Aspirin up‐regulates suppressor of cytokine signaling 3 in glial cells via PPARα

Chakrabarti, Sudipta; Roy, Avik; Prorok, Tim; Patel, Dhruv; Dasarathi, Sridevi; Pahan, Kalipada

doi:10.1111/jnc.14813

Cited by 11 publications

(3 citation statements)

References 50 publications

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“…A previous study has shown that aspirin increases the expression of SOCS3, which is a potent anti-inflammatory molecule. We supposed that aspirin decreased IL-6 through regulating SOCS3 expression (47). Further study is warranted.…”

Section: Discussionmentioning

confidence: 87%

Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury

Dong¹,

Liu²,

Liu³

et al. 2022

Ann Transl Med

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Background: Dual antiplatelet therapy with aspirin and clopidogrel (ASA + CPG) during the first 21 days has been shown to reduce the risk of major ischemic events in patients with transient ischemic attack (TIA) or minor stroke. However, the mechanisms underlying combination treatment with ASA + CPG in experimental ischemic stroke has not been fully elucidated. Methods: Minor cerebral ischemia was induced in mice by transient distal middle cerebral artery occlusion (tdMCAO). Two doses of ASA + CPG (12 and 24 mg/kg/day) or vehicle were administered by gavage daily. Neurological behaviors were assessed using the modified Garcia scores, Rotarod test, Y maze, and open field test. Platelet function was assessed in vitro by flow cytometry and in vivo by bleeding and clotting time. The neutrophil ratio and the levels of inflammatory cytokines were measured by flow cytometry and the Meso Scale Discovery (MSD) electrochemilunimescence, respectively.Results: Sensorimotor function was partially recovered with ASA + CPG treatment after ischemia. Anxiety levels and cognitive functions showed improvement in the ASA + CPG group at 12 mg/kg/day after 21 days.Both tail bleeding time and flow cytometry showed significantly decreased platelet function after ASA + CPG treatment. Notably, ASA + CPG at 12 mg/kg/day prolonged clotting time at 28 days after injury. Furthermore, the ratio of neutrophils, an indicator of inflammation, was reduced with 12 mg/kg/day ASA + CPG treatment in the bone marrow (BM) at 21 days and in the peripheral blood (PB) at 21 and 28 days after tdMCAO. Both doses of ASA + CPG decreased pro-inflammatory cytokine interleukin (IL)-6 expression 21 days after stroke.Taken together, these results demonstrated that combination treatment with ASA + CPG improved longterm neurological function after stroke and may inhibit platelet-neutrophil interaction by decreasing the concentration of pro-inflammatory cytokine, IL-6.Conclusions: These findings indicate a neuroprotective effect of combination treatment with ASA + CPG for a duration of 21 days in an experimental acute minor stroke model. These findings provide further evidence that dual antiplatelet therapy may be a viable neuroprotective treatment to decrease the recurrence of stroke.

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Section: Discussionmentioning

confidence: 87%

Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury

Dong¹,

Liu²,

Liu³

et al. 2022

Ann Transl Med

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“…Astrocytic expression of SOCS3 and modulation of JAK2/STAT3 by this pathway, resulted in reduced amyloid deposition, improved spatial learning and attenuation of neuroinflammation in APP/PS1dE9 transgenic mice [ 144 ]. A study in mice found that low-dose aspirin can up-regulate SOCS3 in astrocytes and microglia by binding to the peroxisome proliferator-activated receptor alpha (PPARα) both in vitro and in vivo, with SOCS3 expression increased in GFAP-positive astrocytes, suggesting that aspirin can be a potent anti-inflammatory therapeutic target in AD [ 145 ].…”

Section: Astrocytes As a Therapeutic Target: Treatment And Neuroprote...mentioning

confidence: 99%

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

Rodríguez-Giraldo

González-Reyes

Ramírez-Guerrero

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a frequent and disabling neurodegenerative disorder, in which astrocytes participate in several pathophysiological processes including neuroinflammation, excitotoxicity, oxidative stress and lipid metabolism (along with a critical role in apolipoprotein E function). Current evidence shows that astrocytes have both neuroprotective and neurotoxic effects depending on the disease stage and microenvironmental factors. Furthermore, astrocytes appear to be affected by the presence of amyloid-beta (Aβ), with alterations in calcium levels, gliotransmission and proinflammatory activity via RAGE-NF-κB pathway. In addition, astrocytes play an important role in the metabolism of tau and clearance of Aβ through the glymphatic system. In this review, we will discuss novel pharmacological and non-pharmacological treatments focused on astrocytes as therapeutic targets for AD. These interventions include effects on anti-inflammatory/antioxidant systems, glutamate activity, lipid metabolism, neurovascular coupling and glymphatic system, calcium dysregulation, and in the release of peptides which affects glial and neuronal function. According to the AD stage, these therapies may be of benefit in either preventing or delaying the progression of the disease.

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“…It has been shown that gemfibrozil is capable of suppressing the expression of different proinflammatory molecules in astrocytes and microglia (Pahan et al, 2002;Xu et al, 2005;Jana et al, 2007;. Usually, proinflammatory signaling pathways are kept in check by different anti-inflammatory molecules like SOCS3 and IL-1Ra in many cell types including brain cells (Gabay et al, 2010;Ghosh et al, 2017;Chakrabarti et al, 2021). It has been reported that low-dose gemfibrozil treatment can upregulate the level of both SOCS3 (Ghosh and Pahan, 2012) and IL-1Ra (Corbett et al, 2012) in brain cells.…”

Section: Introductionmentioning

confidence: 99%

Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

Mondal,

Sheinin,

Rangasamy

et al. 2024

Front. Cell. Neurosci.

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It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood–brain barrier (BBB) and blood–spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα–/– mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα–/– EAE mice, but not PPARβ–/– EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα.

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Aspirin up‐regulates suppressor of cytokine signaling 3 in glial cells via PPARα

Abstract: Neuroinflammation is being recognized as a hallmark of different neurodegenerative disorders,

Cited by 11 publications

References 50 publications

Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury

Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

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