Abscisic Acid Activates the Murine Microglial Cell Line N9 through the Second Messenger Cyclic ADP-ribose

Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2009; 284(22):14777-87. DOI: 10.1074/jbc.M802604200
Source: PubMed


Abscisic acid (ABA) is a phytohormone regulating important functions in higher plants, notably responses to abiotic stress. Recently, chemical or physical stimulation of human granulocytes was shown to induce production and release of endogenous ABA, which activates specific cell functions. Here we provide evidence that ABA stimulates several functional activities of the murine microglial cell line N9 (NO and tumor necrosis factor-alpha production, cell migration) through the second messenger cyclic ADP-ribose and an increase of intracellular calcium. ABA production and release occur in N9 cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate, the chemoattractant peptide f-MLP, or beta-amyloid, the primary plaque component in Alzheimer disease. Finally, ABA priming stimulates N9 cell migration toward beta-amyloid. These results indicate that ABA is a pro-inflammatory hormone inducing autocrine microglial activation, potentially representing a new target for anti-inflammatory therapies aimed at limiting microglia-induced tissue damage in the central nervous system.

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    • "The functional roles of cADPR have been well studied in microglia. cADPR promotes microglial activation and secretion of proinflammatory cytokines (Franco el al., 2006; Mayo et al., 2008; Bodrato et al., 2009). However, little is known of NAADP. "
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    ABSTRACT: Microglial cells, the immunocompetent cells of the central nervous system (CNS), exhibit a resting phenotype under healthy conditions. In response to injury, however, they transform into an activated state, which is a hallmark feature of many CNS diseases. Factors or agents released from the neurons, blood vessels, and/or astrocytes could activate these cells, leading to their functional and structural modifications. Microglial cells are well equipped to sense environmental changes within the brain under both physiological and pathological conditions. Entry of calcium ions (Ca(2+) ) plays a critical role in the process of microglial transformation; several channels and receptors have been identified on the surface of microglial cells. These include store-operated channel, Orai1, and its sensor protein, stromal interaction molecule 1 (STIM1), in microglial cells, and their functions are modulated under pathological stimulations. Transient receptor potential (TRP) channels and voltage- and ligand-gated channels (ionotropic and metabotropic receptors) are also responsible for Ca(2+) influx into the microglial cells. An elevation of intracellular Ca(2+) concentration subsequently regulates microglial cell functions by activating a diverse array of Ca(2+) -sensitive signaling cascades. Perturbed Ca(2+) homeostasis contributes to the progression of a number of CNS disorders. Thus, regulation of Ca(2+) entry into microglial cells could be a pharmacological target for several CNS-related pathological conditions. This Review addresses the recent insights into microglial cell Ca(2+) influx mechanisms, their roles in the regulation of functions, and alterations of Ca(2+) entry in specific CNS disorders. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Apr 2014 · Journal of Neuroscience Research
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    • "Two types of cells were used: rat brain primary astrocyte of and murine N9 microglial cell line [27,28]. "
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    ABSTRACT: Background Our past researches suggested that L. barbarum exhibits direct neuroprotective and immune regulatory effects on the central nervous system, which are highly related to the events involved in the spinal cord injury, but not yet been investigated. Immune responses play an important role in the development of the pathology after secondary injury, particularly the M1 and M2 types of macrophage, on which special emphasis was laid in this study. Methods In our previous studies L. barbarum was administrated orally from 7 days before the injury to ensure a stabilized concentration in the blood. For clinical application, L. barbarum can only be administered after the injury. Therefore, both pre-injury and post-injury administration protocols were compared. In vivo and in vitro studies were conducted and analyzed immunohistochemically, including Western blotting. Results The lesion size in the pre-treated group was much larger than that in the post-treated group. To explain this difference, we first studied the effect of L. barbarum on astrocytes, which forms the glial scar encircling the lesion. L. barbarum did not significantly affect the astrocytes. Then we studied the effect of L. barbarum on microglia/macrophages, particularly the M1 and M2 polarization. After spinal cord injury, the deleterious M1 cells dominant the early period, whereas the beneficial M2 cells dominate later. We found that in the pre-treated group L. barbarum significantly enhanced the expression of M1 cells and suppressed that of M2 cells, while in the post-treated group LBP markedly promoted the activity of M2 cells. This explained the difference between the pre- and post-treated groups. Conclusions Lycium barbarum has been wildly accepted to have beneficial effects in various central nervous system diseases. Our finding of deleterious effect of LBP administered at early period of spinal cord injury, indicates that its application should be avoided. The substantial beneficial effect of LBP when administered at later stage has an important impact for clinical application.
    Full-text · Article · Mar 2013 · BMC Complementary and Alternative Medicine
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    • "Despite our consistent anti-inflammatory in vivo findings , the effect of ABA on inflammation is somewhat ambiguous. In vitro studies from Bruzzone et al. [30], Magnone et al. [44], and Bordrato et al. [45] suggest that ABA has proinflammatory effects as well. In their work which principally dealt with ABA's potential effect on atherogenesis, Magnone et al. show that treatment of monocytes with ABA activates NF-κB and increases MCP-1 and MMP-9 release [44]. "
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    ABSTRACT: The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.
    Full-text · Article · Jan 2011 · Journal of obesity
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