Publications by authors named "Raffaela Cipriani"

11 Publications

  • Page 1 of 1

Sorcin is an early marker of neurodegeneration, Ca dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases.

Cell Death Dis 2020 10 15;11(10):861. Epub 2020 Oct 15.

Institute of Molecular Biology and Pathology, Italian National Research Council, IBPM-CNR, Rome, Italy.

Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.
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http://dx.doi.org/10.1038/s41419-020-03063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566454PMC
October 2020

Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis.

Neuropharmacology 2018 10 30;141:181-191. Epub 2018 Aug 30.

Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28029, Madrid, Spain. Electronic address:

α/β-Hydrolase domain-containing 6 (ABHD6) contributes to the hydrolysis of the major endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS) and in the periphery. ABHD6 blockade has been proposed as novel strategy to treat multiple sclerosis (MS), based on the observation that the inhibitor WWL70 exerts protective anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE). According to recent data, WWL70 exhibits off-target anti-inflammatory activity in microglial cells and the potential of ABHD6 as drug target in MS remains controversial. Here we further investigated the role of ABHD6 during autoimmune demyelination by comparing the efficacy of two novel inhibitors with different CNS permeability in vivo. Preventive treatment with the systemically active inhibitor KT182 ameliorated the neurological signs of EAE during the time-course of disease. By contrast, administration of the peripherally restricted compound KT203 was ineffective in attenuating EAE symptomatology. Both inhibitors failed to improve corticospinal tract conduction latency and to attenuate inflammation at EAE recovery phase, despite being equally active at targeting brain ABHD6. Chronic administration of KT182 was associated to a partial loss of brain CB receptor coupling ability, suggesting the engagement of CB receptor-mediated mechanisms during the EAE disease progression. In cultured neurons, KT182 attenuated NMDA-stimulated excitotoxicity and mitochondrial calcium overload. However, these protective effects were not attributable to ABHD6, as they were not mimicked by the alternative inhibitors KT203, KT195 and WWL70. These results indicate that ABHD6 blockade exerts only modest therapeutic effects against autoimmune demyelination and call into question its utility as novel drug target in MS.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.038DOI Listing
October 2018

Deregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination.

Biochem Pharmacol 2018 11 1;157:189-201. Epub 2018 Aug 1.

Department of Neurosciences, University of the Basque Country UPV/EHU, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid, Spain. Electronic address:

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology in which tissue pathology suggests both immune-dependent attacks to oligodendroglia and primary oligodendrocyte demise. The endocannabinoid system has been crucially involved in the control of autoimmune demyelination and cannabinoid-based therapies exhibit therapeutic potential, but also limitations, in MS patients. In this context, growing evidence suggests that targeting the hydrolysis of the main endocannabinoid 2-arachidonoylglycerol (2-AG) may offer a more favorable benefit-to-risk balance in MS than existing cannabinoid medicines. Here we evaluated the modulation of endocannabinoid signaling and the therapeutic potential of targeting the 2-AG hydrolytic enzyme alpha/beta-hydrolase domain-containing 6 (ABHD6) in the cuprizone model of non-immune dependent demyelination. The concentrations of N-arachidonoylethanolamine (anandamide, AEA) and its congener N-palmitoylethanolamine (PEA) were reduced following 6 weeks of cuprizone feeding. Deregulation of AEA and PEA levels was not due to differences in the expression of the hydrolytic and biosynthetic enzymes fatty acid amide hydrolase and N-acylphosphatidylethanolamine-phospholipase D, respectively. Conversely, we measured elevated transcript levels of 2-AG hydrolytic enzymes monoacylglycerol lipase, ABHD6 and ABHD12 without changes in bulk 2-AG concentration. Upregulated CB and CB receptors expression, ascribed in part to microglia, was also detected in the brain of cuprizone-treated mice. Administration of an ABHD6 inhibitor partially attenuated myelin damage, astrogliosis and microglia/macrophage reactivity associated to cuprizone feeding. However, ABHD6 blockade was ineffective at engaging protective or differentiation promoting effects in oligodendrocyte cultures. These results show specific alterations of the endocannabinoid system and modest beneficial effects resulting from ABHD6 inactivation in a relevant model of primary demyelination.
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http://dx.doi.org/10.1016/j.bcp.2018.07.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239900PMC
November 2018

Effects of FTY720 on brain neurogenic niches in vitro and after kainic acid-induced injury.

J Neuroinflammation 2017 07 24;14(1):147. Epub 2017 Jul 24.

Centro de Investigaciones Biomédicas en Red (CIBERNED), Achucarro Basque Center for Neuroscience and Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), E-48940, Leioa, Spain.

Background: FTY720 (fingolimod, Gilenya™) is an oral, blood-brain barrier (BBB)-passing drug approved as immunomodulatory treatment for relapsing-remitting form of the multiple sclerosis (MS). In addition, FTY720 exerts several effects in the central nervous system (CNS), ranging from neuroprotection to reduction of neuroinflammation. However, the neurogenic and oligodendrogenic potential of FTY720 has been poorly investigated. In this study, we assessed the effect of FTY720 on the production of new neurons and oligodendrocytes from neural stem/precursor cells both in vitro and in vivo.

Methods: Neural stem cells (NSCs) derived from the young rat subventricular zone (SVZ) were exposed to FTY720 (10, 100 nM), and their differentiation into neurons and oligodendrocytes was measured using immunofluorescence for anti-β-III tubulin or CNPase (2',3'-cyclic nucleotide 3'-phosphodiesterase) as markers of mature neurons or oligodendrocytes, respectively. In addition, intracerebroventricular (icv) administration of kainic acid (KA; 0.5 μg/2 μl) in Sprague-Dawley rats was used as an in vivo model of neuronal death and inflammation. FTY720 was applied icv (1 μg/2 μl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 8 days after KA injection. To visualize cell proliferation in the hippocampus and in white matter regions, rats were administered 5-bromo-2-deoxyuridine (BrdU) 100 mg/kg, ip injected every 2 days. Immunohistochemical analyses were performed on rat brain slices to measure the production of new neuronal precursors (doublecortin/DCX cells) and new oligodendrocytes precursors (proteoglycan/NG2 cells).

Results: In this study, we observed that FTY720 increased postnatal NSCs differentiation into both neurons and oligodendrocytes in vitro. In turn, in adult animals, FTY720 enhanced the percentage of BrdU cells coexpressing DCX marker, both in basal (FTY720 alone) and in neurodegenerative (FTY720 + KA) conditions. However, FTY720 had only a partial effect on proliferation and differentiation of oligodendrocyte progenitor cell (OPC) population in vivo.

Conclusions: FTY720 promotes neurogenesis and oligodendrogenesis in vitro under basal conditions. In addition, it increases the generation of neuroblasts and oligodendrocytes after excitotoxic brain injury. This suggests that FTY720 has the potential to activate the neurogenic niche and thus favour tissue repair after lesion.
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http://dx.doi.org/10.1186/s12974-017-0922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525223PMC
July 2017

FTY720 attenuates excitotoxicity and neuroinflammation.

J Neuroinflammation 2015 May 8;12:86. Epub 2015 May 8.

Centro de Investigaciones Biomédicas en Red (CIBERNED), Achucarro Basque Center for Neuroscience Bizkaia Science and Technology Park, Building 205, E-48170, Zamudio, Spain.

Background: FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1R). However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. In this study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death and examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection.

Methods: Primary neuronal and organotypic cortical cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic cell death (measured by lactate dehydrogenase (LDH) assay or propidium iodide uptake, respectively). The effects of FTY720 treatment (10, 100 and 1,000 nM) on neuronal survival were examined. As an in vivo model of neuronal death and inflammation, we used intracerebroventricular (icv) administration of kainic acid (KA; 0.5 μg/2 μl) in Sprague-Dawley rats. FTY720 was applied icv (1 μg/2 μl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 3 days after icv. Rats were evaluated for neurological score, neuronal loss in CA3 hippocampal region and activation of microglia at the lesion site. In addition, we tested FTY720 as a modulator of microglia responses using microglial cell cultures activated with lipopolysaccharide (LPS) and its effects in stress signalling pathways using western blotting for p38 and JNK1/2 mitogen-activated protein kinases (MAPKs).

Results: FTY720 was able to reduce excitotoxic neuronal death in vitro. Moreover, in vivo repeated FTY720 administration attenuated KA-induced neurodegeneration and microgliosis at the CA3 lesion site. Furthermore, FTY720 negatively modulates p38 MAPK in LPS-activated microglia, whereas it had no effect on JNK1/2 activation.

Conclusions: These data support a role for FTY720 as a neuroprotective agent against excitotoxin-induced neuronal death and as a negative modulator of neuroinflammation by targeting the p38 MAPK stress signalling pathway in microglia.
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http://dx.doi.org/10.1186/s12974-015-0308-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429813PMC
May 2015

CX3CL1 protects neurons against excitotoxicity enhancing GLT-1 activity on astrocytes.

J Neuroimmunol 2013 Oct 8;263(1-2):75-82. Epub 2013 Aug 8.

Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; IRCCS Neuromed, Via Atinese 18, 86077 Pozzilli, Italy. Electronic address:

In this paper we show for the first time that: i) astrocytes are required for the neuroprotective activity of CX3CL1 against excitotoxicity; ii) inhibition of the glutamate transporter 1 (GLT-1) prejudices CX3CL1-mediated neuroprotection; iii) CX3CL1 increases GLT-1 activity on astrocytes. The modulation of GLT-1 activity induced by CX3CL1 on astrocytes requires the presence and the activity of A1 adenosine receptor (A1R), being blocked by the specific antagonist DPCPX and absent in A1R(-/-) astrocytes. These data introduce the astrocytes as active players in CX3CL1-mediated signaling between microglia and neurons, identifying GLT-1 as a key mediator of the neuroprotective activity of CX3CL1.
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http://dx.doi.org/10.1016/j.jneuroim.2013.07.020DOI Listing
October 2013

CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents.

J Neurosci 2011 Nov;31(45):16327-35

Institute Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy.

The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A₁R). We show that, in the presence of the A₁R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A₁R⁻/⁻ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1⁻/⁻ and cx3cr1(GFP/GFP) mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1⁻/⁻ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1⁻/⁻ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygen-glucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosine-dependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.
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http://dx.doi.org/10.1523/JNEUROSCI.3611-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633249PMC
November 2011

Anomalous levels of Cl- transporters cause a decrease of GABAergic inhibition in human peritumoral epileptic cortex.

Epilepsia 2011 Sep 2;52(9):1635-44. Epub 2011 Jun 2.

Pasteur Institute-Cenci Bolognetti Foundation, Department of Physiology and Pharmacology, University of Rome La Sapienza, Rome, Italy.

Purpose: Several factors contribute to epileptogenesis in patients with brain tumors, including reduced γ-aminobutyric acid (GABA)ergic inhibition. In particular, changes in Cl(-) homeostasis in peritumoral microenvironment, together with alterations of metabolism, are key processes leading to epileptogenesis in patients afflicted by glioma. It has been recently proposed that alterations of Cl(-) homeostasis could be involved in tumor cell migration and metastasis formation. In neurons, the regulation of intracellular Cl(-) concentration ([Cl(-) ](i) ) is mediated by NKCC1 and KCC2 transporters: NKCC1 increases while KCC2 decreases [Cl(-) ](i) . Experiments were thus designed to investigate whether, in human epileptic peritumoral cortex, alterations in the balance of NKCC1 and KCC2 activity may decrease the hyperpolarizing effects of GABA, thereby contributing to epileptogenesis in human brain tumors.

Methods: Membranes from peritumoral cortical tissues of epileptic patients afflicted by gliomas (from II to IV WHO grade) and from cortical tissues of nonepileptic patients were injected into Xenopus oocytes leading to the incorporation of functional GABA(A) receptors. The GABA-evoked currents were recorded using standard two-microelectrode voltage-clamp technique. In addition, immunoblot analysis and immunohistochemical staining were carried out on membranes and tissues from the same patients.

Key Findings: We found that in oocytes injected with epileptic peritumoral cerebral cortex, the GABA-evoked currents had a more depolarized reversal potential (E(GABA) ) compared to those from nonepileptic healthy cortex. This difference of E(GABA) was abolished by the NKCC1 blocker bumetanide or unblocking of KCC2 with the Zn(2+) chelator TPEN. Moreover, Western blot analysis revealed an increased expression of NKCC1, and more modestly, of KCC2 transporters in epileptic peritumoral tissues compared to nonepileptic control tissues. In addition, NKCC1 immunoreactivity was strongly increased in peritumoral cortex with respect to nonepileptic cortex, with a prominent expression in neuronal cells.

Significance: We report that the positive shift of E(GABA) in epileptic peritumoral human cortex is due to an altered expression of NKCC1 and KCC2, perturbing Cl(-) homeostasis, which might lead to a consequent reduction in GABAergic inhibition. These findings point to a key role of Cl(-) transporters KCC2 and NKCC1 in tumor-related epilepsy, suggesting a more specific drug therapy and surgical approaches for the epileptic patients afflicted by brain tumors.
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http://dx.doi.org/10.1111/j.1528-1167.2011.03111.xDOI Listing
September 2011

Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death.

Neuropsychopharmacology 2010 Jun 3;35(7):1550-9. Epub 2010 Mar 3.

Istituto Pasteur, Fondazione Cenci Bolognetti, Rome, Italy.

Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-alpha, interleukin-1-beta, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A(1) receptors (A(1)R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A(1)R(-/-) mice are not protected by CX3CL1 whereas A(2A)R(-/-) neurons are. The requirement of functional A(1)R for neuroprotection is not unique for CX3CL1 as A(1)R(-/-) hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.
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http://dx.doi.org/10.1038/npp.2010.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055460PMC
June 2010

Chemokine CXCL8 modulates GluR1 phosphorylation.

J Neuroimmunol 2008 Jul 27;198(1-2):75-81. Epub 2008 May 27.

Istituto Pasteur-Fondazione Cenci Bolognetti, Centro di Eccellenza BEMM, Università di Roma "Sapienza", P.le A. Moro 5, I00185 Roma, Italy.

The chemokine interleukin 8/CXCL8 induces the phosphorylation of the GluR1 subunit of the AMPA-type glutamate receptor in neurons and transfected HEK cells, on both serine 845 (S845) and 831 (S831) residues. We previously described that CXCL8 receptor CXCR2 and GluR1 co-precipitate and that GluR1/CXCR2 co-expression both in HEK cells and neurons impairs CXCL8-induced cell migration. Here we show that replacement of S845 with Ala (A), but not with Glu (E), strongly reduces GluR1/CXCR2 interaction and abolishes the impairment of CXCL8-induced cell migration. Considered together our findings point to the phosphorylated state of S845GluR1 as a determinant of GluR1-CXCR2 physical coupling.
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http://dx.doi.org/10.1016/j.jneuroim.2008.04.017DOI Listing
July 2008

Activity of adenosine receptors type 1 Is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons.

J Immunol 2008 Jun;180(11):7590-6

Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Università Sapienza, Roma.

The chemokine fractalkine (CX(3)CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX(3)CR1, CX(3)CL1 exerts both neuroprotection against glutamate (Glu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX(3)CR1(-/-) (CX(3)CR1(GFP/GFP)) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX(3)CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX(3)CL1-induced neuroprotection from Glu toxicity is mediated through the adenosine receptor 1 (AR(1)), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR(1), and mimicked by both adenosine and the specific AR(1) agonist 2-chloro-N(6)-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX(3)CR1(+/+) mice, show that CX(3)CL1-induced depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (AMPA-) type Glu receptor-mediated current (AMPA-current), is associated with AR(1) activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX(3)CR1(GFP/GFP) hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX(3)CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX(3)CL1, along with AR(1), are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR(1) mediates neuromodulatory action of CX(3)CL1 on hippocampal neurons.
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http://dx.doi.org/10.4049/jimmunol.180.11.7590DOI Listing
June 2008