Loss of Calcium/Calmodulin-dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP

Ashpole, Nicole M.; Chawla, Aarti; Martin, Matthew; Brustovetsky, Tatiana; Brustovetsky, Nickolay; Hudmon, Andy

doi:10.1074/jbc.m113.466235

Cited by 43 publications

(49 citation statements)

References 98 publications

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“…Astrocytes are involved in maintaining brain integrity in conditions of cerebral ischemia-reperfusion injury. And astrocyte dysfunction during cerebral ischemia may damage the survival ability of neurons [38]. Thus, it is possible that interventions aimed at blocking astrocyte apoptosis could both limit neuron death and promote recovery.…”

Section: Discussionmentioning

confidence: 99%

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Liu

You²,

Tu³

et al. 2015

Cell Physiol Biochem

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Background: There is an increasing interest in the role of astrocytes contributing to the intrinsic bioremediation of ischemic brain injury. The purpose of this study was to disclose the effects and mechanism of midazolam (MDZ) on the proliferation and apoptosis of astrocytes under oxygen glucose deprivation (OGD) condition. Methods: The astrocytes were assigned randomly into four groups: control group, OGD group, OGD+MDZ group, and OGD+MDZ+IL-6 group. The astrocytes were treated with MDZ at dose of 10 μmol/L in OGD+MDZ group. And in OGD+MDZ+IL-6 group, the astrocytes were treated with MDZ at dose of 10μmol/L and IL-6 at dose of 50 ng/mL. MTT assay was used to assess cell proliferation, and cell apoptosis was analyzed by TUNEL apoptosis assay kit and flow cytometry. Furthermore, the expression of JAK2, p-JAK2, STAT3, p-STAT3, Bcl-2, Bax and Caspase-3 proteins were determined by western blotting assay. Results: Astrocytes proliferation was decreased obviously in OGD group, while MDZ could increase astrocytes proliferation under OGD condition. Moreover, OGD could induce apoptosis in astrocytes and MDZ could play an anti-apoptotic role. However, IL-6, a JAK2 activator, could attenuate cell proliferation and anti-apoptotic effects of MDZ in astrocytes. In addition, the expression of Bcl-2 protein in MDZ group increased markedly, while the JAK2/STAT3 signal proteins, Bax and Caspase-3 proteins decreased relative to OGD group. But IL-6 could counteract the anti-apoptotic effects of MDZ. Conclusion: Midazolam has protective effects on the proliferation and apoptosis of astrocytes via JAK2/STAT3 signal pathway in vitro. We firstly disclose the beneficial roles of midazolam in astrocytes under ischemic condition, which may be a rational treatment selection for ischemic cerebral protection.

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Section: Discussionmentioning

confidence: 99%

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Liu

You²,

Tu³

et al. 2015

Cell Physiol Biochem

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“…Primary cultures of astrocytes were derived from postnatal days 2-5 F344 rat pups following previously described methods (2). Briefly, cortical tissue was enzymatically and mechanically digested, resuspended in growth media [DMEM containing 2% NuSerum, 10% fetal bovine serum, penicillin (10 U/ml), streptomycin (10 g/ml), and L-glutamine (29.2 g/ml)] at a density of 2.5 million cells/ml, and seeded on 50 g/ml poly-D-lysine-coated T75-flasks.…”

Section: Measurement Of Cerebral Blood Flow Responses To Whisker Stimmentioning

confidence: 99%

Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase

Tóth

Tarantini

Tucsek

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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177

236

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Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher cortical function, increasing the risk for vascular cognitive impairment. Resveratrol is a polyphenolic compound that exerts significant antiaging protective effects in large vessels, but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24-mo-old) C57BL/6 mice N(ω)-nitro-l-arginine methyl ester-sensitive, nitric oxide-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired compared with those in young (3-mo-old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with downregulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in reactive oxygen species (ROS) production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via downregulation of NADPH oxidase-derived ROS production. Beneficial cerebromicrovascular effects of resveratrol may contribute to its protective effects on cognitive function in aging.

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“…Under conditions of high-frequency neuronal firing, there is also a decline in extracellular Ca 2+ (Heinemann et al, 1977;Borst and Sakmann, 1999;Engelborghs et al, 2000;Stanley, 2000;Massimi and Amzica, 2001;Rusakov and Fine, 2003;Engel et al, 2012;Torres et al, 2012;Jimenez-Pacheco et al, 2013) that can both trigger ATP release from astrocytes (Torres et al, 2012) and increase the activity of P2X7 receptors, since divalent ions (like Ca 2+ ) are negative modulators of this purinoceptor subtype (Virginio et al, 1997;Jiang, 2009;Yan et al, 2011) rendering P2X7 receptor activation an intense but shortlived modulatory capacity over Na + -coupled high-affinity transport energy. Such low-affinity high-capacity mechanism may precede other forms of modulation involving activation of adenosine receptors following extracellular ATP breakdown (Nishizaki et al, 2002;Cristo´va˜o-Ferreira et al, 2009) as well as low intracellular Ca 2+ concentration (micromolar levels) modulation of both GABA and glutamate high-affinity transporters through enzymatic signaling cascades (Casado et al, 1993;Corey et al, 1994;Gonc¸alves et al, 1997;Beckman et al, 1998;Cordeiro et al, 2000Cordeiro et al, , 2003Ashpole et al, 2013). It is, therefore, tempting to focus our research efforts on the energetic component of Na + -coupled transport by performing most of the experiments in the absence of extracellular Ca 2+ .…”

Section: Introductionmentioning

confidence: 97%

P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

et al. 2015

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Loss of Calcium/Calmodulin-dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP

Cited by 43 publications

References 98 publications

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase

P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

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