Bone marrow mesenchymal stem cells upregulate PI3K/AKT pathway and down-regulate NF-κB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats

Zhong, Zhenzhong; Chen, Ao; Fa, Zhiqiang; Ding, Zhiquan; Xiao, Linglong; Wu, Guiwei; Wang, Qinghua; Zhang, Run

doi:10.1016/j.nbd.2020.104945

Cited by 43 publications

(24 citation statements)

References 32 publications

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“…The administration of mesenchymal stem cells (MSCs) has emerged as a promising therapeutic strategy for brain neurodegenerative and inflammatory diseases due to their pleiotropic mechanisms of actions that include cell replacement, promotion of survival via paracrine signaling, modulation of inflammation, and reduction of oxidative damage [192]. Among the different types of adult stem cells, MSCs are one of the most employed in pre-clinical studies since these: (i) can be easily isolated from different tissues (e.g., fat depots, bone marrow, cord blood, menstrual blood) and expanded in vitro; (ii) exhibit great proliferative potential [193]; (iii) produce high levels of antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase; thus being able to reduce oxidative stress [194]; (iv) have potent immunomodulatory properties mediated by the secretion of anti-inflammatory molecules and the inhibition of microglia and astrocyte activation [195][196][197] (thus having a dual impact blunting the agents that promote the oxidative stress-neuroinflammation potentiation), and (v) have a good safety profile [198]. Importantly, MSCs show low immunogenicity [199], allowing allogeneic transplantation without immunosuppression.…”

Section: Mesenchymal Stem Cells and Their Productsmentioning

confidence: 99%

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

et al. 2020

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Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc− activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

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Section: Mesenchymal Stem Cells and Their Productsmentioning

confidence: 99%

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

et al. 2020

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“…Zhang et al (Zhang et al, 2013) showed that NF-κB activation was ascended in rat lumbar DRG neurons following type 2 diabetes mellitus-induced NP. Zhong et al (Zhong et al, 2020) have shown that bone marrow mesenchymal stem cells down-regulate the NF-κB pathway to alleviate deafferentation pain in rats. Recently, a revolutionary idea has been put forward suggesting that induction of pyroptosis is accompanied by NF-κB activation during in ammation (Yao & Sun, 2019).…”

Section: Discussionmentioning

confidence: 99%

Melatonin Attenuates Pyroptosis Upon Spinal Nerve Ligation in Rats via the NF-κB/NLRP3 Inflammasome Signaling Pathway

Wang

Gao

Tang

et al. 2021

Preprint

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Accumulated evidences have demonstrated causative links between neuropathic pain (NP) and immune-mediated inflammatory disorders. However, the role of inflammasome-induced pyroptosis in NP remains elusive. Melatonin possesses a well-documented analgesic action in various pain models. A rat model of spinal nerve ligation was established to explore the potential mechanism of melatonin in pyroptosis. The current study aimed to test our hypothesis that melatonin regulated pyroptosis to alleviate NP by inhibiting NF-κB/NLRP3-dependent signaling. Behavioral experiments revealed that SNL provoked severe allodynia which were suppressed by the administration of melatonin, caspase-1 inhibitor (VX-765) or NF-κB inhibitor (BAY 11-7085). SNL significantly up-regulated the inflammatory cytokines associated with the excessive activation of NLRP3 components and NF-κB signaling, as well as the marked pyroptosis activation which were partially inhibited by melatonin, VX-765 or BAY 11-7085. Collectively, Melatonin has potent analgesic and anti-inflammatory effects in SNL models through preventing pyroptosis via the NF-κB/NLRP3 inflammasome signaling pathway.

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“…In deafferentation pain model the bone marrow mesenchymal stem cells (BMSC) inhibited neuroinflammation by transforming microglial destructive M1 phenotype into regenerative M2 phenotype, thus alleviating pain. This process likely occurred via GDNF-induced suppression of NF-κB and activation of PI3K/AKT signaling pathways (Zhong et al, 2020).…”

Section: Effects Of Glial Cell Line-derived Neurotrophic Factor Family Ligands In Glial Cellsmentioning

confidence: 99%

Glial Cell Line-Derived Neurotrophic Factor Family Ligands, Players at the Interface of Neuroinflammation and Neuroprotection: Focus Onto the Glia

Kotliarova

Sidorova

2021

Front. Cell. Neurosci.

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Well-known effects of neurotrophic factors are related to supporting the survival and functioning of various neuronal populations in the body. However, these proteins seem to also play less well-documented roles in glial cells, thus, influencing neuroinflammation. This article summarizes available data on the effects of glial cell line derived neurotrophic factor (GDNF) family ligands (GFLs), proteins providing trophic support to dopaminergic, sensory, motor and many other neuronal populations, in non-neuronal cells contributing to the development and maintenance of neuropathic pain. The paper also contains our own limited data describing the effects of small molecules targeting GFL receptors on the expression of the satellite glial marker IBA1 in dorsal root ganglia of rats with surgery- and diabetes-induced neuropathy. In our experiments activation of GFLs receptors with either GFLs or small molecule agonists downregulated the expression of IBA1 in this tissue of experimental animals. While it can be a secondary effect due to a supportive role of GFLs in neuronal cells, growing body of evidence indicates that GFL receptors are expressed in glial and peripheral immune system cells. Thus, targeting GFL receptors with either proteins or small molecules may directly suppress the activation of glial and immune system cells and, therefore, reduce neuroinflammation. As neuroinflammation is considered to be an important contributor to the process of neurodegeneration these data further support research efforts to modulate the activity of GFL receptors in order to develop disease-modifying treatments for neurodegenerative disorders and neuropathic pain that target both neuronal and glial cells.

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Bone marrow mesenchymal stem cells upregulate PI3K/AKT pathway and down-regulate NF-κB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats

Cited by 43 publications

References 32 publications

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Melatonin Attenuates Pyroptosis Upon Spinal Nerve Ligation in Rats via the NF-κB/NLRP3 Inflammasome Signaling Pathway

Glial Cell Line-Derived Neurotrophic Factor Family Ligands, Players at the Interface of Neuroinflammation and Neuroprotection: Focus Onto the Glia

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