A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui, Shigeki; Schnermann, Jürgen; Noorbakhsh, Farshid; Henry, Scot D.; Yong, V. Wee; Winston, Brent W.; Warren, Kenneth G.; Power, Christopher

doi:10.1523/jneurosci.4271-03.2004

Cited by 300 publications

(279 citation statements)

References 55 publications

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“…CD73 is a key regulator of extracellular ATP metabolism and inflammation as it shifts the balance from pro-inflammatory ATP and prothrombotic ADP to anti-inflammatory adenosine by converting AMP into adenosine. Adenosine is a known anti-inflammatory agent, which promotes endothelial integrity and has neuroprotective properties [17,[22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, ecto-5 0 -nucleotidase activity is upregulated in ischemic rat brains leading to increased protective purine synthesis [14]. It has been shown that A1 adenosine receptor (A1aR) knockout mice have a more severe phenotype in the murine EAE model compared with wild-type controls [24], suggesting a role for adenosine-mediated protection in EAE. A1aRs are highly expressed on microglia/macrophages and neurons in CNS and, interestingly, A1aR expression and activity on macrophage/microglial cells were shown to be diminished in MS patients compared with controls [35].…”

Section: Discussionmentioning

confidence: 99%

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IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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IFN-b treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-b in the treatment of MS. We assessed the influence of IFN-b treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4 1 T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5 0 -nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-b increases the expression of ecto-5 0 -nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using a,b-methyleneadenosine-5 0 -diphosphate, a specific inhibitor of ecto-5 0 -nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5 0 -nucleotidase activity and skin microvascular CD73 expression after IFN-b treatment. Upregulation of ecto-5 0 -nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-b on MS via enhancing the endothelial barrier function.Key words: Adenosine . Blood-brain barrier . CD73 . IFN-b . MS Introduction MS is a demyelinating disease characterized by perivascular inflammatory cell infiltrates in the white matter of the CNS. MS is generally thought to be an autoimmune disease in which the immune system attack against self-antigens results in inflammation and neurological symptoms [1]. First line treatment of MS is subcutaneous or intramuscular administration of IFN-b, which leads to a reduced number of relapses and a slower disease progression [2][3][4]. The proposed beneficial effects of IFN-b include a decrease in antigen presentation, MHC class II expression, T-cell proliferation, IFN-b production, ECM degradation, and the expression of adhesion molecules [5]. Moreover, recent reports describe IFN-b as a suppressor of both myeloid [6] and Th17-cells [7]. IFN-b also reduces the number of gadolinium enhancing lesions in brain magnetic resonance imaging of MS patients [2,3,8], which is thought to reflect its ability to regulate the blood-brain barrier (BBB) function [9]. Ecto-5 0 -nucleotidase (CD73; EC 3.1.3.5) is a 70 kDa GPI-anchored glycoprotein. It is abundantly expressed on vascular endothelium and subpopulations of lymphocytes, but not on granulocytes or monocytes [10] and it also circulates in blood in a soluble 2718form [11]. Ecto-5 0 -nucleotidase activity is found on many CNS cell types such as astrocytes, oligodendrocytes, microglial cells and brain EC in many species including human, rat, mouse and bovine [12][13][14][15]. CD73 modulates the extent of immune and inflammatory responses in vitro and in vivo. These effects are mediated via its enzymatic capability ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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“…In fact, although there is a general downregulation of A 1 Rs caused by noxious stimuli, this does not mean that the ability of A 1 Rs to control neuronal damage is eliminated. In fact, some reports indicate that A 1 Rmediated neuroprotective effects may still be achieved in chronic brain noxious conditions in adult animals, such as in animal models of epilepsy [165,330,331], multiple sclerosis [332], paroxysmal dystonia [333] or 3-nitropionic acid-induced neurotoxicity [334]. It has already been discussed that the use of A 1 R agonists as neuroprotective tools in vivo may be of limited use because of their profound peripheral effects (see BAcute A 1 receptor activation increases the threshold for acute neurodegeneration^).…”

Section: Therapeutic Neuroprotective Potential Based On Adenosine In mentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

484

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…Frontal brain white matter was collected at autopsy with consent from ageand sex-matched MS patients (total: n = 8; median age: 63 y; chronic progressive MS: n = 3; secondary progressive MS: n = 5) and non-MS (control) patients (total: n = 7; median age: 58 y; sepsis: n = 2; myocardial infarction: n = 2; HIV/AIDS: n = 1: cancer/leukemia n = 2) for RT-PCR analyses, as previously reported (32)(33)(34). Normal-appearing white matter (NAWM) was used from all clinical samples.…”

Section: Human Brain Tissue Samplesmentioning

confidence: 99%

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

Deslauriers

Afkhami-Goli

Paul

et al. 2011

The Journal of Immunology

113

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Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1–expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1–expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

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A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Cited by 300 publications

References 55 publications

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

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