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| Sample | Receptors | Main findings | Reference |
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| Cerebral cortex from healthy and MS patients | P2Y12 receptor | Reduction in the P2Y12R is immunoreactive in the lesions. This event was directly correlated with the extent demyelination found in grey matter cortical and subcortical white matter. | [201] |
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| Tissues of rats exposed to EAE model and brain tissue from healthy and MS patients | P2X7 receptor
P2Y12 receptor | P2X7R is highly expressed in microglia in MS lesions during the peak of EAE. P2X7R is associated with a proinflammatory phenotype of human microglia. In parallel, P2Y12R was associated with an anti-inflammatory phenotype in human microglia. P2Y12R was expressed at lower levels in active inflammatory MS lesions. P2Y12R expression increased in the remission phase of EAE. | [202] |
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| Spleen and lymph node cell from P2X7R−/− mice exposed to EAE model | P2X7 receptor | Coculture of P2X7R−/− macrophages with wild-type lymphocytes showed that enhanced proliferative activity resided within the P2X7R−/− lymphocyte population. Furthermore, mRNA and protein for IFN-γ were significantly reduced in the CNS of P2X7R−/− mice with EAE. Enhanced susceptibility of P2X7R−/− mice to EAE reflects a loss of apoptotic activity in lymphocytes. | [203] |
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| EAE induced in rats by guinea pig spinal cord homogenates (GPSCH model) | A1 receptor | Investigation of the role of the A1 receptor using antagonists. Caffeine (10–30 m/kg) decreases the incidence of EAE and attenuates EAE pathology at behavioral, histological (inflammatory cell infiltration and demyelination), and neurochemical (expression of inflammatory cytokines) levels. In addition, caffeine also upregulated A1 receptor and TGF-β mRNAs and suppressed INF-γ mRNA in EAE rats. | [204] |
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| Brain of female Lewis rats exposed to EAE model | P2X7 receptor | Enhanced expression of GFAP and S100β is associated with expression of P2X7R. Brilliant blue G, an antagonist of P2X7R, significantly decreases astrogliosis (GFAP and S100β). | [205] |
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| Brain of rats exposed to EAE model | P2X7 receptor | The enhancement in the expression of the P2X7 receptor at the level of both mRNA and protein was observed in the peak of neurological symptoms and was connected mostly with neurons (4, 6, 8, and 10 days postimmunization). | [206] |
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| Human monocytes from Australasian patients with MS | P2X7 receptor | A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in MS. | [207] |
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| Two independent mouse EAE models: by immunization in C57BL/6 using MOG35–55 and by PLP139–155 in mouse wild-type and lacking A2AR (A2AR−/−) | A2A receptor | Upregulation of A2AR in the CNS in EAE, predominantly detected on T cells and macrophages/microglia. A preventive EAE treatment with A2AR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease. In parallel, the application of the same agonist after disease onset exacerbated nonremitting EAE progression and resulted in more severe tissue destruction. A2AR-deficient mice showed accelerated and exacerbated disease manifestation with higher numbers of inflammatory lesions in the early stage. EAE quickly ameliorated and myelin debris accumulation was lower in A2AR−/− mice. Finally, an in vitro activation of A2AR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4+ T cells, macrophages, and primary microglia. | [194] |
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| Lymphocyte isolation from nerve tissue and lumbar spinal cord of female mice exposed to EAE | A2A receptor | CGS21680 (CGS, A2AR agonist) significantly suppressed specific lymphocyte proliferation, reduced infiltration of CD4+ T lymphocytes, and attenuated the expression of inflammatory cytokines, which in turn inhibited the EAE progression. CGS can increase the [Ca2+]i in murine lymphocytes, which may be the mechanism underlying the suppressive effects of CGS-induced A2AR activation on EAE progression. | [208] |
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| Oligodendrocyte cultures and postmortem optic nerve samples from MS patients | P2X7 receptor | Sustained activation of P2X7R in vivo causes lesions that are reminiscent of the major features of MS plaques (demyelination, oligodendrocyte death, and axonal damage). In addition, treatment with P2X7R antagonists reduces demyelination and ameliorates the associated neurological symptoms. The study suggests that ATP can kill oligodendrocytes via P2X7R activation and this process contributes to EAE. Importantly, P2X7R expression is elevated in normal-appearing axon tracts in MS patients. | [209] |
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| Peripheral blood mononuclear cells from MS patients | A1 receptor | Decreased levels of adenosine and its A1 receptor modulate TNFα and IL-6 levels and may contribute to the pathogenesis of MS. | [210] |
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| Brain and spinal cord of female SJL/J mice infected with Theiler’s virus infection | A2A receptor | A2A receptors participate in anti-inflammatory effects of cannabidiol. A2A antagonist ZM241385 partially blocks the protective effects of cannabidiol in the initial stages of inflammation. | [211] |
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| Human microglia | P2Y12 receptor | P2Y12 is expressed on parenchymal microglia and is stable throughout human brain development, including fetal phases. MS result in decreased P2Y12 immunoreactivity in plaque- or lesion-associated myeloid cells. P2Y12 is a useful marker for the identification of human microglia throughout the lifespan. | [212] |
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| Blood from MS patients | P2X4 receptor
P2X7 receptor | A rare genetic variant in P2RX4 and P2RX7 is a major genetic contributor to disease (description of the three variant haplotypes: P2RX7 rs140915863:C>T [p.T205M]; P2RX7 rs201921967:A>G [p.N361S]; and P2RX4 rs765866317:G>A [p.G135S]). | [213] |
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| C57BL6 mice and P2X7-deficient mice exposed to EAE model | P2X7 receptor | The incidence of EAE disease in P2X7 mice was reduced 4-fold compared to the wild type. Mouse splenic T cells isolated from P2X7 null mice produced greater IFNγ and IL-17 (from 3- to 12-fold greater levels) than wild-type cells. Although infiltrating cells were detected in the brains of both the P2X7 and wild type, astroglial activation and axonal damage were reduced compared to wild type. | [214] |
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| Brain and spinal cord from female mice exposed to EAE model | A1A receptor | A1AR−/− mice developed a severe progressive-relapsing form of EAE compared with their wild type. Demyelination, axonal injury, and enhanced activation of microglia and macrophages were observed in A1AR−/−. Spinal cords from A1AR−/− mice demonstrated increased proinflammatory gene expression. A1AR−/− macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. | [215] |
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| Spinal cord from MS patients | P2X7 receptor | In control spinal cord, few small microglial cells/macrophages were scattered throughout the tissue. However, MS specimens had significantly greater density of such cells with longer processes in affected regions. MS also had significantly greater density of P2X7 and immunoreactive microglial cells/macrophages in affected regions. | [216] |
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