A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

Clare Howarth, Brad Sutherland, Hyun B Choi, Chris Martin, Barbara Lykke Lind, Lila Khennouf, Jeffrey M LeDue, Janelle M P Pakan, Rebecca W Y Ko, Graham Ellis-Davies, Martin Lauritzen, Nicola R Sibson, Alastair M Buchan, Brian A MacVicar, Clare Howarth, Brad Sutherland, Hyun B Choi, Chris Martin, Barbara Lykke Lind, Lila Khennouf, Jeffrey M LeDue, Janelle M P Pakan, Rebecca W Y Ko, Graham Ellis-Davies, Martin Lauritzen, Nicola R Sibson, Alastair M Buchan, Brian A MacVicar

Abstract

Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mmHg variation in arterial CO2 changes CBF by 3%-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2 (PgE2) plays a key role for cerebrovascular CO2 reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57BL/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased astrocyte [Ca2+]iin vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2 Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.SIGNIFICANCE STATEMENT Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2 We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling, which in turn stimulates COX-1 activity and generates downstream PgE2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE2 is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.

Keywords: astrocyte; calcium; cerebral blood flow; glutathione; hypercapnia.

Copyright © 2017 Howarth, Sutherland et al.

Figures

Figure 1.
Figure 1.
Astrocyte [Ca2+]i transients are evoked by CO2in vivo. A, Example still images of mouse cortical layer II/III from 2PLSM. OGB is used as a calcium indicator (Ai–Aiii) and sulforhodamine 101 (SR101, Aiv, average image for whole recording) is used to stain astrocytes. Color scale refers to images Ai–Aiii. White arrows indicate astrocytes that show a Ca2+ response to CO2 of at least twice its baseline Ca2+ fluctuation. In this case, CO2 stimulus begins at t = 0 s and is applied for 36 s. Aiii, Recovery of immediate CO2 induced Ca2+ transient. Scale bars, 40 μm. Bi, Biii, Further example images of mouse cortical layer II/III from 2PLSM showing example ROI placement. Merge images showing OGB and SR101 (Bi, Biii). Red ROI1 indicates astrocyte endfoot. Red RO12 indicates astrocyte soma (layer II: n = 181, 8 mice). Green ROI indicates neuron soma (layer II: n = 153, 8 mice). Blue ROI indicates neuropil (layer II: n = 104, 8 mice). Scale bar, 20 μm. Example time series (Bii, Biv) of [Ca2+]i response in astrocyte and neuron soma ROIs (as indicated in Bi, Biii). Blue box represents time during which expired CO2 level is increased. C, Mean Ca2+ response in ROIs. Colors represent ROIs located as shown in Bi. D, Percentage of ROIs for each cell type that showed a Ca2+ response with and without a hypercapnia stimulus. For no hypercapnia (control), n = 170 astrocyte somas, n = 148 neuronal soma, and n = 96 neuropil ROIs, n = 8 mice. Colors represent description in B. E, Delay from hypercapnia start time to start of Ca2+ response in ROI. F, Duration of Ca2+ response in each ROI in response to CO2 stimulus. E, F, Box plots represent the mean (small square). Edges of the box represent 25% and 75% of data. End lines indicate maximum and minimum values. Data are mean ± SEM. **p < 0.01. ***p < 0.001.
Figure 2.
Figure 2.
Astrocyte [Ca2+]i signals evoke COX-1- and GSH-dependent vasodilations in vitro. A, 2PLSM imaging: example Ca2+ and arteriole diameter changes in response to tACPD with and without BSO. Images represent overlay of pseudo-colored Ca2+ changes and transmitted light images. Dotted line indicates initial vessel diameter. Scale bar, 10 μm. B, Mean time course of increase in astrocyte [Ca2+]i in response to tACPD. Colored box represents time of tACPD application. Control, n = 56 from 26 rats; BSO, n = 39 from 18 rats. C, Mean tACPD-evoked increase in astrocyte [Ca2+]i. tACPD, n = 56 from 26 rats; tACPD + SC560, n = 12 from 7 rats; tACPD + BSO, n = 39 from 18 rats. D, Mean tACPD-evoked PgE2 release, measured by ELISA. Within a group, each experiment (n) uses tissue from a different rat (i.e., control, n = 8 from 8 rats). E, Mean tissue GSH concentration; data from 4 rats for each group. F, Mean time course of tACPD-evoked change in lumen diameter. Colored box represents time of tACPD application. Control, n = 31 slices from 26 rats; BSO, n = 21 slices from 18 rats. G, Mean changes in lumen diameter evoked by tACPD and clonidine. tACPD, n = 31 slices from 26 rats; SC560 + tACPD, n = 7 slices from 7 rats; BSO + tACPD, n = 21 slices from 18 rats; clonidine, n = 8 slices from 8 rats; BSO + clonidine, n = 8 slices from 7 rats. H, Mean changes in lumen diameter evoked by PgE2 and NE. PgE2, n = 5 slices from 4 rats; BSO + PgE2, n = 3 slices from 3 rats; NE, n = 14 slices from 11 rats; BSO + NE, n = 8 slices from 7 rats. Data are mean ± SEM. **p < 0.01. ***p < 0.001. n, number of experiments conducted or, for calcium measurements, number of astrocyte ROIs analyzed.
Figure 3.
Figure 3.
Astrocytes express mPGES-1 and contain high levels of GSH. A, Immunohistochemistry showing astrocytic expression of GSH-dependent mPGES-1 in the CA3 of the hippocampus. Astrocyte marker, GFAP (red), mPGES-1 (green), and merge (yellow). Scale bar, 20 μm. B, MCB-loaded hippocampal-neocortical slices. Astrocytes (identified by SR101, red, white arrowheads) contain higher levels of GSH (as indicated by MCB staining, green) than neurons (white arrows). Merge (yellow). Scale bar, 20 μm.
Figure 4.
Figure 4.
Astrocyte [Ca2+]i transient-evoked vasodilations are GSH dependent in vitro. A, Mean IP3-evoked increases in astrocyte [Ca2+]i. Control, n = 21 from 6 rats; +BSO, n = 11 from 4 rats. B, Mean time course of increase in astrocyte [Ca2+]i. Dotted line indicates time of photolysis of caged IP3. n as described in A. C, Mean lumen diameter change in response to uncaging of IP3. Uncage IP3, n = 11 slices from 6 rats; +BSO, n = 6 slices from 4 rats. Data are mean ± SEM. **p < 0.01. n, number of experiments conducted or, for calcium measurements, number of astrocyte ROIs analyzed.
Figure 5.
Figure 5.
CO2 evoked CBF responses in vivo are GSH dependent. A, Mean traces of local CBF response to hypercapnia, measured by laser speckle contrast imaging, in vehicle (DMSO)- (blue) and SC560- (red) injected animals. n = 7 rats for each group. Colored box represents time of CO2 application. Data shown as fractional change with baseline of 0 (baseline taken during 60 s prechallenge) and a pretreatment peak of 1 (black dotted line on graph). B, Mean AUC of CBF response to hypercapnia in the presence of vehicle (DMSO) or SC560 (normalized to pretreatment maxima for each animal). n = 7 rats for each group. C, Tissue GSH levels 24 h after injection of BSO or saline into the barrel cortex (n = 7 rats). D, Mean trace of local CBF response to hypercapnia, measured by laser Doppler flowmetry, in saline- (blue) and BSO- (red) injected rats. n = 6 rats in each group. E, Mean values of AUC of CBF response to hypercapnia. n = 6 rats in each group. F, G, Neural activity. Power in frequency bands. F, During baseline (Base) and in response to hypercapnia (HCN) for saline- (blue) and BSO- (red) treated animals. n = 3 rats. G, Hypercapnia (HCN)/baseline (Base). Treatment with BSO does not change the effect of hypercapnia on neural activity. n = 3 rats. Data are mean ± SEM. * p < 0.05.
Figure 6.
Figure 6.
CBF responses to whisker pad stimulation in vivo are independent of GSH. A, Mean time course of local CBF response to whisker pad stimulation, measured by laser speckle contrast imaging, in vehicle (DMSO)- (blue) and SC560- (red) injected rats. Colored box represents time of stimulation. Dotted black line indicates pretreatment peak of 1. B, Mean AUC of the CBF response to whisker pad stimulation. n = 7 rats for each group. C, Mean neural response (LFP) magnitude to whisker pad stimulus (summed over total 16 s length of stimulus). Responses are normalized to the first pulse response for each rat. n = 4 DMSO-treated rats; n = 3 SC560-treated rats. D, Mean AUC of the whisker pad stimulation-evoked CBF response in saline- (blue) and BSO- (red) injected rats. n = 10 rats for each group. E, Mean neural response (LFP) magnitude to whisker pad stimulation (summed over total 16 s length of stimulus). Responses are normalized to the first pulse response for each rat. n = 3 rats in each group. Data are mean ± SEM.
Figure 7.
Figure 7.
Increases in astrocytic [Ca2+]i may lead to GSH-dependent, PgE2-mediated vasodilation. Schematic diagram depicting how CO2-evoked increases in astrocytic [Ca2+]i may lead to PgE2-mediated vasodilation. As a result of elevated [Ca2+]i, PLA2 is activated. PLA2 generates AA from the plasma membrane. AA can be processed locally by COX enzymes to produce AA derivatives, such as prostaglandin H2 (PgH2). PgE2 is produced from PgH2 by the enzyme PGEs, which requires GSH as a cofactor (Jakobsson et al., 1999; Murakami et al., 2000; Tanioka et al., 2000). PgE2 is released from astrocyte endfeet, which are apposed to the smooth muscle layer surrounding arterioles, resulting in activation of K+ channels, a decrease in Ca2+ entry into the smooth muscle cell and vasodilation.

References

    1. Ainslie PN, Duffin J (2009) Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation. Am J Physiol Regul Integr Comp Physiol 296:R1473–R1495. 10.1152/ajpregu.91008.2008
    1. Ansari MA, Scheff SW (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69:155–167. 10.1097/NEN.0b013e3181cb5af4
    1. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243. 10.1038/nature09613
    1. Blanco VM, Stern JE, Filosa JA (2008) Tone-dependent vascular responses to astrocyte-derived signals. Am J Physiol 294:H2855–H2863. 10.1152/ajpheart.91451.2007
    1. Bonder DE, McCarthy KD (2014) Astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo. J Neurosci 34:13139–13150. 10.1523/JNEUROSCI.2591-14.2014
    1. Bragin DE, Zhou B, Ramamoorthy P, Müller WS, Connor JA, Shi H (2010) Differential changes of glutathione levels in astrocytes and neurons in ischemic brains by two-photon imaging. J Cereb Blood Flow Metab 30:734–738. 10.1038/jcbfm.2010.9
    1. Busija DW, Leffler CW (1987) Exogenous norepinephrine constricts cerebral arterioles via alpha 2-adrenoceptors in newborn pigs. J Cereb Blood Flow Metab 7:184–188. 10.1038/jcbfm.1987.42
    1. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278. 10.1523/JNEUROSCI.4178-07.2008
    1. Casper KB, Jones K, McCarthy KD (2007) Characterization of astrocyte-specific conditional knockouts. Genesis 45:292–299. 10.1002/dvg.20287
    1. Duffy S, MacVicar BA (1995) Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J Neurosci 15:5535–5550.
    1. Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, Nelson MT (2006) Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9:1397–1403. 10.1038/nn1779
    1. Font-Nieves M, Sans-Fons MG, Gorina R, Bonfill-Teixidor E, Salas-Pérdomo A, Márquez-Kisinousky L, Santalucia T, Planas AM (2012) Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. J Biol Chem 287:6454–6468. 10.1074/jbc.M111.327874
    1. Gordon GR, Choi HB, Rungta RL, Ellis-Davies GC, MacVicar BA (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456:745–749. 10.1038/nature07525
    1. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, Teschemacher AG, Spyer KM, Deisseroth K, Kasparov S (2010) Astrocytes control breathing through pH-dependent release of ATP. Science 329:571–575. 10.1126/science.1190721
    1. Hauge A, Thoresen M, Walløe L (1980) Changes in cerebral blood flow during hyperventilation and CO2-breathing measured transcutaneously in humans by a bidirectional, pulsed, ultrasound Doppler blood velocitymeter. Acta Physiol Scand 110:167–173. 10.1111/j.1748-1716.1980.tb06647.x
    1. He L, Linden DJ, Sapirstein A (2012) Astrocyte inositol triphosphate receptor type 2 and cytosolic phospholipase A2 alpha regulate arteriole responses in mouse neocortical brain slices. PLoS One 7:e42194. 10.1371/journal.pone.0042194
    1. Huckstepp RT, id Bihi R, Eason R, Spyer KM, Dicke N, Willecke K, Marina N, Gourine AV, Dale N (2010) Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity. J Physiol 588:3901–3920. 10.1113/jphysiol.2010.192088
    1. Jakobsson PJ, Thorén S, Morgenstern R, Samuelsson B (1999) Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A 96:7220–7225. 10.1073/pnas.96.13.7220
    1. Kulak A, Steullet P, Cabungcal JH, Werge T, Ingason A, Cuenod M, Do KQ (2013) Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models. Antioxid Redox Signal 18:1428–1443. 10.1089/ars.2012.4858
    1. Lacroix A, Toussay X, Anenberg E, Lecrux C, Ferreirós N, Karagiannis A, Plaisier F, Chausson P, Jarlier F, Burgess SA, Hillman EM, Tegeder I, Murphy TH, Hamel E, Cauli B (2015) COX-2-derived prostaglandin E2 produced by pyramidal neurons contributes to neurovascular coupling in the rodent cerebral cortex. J Neurosci 35:11791–11810. 10.1523/JNEUROSCI.0651-15.2015
    1. Lathia JD, Okun E, Tang SC, Griffioen K, Cheng A, Mughal MR, Laryea G, Selvaraj PK, ffrench-Constant C, Magnus T, Arumugam TV, Mattson MP (2008) Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 28:13978–13984. 10.1523/JNEUROSCI.2140-08.2008
    1. Lecrux C, Toussay X, Kocharyan A, Fernandes P, Neupane S, Lévesque M, Plaisier F, Shmuel A, Cauli B, Hamel E (2011) Pyramidal neurons are “neurogenic hubs” in the neurovascular coupling response to whisker stimulation. J Neurosci 31:9836–9847. 10.1523/JNEUROSCI.4943-10.2011
    1. Lind BL, Brazhe AR, Jessen SB, Tan FC, Lauritzen MJ (2013) Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo. Proc Natl Acad Sci U S A 110:E4678–E4687. 10.1073/pnas.1310065110
    1. Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199. 10.1038/nature02827
    1. Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh S, Kudo I (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275:32783–32792. 10.1074/jbc.M003505200
    1. Nimmerjahn A, Kirchhoff F, Kerr JN, Helmchen F (2004) Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat Methods 1:31–37. 10.1038/nmeth706
    1. Niwa K, Araki E, Morham SG, Ross ME, Iadecola C (2000) Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 20:763–770.
    1. Niwa K, Haensel C, Ross ME, Iadecola C (2001) Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res 88:600–608. 10.1161/01.RES.88.6.600
    1. Nizar K, Uhlirova H, Tian P, Saisan PA, Cheng Q, Reznichenko L, Weldy KL, Steed TC, Sridhar VB, MacDonald CL, Cui J, Gratiy SL, Sakadzić S, Boas DA, Beka TI, Einevoll GT, Chen J, Masliah E, Dale AM, Silva GA, et al. (2013) In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. J Neurosci 33:8411–8422. 10.1523/JNEUROSCI.3285-12.2013
    1. Nogawa S, Zhang F, Ross ME, Iadecola C (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17:2746–2755.
    1. Olajide OA, Velagapudi R, Okorji UP, Sarker SD, Fiebich BL (2014) Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1beta-stimulated SK-N-SH neuronal cells. J Ethnopharmacol 152:377–383. 10.1016/j.jep.2014.01.027
    1. Otsu Y, Couchman K, Lyons DG, Collot M, Agarwal A, Mallet JM, Pfrieger FW, Bergles DE, Charpak S (2015) Calcium dynamics in astrocyte processes during neurovascular coupling. Nat Neurosci 18:210–218. 10.1038/nn.3906
    1. Pelligrino DA, Vetri F, Xu HL (2011) Purinergic mechanisms in gliovascular coupling. Semin Cell Dev Biol 22:229–236. 10.1016/j.semcdb.2011.02.010
    1. Petzold GC, Albeanu DF, Sato TF, Murthy VN (2008) Coupling of neural activity to blood flow in olfactory glomeruli is mediated by astrocytic pathways. Neuron 58:897–910. 10.1016/j.neuron.2008.04.029
    1. Pileblad E, Magnusson T (1989) Intracerebroventricular administration of l-buthionine sulfoximine: a method for depleting brain glutathione. J Neurochem 53:1878–1882. 10.1111/j.1471-4159.1989.tb09256.x
    1. Robillard JM, Gordon GR, Choi HB, Christie BR, MacVicar BA (2011) Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult. PLoS One 6:e20676. 10.1371/journal.pone.0020676
    1. Rosenegger DG, Tran CH, Wamsteeker Cusulin JI, Gordon GR (2015) Tonic local brain blood flow control by astrocytes independent of phasic neurovascular coupling. J Neurosci 35:13463–13474. 10.1523/JNEUROSCI.1780-15.2015
    1. Schulz K, Sydekum E, Krueppel R, Engelbrecht CJ, Schlegel F, Schröter A, Rudin M, Helmchen F (2012) Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex. Nat Methods 9:597–602. 10.1038/nmeth.2013
    1. Sekiguchi KJ, Shekhtmeyster P, Merten K, Arena A, Cook D, Hoffman E, Ngo A, Nimmerjahn A (2016) Imaging large-scale cellular activity in spinal cord of freely behaving mice. Nat Commun 7:11450. 10.1038/ncomms11450
    1. Slivka A, Cohen G (1993) Brain ischemia markedly elevates levels of the neurotoxic amino acid, cysteine. Brain Res 608:33–37. 10.1016/0006-8993(93)90770-N
    1. Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zweifel BS, Shaffer A, Talley JJ, Masferrer JL, Seibert K, Isakson PC (1998) Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci U S A 95:13313–13318. 10.1073/pnas.95.22.13313
    1. Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M (2013) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339:197–200. 10.1126/science.1226740
    1. Sun X, Shih AY, Johannssen HC, Erb H, Li P, Murphy TH (2006) Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface. J Biol Chem 281:17420–17431. 10.1074/jbc.M601567200
    1. Tachikawa M, Ozeki G, Higuchi T, Akanuma S, Tsuji K, Hosoya K (2012) Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E(2) produced in the brain. J Neurochem 123:750–760. 10.1111/jnc.12018
    1. Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267. 10.1038/nn1623
    1. Takata N, Nagai T, Ozawa K, Oe Y, Mikoshiba K, Hirase H (2013) Cerebral blood flow modulation by basal forebrain or whisker stimulation can occur independently of large cytosolic Ca2+ signaling in astrocytes. PLoS One 8:e66525. 10.1371/journal.pone.0066525
    1. Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I (2000) Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 275:32775–32782. 10.1074/jbc.M003504200
    1. Teng XW, Abu-Mellal AK, Davies NM (2003) Formulation dependent pharmacokinetics, bioavailability and renal toxicity of a selective cyclooxygenase-1 inhibitor SC-560 in the rat. J Pharm Pharmacol Sci 6:205–210.
    1. Tohgi H, Abe T, Saheki M, Hamato F, Sasaki K, Takahashi S (1995) Reduced and oxidized forms of glutathione and alpha-tocopherol in the cerebrospinal fluid of parkinsonian patients: comparison between before and after l-dopa treatment. Neurosci Lett 184:21–24. 10.1016/0304-3940(94)11158-F
    1. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C (1999) Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis. Neurosci Lett 260:204–206. 10.1016/S0304-3940(98)00986-0
    1. Turovsky E, Theparambil SM, Kasymov V, Deitmer JW, Del Arroyo AG, Ackland GL, Corneveaux JJ, Allen AN, Huentelman MJ, Kasparov S, Marina N, Gourine AV (2016) Mechanisms of CO2/H+ sensitivity of astrocytes. J Neurosci 36:10750–10758. 10.1523/JNEUROSCI.1281-16.2016
    1. Tuure L, Hämäläinen M, Moilanen T, Moilanen E (2015) Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes. Scand J Rheumatol 44:74–79. 10.3109/03009742.2014.927917
    1. Wagerle LC, Degiulio PA (1994) Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin. J Physiol 266:H1332–H1338.
    1. Wagerle LC, Mishra OP (1988) Mechanism of CO2 response in cerebral arteries of the newborn pig: role of phospholipase, cyclooxygenase, and lipoxygenase pathways. Circ Res 62:1019–1026. 10.1161/01.RES.62.5.1019
    1. Zhang C, Rodriguez C, Spaulding J, Aw TY, Feng J (2012) Age-dependent and tissue-related glutathione redox status in a mouse model of Alzheimer's disease. J Alzheimers Dis 28:655–666. 10.3233/JAD-2011-111244
    1. Zhang YH, Lu J, Elmquist JK, Saper CB (2003) Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain. J Comp Neurol 463:3–12. 10.1002/cne.10743
    1. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. 10.1523/JNEUROSCI.1860-14.2014
    1. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50. 10.1038/nn980

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