Anti-inflammatory effect of P2Y1 receptor blocker MRS2179 in a rat model of traumatic brain injury

Kumagawa, Takahiro; Moro, Nobuhiro; Maeda, Takeshi; Kobayashi, Masato; Furukawa, Yuto; Shijo, Katsunori; Yoshino, Atsuo

doi:10.1016/j.brainresbull.2022.01.008

Cited by 7 publications

(5 citation statements)

References 76 publications

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“…P2Y 1 R is a G-protein coupled metabotropic receptor for adenosine 5’-triphosphate (ATP), which is known as the intracellular energy currency [ 36 ]. It has been shown that P2Y 1 R-ANT suppresses microglial activation but fails to improve functional recovery after traumatic brain injury, whereas the stimulation of P2Y 1 R on microglia suppresses TNF-α production and exerts neuroprotection in the early stage of stroke [ 24 , 37 , 38 ]. We elucidated that the inhibition of P2Y1R activity induced modest effects, including the early suppression of inflammatory marker and late sustained the level of restorative marker after ischemia, but did not transform the morphological alterations in microglia induced by ischemia.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery

Kijima,

Inaba,

Hira

et al. 2023

Mol Neurobiol

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There are no effective treatments for post-stroke glial scar formation, which inhibits axonal outgrowth and functional recovery after stroke. We investigated whether astrocytic extracellular vesicles (AEVs) regulated by microglia modulate glial scars and improve stroke recovery. We found that peri-infarct glial scars comprised reactive astrocytes with proliferating C3d and decreased S100A10 expression in chronic stroke. In cultured astrocytes, microglia-conditioned media and treatment with P2Y1 receptor antagonists increased and reduced the area of S100A10- and C3d-expressing reactive astrocytes, respectively, by suppressing mitogen-activated protein kinase/nuclear factor-κβ (NF-κB)/tumor necrosis factor-α (TNF-α)/interleukin-1β signaling after oxygen–glucose deprivation. Intracerebral administrations of AEVs enriched miR-146a-5p, downregulated NF-κB, and suppressed TNF-α expressions, by transforming reactive astrocytes to those with S100A10 preponderance, causing functional recovery in rats subjected to middle cerebral artery occlusion. Modulating neuroinflammation in post-stroke glial scars could permit axonal outgrowth, thus providing a basis for stroke recovery with neuroprotective AEVs.

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Section: Discussionmentioning

confidence: 99%

Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery

Kijima,

Inaba,

Hira

et al. 2023

Mol Neurobiol

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“…In our previous study, in situ administration of a competitive P2Y1 receptor antagonist MRS2179 significantly reduced the extracellular ATP level both before and after CCI in a rat model (9). Other studies reported that administration of MRS2179 in a TBI model reduced inflammatory responses (15).…”

Section: Discussionmentioning

confidence: 76%

“…The source of this rapid increase is the damaged brain cells which leak intracellular ATP and subsequent activation of neuronal cells and astrocytes that release ATP into the extracellular space, but is significantly attenuated by the selective P2Y1 receptor blocker, MRS2179, or store-operated calcium channels. Furthermore, in our previous study (14,15), in situ administration of MRS2179 successfully suppressed microglial activation in a rat CCI model, which can inhibit the initiation of inflammation. In this study, we focused on the ATP receptors, P2X4 and P2X7, which are more involved in microglial activation, and investigated whether antagonists of P2X4 and/or P2X7 could be beneficial for the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI (16,17).…”

Section: Inhibition Of P2x4 and P2x7 Receptors Improves Histological ...mentioning

confidence: 92%

“…CCI was made using a 4.0 mm diameter flap-tip impactor with fixed magnitude such as depth (2.0 mm), velocity (3.5 m/sec), and dwell time (100 msec). This intensity is known to induce cortical brain contusion and delayed hippocampus cell death, but will not mechanically damage the hippocampus (15,19). Immediately after CCI, an Alzet Brain Infusion Kit 2 (Alzet 8663; DURECT Corp., Cupertino, CA) was implanted 2.0 mm deep from the brain surface at the center of contusion, connected with an osmotic pump (Alzet Mini-Osmotic Pump Model 2001; DURECT Corp.) and implanted subcutaneously.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of P2X4 and P2X7 receptors improves histological and behavioral outcomes after experimental traumatic brain injury in rats

et al. 2023

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Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naïve group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury.

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“…Low P2Y1R expression and activity underpin abnormal neurogenesis, neuronal precursors’ differentiation, and migration, as well as disturbances in glutamate and GABA signaling [ 128 ]. At the same time, MRS2179, a selective P2Y1R blocker, suppresses microglial activation that normally leads to ATP-triggered neuroinflammation, although it does not alleviate behavioral symptoms typical for post-injury inflammation [ 142 ]. Other studies show that P2Y1 receptors may decrease the susceptibility of neurons to excitotoxicity through the reduction of glutamate receptors (NMDAs), leading to neuronal damage and oxidative stress in patients with ASD [ 143 , 144 ].…”

Section: Role Of Purinergic Signaling In Asd and Comorbiditiesmentioning

confidence: 99%

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

Wikarska,

Roszak,

Roszek

2024

Biomedicines

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The prevalence of autism spectrum disorder (ASD) is still increasing, which means that this neurodevelopmental lifelong pathology requires special scientific attention and efforts focused on developing novel therapeutic approaches. It has become increasingly evident that neuroinflammation and dysregulation of neuro-immune cross-talk are specific hallmarks of ASD, offering the possibility to treat these disorders by factors modulating neuro-immunological interactions. Mesenchymal stem cell-based therapy has already been postulated as one of the therapeutic approaches for ASD; however, less is known about the molecular mechanisms of stem cell influence. One of the possibilities, although still underestimated, is the paracrine purinergic activity of MSCs, by which stem cells ameliorate inflammatory reactions. Modulation of adenosine signaling may help restore neurotransmitter balance, reduce neuroinflammation, and improve overall brain function in individuals with ASD. In our review article, we present a novel insight into purinergic signaling, including but not limited to the adenosinergic pathway and its role in neuroinflammation and neuro-immune cross-talk modulation. We anticipate that by achieving a greater understanding of the purinergic signaling contribution to ASD and related disorders, novel therapeutic strategies may be devised for patients with autism in the near future.

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Anti-inflammatory effect of P2Y1 receptor blocker MRS2179 in a rat model of traumatic brain injury

Cited by 7 publications

References 76 publications

Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery

Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery

Inhibition of P2X4 and P2X7 receptors improves histological and behavioral outcomes after experimental traumatic brain injury in rats

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

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