK-2, AG490, in cultured astrocytes in vitro, to investigate potential functions and molecules influenced by STAT3 signaling in relation to mitochondrial function and oxidative stress. Our findings show that the absence of STAT3 signaling in astrocytes leads to (i) increased production of superoxide anion and other reactive oxygen species and decreased level of glutathione, (ii) decreased mitochondrial membrane potential and decreased ATP production, and (iii) decreased rate of cell proliferation. Many of the differences observed in STAT3-CKO astrocytes were distinctly altered by exposure to rotenone, suggesting a role for complex I of the mitochondrial electron transport chain. Gene expression microarray studies identified numerous changes in STAT3-CKO cells that may have contributed to the identified deficits in cell function.
Taken together, these STAT3-dependent alterations in cell function and gene expression have relevance to both reactive gliosis and to the support and protection of surrounding cells in neural tissue.

Download full-text


Available from: Michael V Sofroniew
  • Source
    • "Astrocytes and pericytes helps in differentiation as well as maintenance of BBB function. Astrocytes are most abundant non-neuroncells and play many essential roles in the healthy central nervous system (CNS), including biochemical support of endothelial cells which form the blood-brain barrier, regulation of blood flow, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance and a principal role in the repair and scarring process of the brain and spinal cord following traumatic injuries (Sarafian et al., 2010). Pericytes are perivascular cells which are important for the maturation, remodeling and maintenance of the vascular system via the secretion of growth factors or modulation of the extracellular matrix. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many neurotherapeutics are unsuccessful in treating CNS disorders because they cannot be effectively drug delivered. Drug delivery to the brain is a challenge even though there is relatively high blood flow. There are two physiological barriers likes blood-brain barrier and blood-cerebrospinal fluid barrier which separates the brain from its blood supply controlling the transport of compounds. Many of the brain or CNS associated diseases remain untreated by effective therapies. This is not because there is a lack of candidate drugs but due to the inability of many therapeutic molecules to cross the BBB, the BCSFB or other specialized CNS barriers to reach the specific areas of brain. Hence there is a need in the modern approaches and present insights into using ligand conjugation and nanotechnology to target the BBB via different transport pathways and mechanisms. The field of novel drug delivery system has fully emerged and came into existence as an ideal approach of drug targeting and delivery to brain. The new approaches of drug delivery to brain help in successful transporting drugs across the BBB.
    Full-text · Article · May 2015 · Journal of Applied Pharmaceutical Science
  • Source
    • "Rotenone has been widely used in neurotoxic models as it causes molecular and cellular processes similar to those observed in neurodegenerative disease like PD (Cabezas et al. 2012; de Oliveria et al. 2009, 2011; Greenamyre et al. 2003; Valverde et al. 2008). Rotenone has a direct effect on mitochondrial functions, including an interference with the electron transport chain, loss of mitochondrial membrane's potential, and ATP generation (Greenamyre et al. 2003; Sarafian et al. 2010; Simpkins et al. 2010). These cellular processes in turn cause the release of cytochrome C from the inner mitochondrial membrane, thus activating apoptotic effectors such as Bid, Bax, caspase 3, and 9 in neurons (Gyulkhandanyan et al. 2003; Swarnkar et al. 2012; Tiwari et al. 2011; Wang et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rotenone is one of the most-studied neurotoxic substances as it induces oxidative stress processes both in cellular and animal models. Rotenone affects ATP generation, reactive oxygen species (ROS) production, and mitochondrial membrane potential in neurons and astrocyte-like cells. Previous epidemiologic studies have supported the role of neurotrophic factors such as BDNF and GDNF in neuroprotection mainly in neurons; however, only very few studies have focused on the importance of astrocytic protection in neurodegenerative models. In the present study, we assessed the neuroprotective effects of PDGF-BB against toxicity induced by rotenone in the astrocytic-like model of T98G human glioblastoma cell line. Our results demonstrated that pretreatment with PDGF-BB for 24 h increased cell viability, preserved nuclear morphology and mitochondrial membrane potential following stimulation with rotenone, and reduced ROS production nearly to control conditions. These observations were accompanied by important morphological changes induced by rotenone and that PDGF-BB was able to preserve cellular morphology under this toxic stimuli. These findings indicated that PDGF-BB protects mitochondrial functions, and may serve as a potential therapeutic strategy in rotenone-induced oxidative damage in astrocytes.
    Full-text · Article · Dec 2014 · Neurotoxicity Research
  • Source
    • "One major benefit brought by reactive astrocytes is the neuroprotection mediated by the degradation of amyloid-beta peptides (Koistinaho et al., 2004) and the release of neurotrophic factors and growth supportive factors, such as brain-derived neurotrophic factor (BDNF) (Ikeda et al., 2001), ciliary neurotrophic factor (CNTF) (Lee et al., 1998), laminin (Costa et al., 2002; Frisen et al., 1995), and fibronectin (Tom et al., 2004). By clearing excitotoxic glutamate with increased expression of the glial transporters such as Glu-Asp transporter (GLAST) and glial glutamate transporter 1 (GLT-1) (Bush et al., 1999; Rothstein et al., 1996; Swanson et al., 2004), reactive astrocytes protect the spared neurons from oxidative stress (Chen et al., 2001; Sarafian et al., 2010; Shih et al., 2003; Swanson et al., 2004; Vargas et al., 2008) and NH4+ toxicity (Rao et al., 2005). Moreover, selective proliferation of juxtavascular astrocytes repairs the integrity of the BBB and BSB (Bardehle et al., 2013; Bush et al., 1999) and restricts the spread of inflammation (Bardehle et al., 2013; Bush et al., 1999; Myer et al., 2006; Voskuhl et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinal cord injury (SCI) often causes incurable neurological dysfunction because axonal regeneration in adult spinal cord is rare. Astrocytes are gradually recognized as being necessary for the regeneration after SCI as they promote axonal growth under both physiological and pathophysiological conditions. Heterogeneous populations of astrocytes have been explored for structural and functional restoration. The results range from the early variable and modest effects of immature astrocyte transplantation to the later significant, but controversial, outcomes of glial-restricted precursor (GRP)-derived astrocyte (GDA) transplantation. However, the traditional neuron-centric view and the concerns about the inhibitory roles of astrocytes after SCI, along with the sporadic studies and the lack of a comprehensive review, have led to some confusion over the usefulness of astrocytes in SCI. It is the purpose of the review to discuss the current status of astrocyte transplantation for SCI based on a dialectical view of the context-dependent manner of astrocyte behavior and the time-associated characteristics of glial scarring. Critical issues are then analyzed to reveal the potential direction of future research.
    Full-text · Article · Aug 2014 · Brain Research Bulletin
Show more