Carbon Monoxide Modulation of Microglia-neuron Communication: Anti-neuroinflammatory and Neurotrophic Role

Abstract Microglia, the ‘resident immunocompetent cells’ of the central nervous system (CNS), are key players in innate immunity, synaptic refinement and homeostasis. Dysfunctional microglia contribute heavily to creating a toxic inflammatory milieu, a driving factor in the pathophysiology of several CNS disorders. Therefore, strategies to modulate the microglial function are required to tackle exacerbated tissue inflammation. Carbon monoxide (CO), an endogenous gaseous molecule produced by the degradation of haem, has anti-inflammatory, anti-apoptotic, pro-homeostatic and cytoprotective roles, among others.ALF826A, a novel molybdenum-based CO-releasing molecule, was used for the assessment of neuron-microglia remote communication. Primary cultures of rat microglia and neurons, or the BV-2 microglial and CAD neuronal murine cell lines, were used to study the microglia-neuron interaction. An approach based on microglial-derived conditioned media in neuronal culture was applied. Medium derived from CO-treated microglia provided indirect neuroprotection against inflammation by limiting the lipopolysaccharide (LPS)-induced expression of reactivity markers (CD11b), the production of reactive oxygen species (ROS) and the secretion of inflammatory factors (TNF-α, nitrites). This consequently prevented neuronal cell death and maintained neuronal morphology In contrast, in the absence of inflammatory stimulus, conditioned media from CO-treated microglia improved neuronal morphological complexity, which is an indirect manner of assessing neuronal function. Likewise, the microglial medium also prevented neuronal cell death induced by pro-oxidant tert-Butyl hydroperoxide (t-BHP). ALF826 treatment reinforced microglia secretion of Interleukin-10 (IL-10) and adenosine, mediators that may protect against t-BHP stress in this remote communication model. Chemical inhibition of the adenosine receptors A2A and A1 reverted the CO-derived neuroprotective effect, further highlighting a role for CO in regulating neuron-microglia communication via purinergic signalling.Our findings indicate that CO has a modulatory role on microglia-to-neuron communication, promoting neuroprotection in a non-cell autonomous manner. CO enhances the microglial release of neurotrophic factors and blocks exacerbated microglial inflammation. CO improvement of microglial neurotrophism under non-inflammatory conditions is here described for the first time.

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Carbon Monoxide Modulation of Microglia-Neuron Communication: Anti-Neuroinflammatory and Neurotrophic Role

10.21203/rs.3.rs-745011/v1 ◽

2021 ◽

Author(s):

Nuno L. Soares ◽

Inês Paiva ◽

Joana Bravo ◽

Claudia S.F. Queiroga ◽

Bernadete F. Melo ◽

...

Keyword(s):

Carbon Monoxide ◽

Cell Death ◽

Cell Line ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Mouse Cell ◽

Neuronal Morphology ◽

Conditioned Media ◽

Remote Communication ◽

Mouse Cell Line

Abstract Background Microglia, the ‘resident immunocompetent cells’ of the central nervous system (CNS), are key players in innate immunity, synaptic refinement and homeostasis. Dysfunctional microglia contribute heavily to the creation of a toxic inflammatory milieu, a driving factor in the pathophysiology of several CNS disorders. Strategies for modulation of microglial function are required to tackle exacerbated tissue inflammation. Carbon monoxide (CO) is an endogenous gaseous molecule, produced by the degradation of haem, which presents several biological functions, namely anti-inflammatory, anti-apoptotic, pro-homeostatic and cytoprotective.Methods A novel molybdenum based CO-releasing molecule ALF826 was used for the assessment of neuron-microglia remote communication. Primary cultures of rat microglia and neurons, or BV-2 microglial mouse cell line and CAD neuronal mouse cell line were used to study microglia to neuron interaction. An approach based on microglial derived conditioned media in neuronal culture was applied.Results Medium derived from CO-treated microglia provided indirect neuroprotection against inflammation by limiting lipopolysaccharide (LPS)-induced expression of reactivity markers (CD11b), production of reactive oxygen species (ROS) and secretion of inflammatory factors (TNF-α, nitrites). This consequently prevented neuronal cell death and maintained neuronal morphology. In contrast, in the absence of inflammatory stimulus, conditioned media from CO-treated microglia improved neuronal morphological complexity, which is an indirect manner of assessing neuronal function. Likewise, microglial medium also prevented neuronal cell death induced by pro-oxidant tert-Butyl hydroperoxide (t-BHP). ALF826 treatment reinforced microglia secretion of Interleukin-10 (IL-10) and adenosine, mediators which may be involved in providing protection against t-BHP stress in this remote communication model. Chemical inhibition of adenosine receptors A2A and A1 reverted CO-derived neuroprotective effect, further highlighting a role for CO in regulating neuron-microglia communication via purinergic signalling.Conclusions Our findings indicate that CO has a modulatory role on microglia-to-neuron communication, promoting neuroprotection in a non-cell autonomous manner. In conclusion, CO-induced neuroprotection is afforded (i) by blocking exacerbated microglial inflammation and (ii) by the microglial release of neurotrophic factors. For the first time it is described CO improvement of microglial neurotrophism under non-inflammatory conditions.

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NMDA Receptor-Mediated Neuroprotective Effect of theScutellaria baicalensisGeorgi Extract on the Excitotoxic Neuronal Cell Death in Primary Rat Cortical Cell Cultures

The Scientific World JOURNAL ◽

10.1155/2014/459549 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Jinsong Yang ◽

Xiaohong Wu ◽

Haogang Yu ◽

Xinbiao Liao ◽

Lisong Teng

Keyword(s):

Cell Death ◽

Nmda Receptor ◽

Cell Cultures ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Cortical Cell ◽

Neuronal Cell ◽

Ethanol Extract ◽

Phytochemical Analysis ◽

Cortical Cell Cultures

The objective of the current research work was to evaluate the neuroprotective effect of the ethanol extract ofScutellaria baicalensis(S.B.) on the excitotoxic neuronal cell death in primary rat cortical cell cultures. The inhibitory effects of the extract were qualitatively and quantitatively estimated by phase-contrast microscopy and lactate dehydrogenase (LDH) assays. The extract exhibited a potent and dose-dependent inhibition of the glutamate-induced excitotoxicity in the culture media. Further, using radioligand binding assays, it was observed that the inhibitory effect of the extract was more potent and selective for the N-methyl-D-aspartate (NMDA) receptor-mediated toxicity. The S.B. ethanol extract competed with [3H] MDL 105,519 for the specific binding to the NMDA receptor glycine site with 50% inhibition occurring at 35.1 μg/mL. Further, NMDA receptor inactivation by the S.B. ethanol extract was concluded from the decreasing binding capability of [3H]MK-801 in the presence of the extract. Thus, S.B. extract exhibited neuroprotection against excitotoxic cell death, and this neuroprotection was mediated through the inhibition of NMDA receptor function by interacting with the glycine binding site of the NMDA receptor. Phytochemical analysis of the bioactive extract revealed the presence of six phytochemical constituents including baicalein, baicalin, wogonin, wogonoside, scutellarin, and Oroxylin A.

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Protective Effects of Active Compounds from Salviae miltiorrhizae Radix against Glutamate-Induced HT-22 Hippocampal Neuronal Cell Death

Processes ◽

10.3390/pr8080914 ◽

2020 ◽

Vol 8 (8) ◽

pp. 914

Author(s):

Hung Manh Phung ◽

Sullim Lee ◽

Ki Sung Kang

Keyword(s):

Cell Death ◽

Rosmarinic Acid ◽

Calcium Influx ◽

Salvia Miltiorrhiza ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Salvianolic Acid B ◽

Tanshinone Iia ◽

Salvianolic Acid

Oxidative stress is considered one of the factors that cause dysfunction and damage of neurons, causing diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD).Recently, natural antioxidant sources have emerged as one of the main research areas for the discovery of potential neuroprotectants that can be used to treat neurological diseases. In this research, we assessed the neuroprotective effect of a 70% ethanol Salvia miltiorrhiza Radix (SMR) extract and five of its constituent compounds (tanshinone IIA, caffeic acid, salvianolic acid B, rosmarinic acid, and salvianic acid A) in HT-22 hippocampal cells. The experimental data showed that most samples were effective in attenuating the cytotoxicity caused by glutamate in HT-22 cells, except for rosmarinic acid and salvianolic acid B. Of the compounds tested, tanshinone IIA (TS-IIA) exerted the strongest effect in protecting HT-22 cells against glutamate neurotoxin. Treatment with 400 nM TS-IIA restored HT-22 cell viability almost completely. TS-IIA prevented glutamate-induced oxytosis by abating the accumulation of calcium influx, reactive oxygen species, and phosphorylation of mitogen-activated protein kinases. Moreover, TS-IIA inhibited glutamate-induced cytotoxicity by reducing the activation and phosphorylation of p53, as well as by stimulating Akt expression. This research suggested that TS-IIA is a potential neuroprotective component of SMR, with the ability to protect against neuronal cell death induced by excessive amounts of glutamate.

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Neuroprotective effect of Scutellaria baicalensis flavones against global ischemic model in rats

Journal of Nepal Pharmaceutical Association ◽

10.3126/jnpa.v27i1.12144 ◽

2015 ◽

Vol 27 (1) ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Bjakta Prasad Gaire ◽

Young Ock Kim ◽

Zhen Hua Jin ◽

Juyeon Park ◽

Hoyoung Choi ◽

...

Keyword(s):

Cell Death ◽

Gastric Ulcer ◽

Methanol Extract ◽

Biological Effects ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Alternative Therapies ◽

Scutellaria Baicalensis ◽

Scutellaria Baicalensis Georgi

Scutellaria baicalensis Georgi (SB) is the medicinal plants mainly used in traditional Chinese medicine. It has been used for the treatment of various chronic inflammatory syndromes including respiratory disease, fever and gastric ulcer in traditional Eastern medicine and its major components; baicalin, baicalein and wogonin; were reported to have various biological effects. The aim of this study was to isolate the neuroprotective flavones from the root of S. baicalensis (SB) by bioactivity-guided fractionation of S. baicalensis methanol extract (SBME). Neuroprotective effect of isolated flavones, namely was studied on global ischemic model in rat by 4-VO. SBME was fractionated with different solvent and resulting fractions were administered at a dose of 25 mg/kg to the rat and potent neuroprotective fractions were sub-fractionated. At a dose of 10 mg/kg, isolated compounds, wogonin, and baicalein inhibited the hippocampal neuronal cell death by 78.6% and 81.0% respectively. Our study suggested that SB and its isolated flavones have potential neuroprotective effect and these findings may be one of the alternative therapies for the management of stroke and other neurodegenerative diseases. DOI: http://dx.doi.org/10.3126/jnpa.v27i1.12144 Journal of Nepal Pharmaceutical Association 2014 Vol.XXVII: 1-8

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Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

Journal of Endocrinology ◽

10.1677/joe-10-0040 ◽

2010 ◽

Vol 205 (3) ◽

pp. 263-270 ◽

Cited By ~ 69

Author(s):

Jiyeon Lee ◽

Eunjin Lim ◽

Yumi Kim ◽

Endan Li ◽

Seungjoon Park

Keyword(s):

Cell Death ◽

Kainic Acid ◽

Hippocampal Neurons ◽

Therapeutic Potential ◽

Excitatory Amino Acid ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Proinflammatory Mediators ◽

Hippocampal Neurodegeneration

Ghrelin is an endogenous ligand for GH secretagogue receptor type 1a (GHSR1a), and is produced and released mainly from the stomach. It has been recently demonstrated that ghrelin can function as a neuroprotective factor by inhibiting apoptotic pathways. Kainic acid (KA), an excitatory amino acid l-glutamate analog, causes neuronal death in the hippocampus; previous studies suggest that activated microglia and astrocytes actively participate in the pathogenesis of KA-induced hippocampal neurodegeneration. However, it is unclear whether ghrelin has neuroprotective effect in KA-induced hippocampal neurodegeneration. I.p. injection of KA produced typical neuronal cell death in the CA1 and CA3 pyramidal layers of the hippocampus, and the systemic administration of ghrelin significantly attenuated KA-induced neuronal cell death in these regions through the activation of GHSR1a. Ghrelin prevents KA-induced activation of microglia and astrocytes, and the expression of proinflammatory mediators tumor necrosis factor α, interleukin-1β, and cyclooxygenase-2. The inhibitory effect of ghrelin on the activation of microglia and astrocytes appears to be associated with the inhibition of matrix metalloproteinase-3 expression in damaged hippocampal neurons. Our data suggest that ghrelin has a therapeutic potential for suppressing KA-induced pathogenesis in the brain.

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Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

10.21203/rs.3.rs-220057/v1 ◽

2021 ◽

Author(s):

Qing Ye ◽

Nasser Al-Kuwari ◽

Pranay Srivast ◽

Xiqun Chen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Glial Cells ◽

Primary Cultures ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Braf V600e ◽

Downstream Effectors ◽

Mutational Activation

Abstract Background Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAFV600E as well as BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAFV600E-expressing microglia induced neuronal cell death. In neuronal cells, BRAFV600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

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Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6565396 ◽

2020 ◽

Vol 2020 ◽

pp. 1-30 ◽

Cited By ~ 6

Author(s):

Nur Shafika Mohd Sairazi ◽

K. N. S. Sirajudeen

Keyword(s):

Cell Death ◽

Natural Products ◽

Neurodegenerative Diseases ◽

Bioactive Compounds ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuronal Structure ◽

And Function

In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

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Hypothermia Reduces Toll-Like Receptor 3-Activated Microglial Interferon-βand Nitric Oxide Production

Mediators of Inflammation ◽

10.1155/2013/436263 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Tomohiro Matsui ◽

Yukari Motoki ◽

Yusuke Yoshida

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Therapeutic Hypothermia ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Dependent Manner ◽

Cns Injury ◽

Concentration Dependent Manner ◽

Polycytidylic Acid

Therapeutic hypothermia protects neurons after injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in the pathogenesis of sterile CNS injury. To elucidate the possible mechanisms involved in the neuroprotective effect of therapeutic hypothermia, we examined the effects of hypothermic culture on TLR3-activated microglial release of interferon (IFN)-βand nitric oxide (NO), which are known to be associated with neuronal cell death. When rat or mouse microglia were cultured under conditions of hypothermia (33°C) and normothermia (37°C) with a TLR3 agonist, polyinosinic-polycytidylic acid, the production of IFN-βand NO in TLR3-activated microglia at 48 h was decreased by hypothermia compared with that by normothermia. In addition, exposure to recombinant IFN-βand sodium nitroprusside, an NO donor, caused death of rat neuronal pheochromocytoma PC12 cells in a concentration-dependent manner after 24 h. Taken together, these results suggest that the attenuation of microglial production of IFN-βand NO by therapeutic hypothermia leads to the inhibition of neuronal cell death.

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Neuroprotective γ-Pyrones from Fusarium Solani JS-0169: Cell-Based Identification of Active Compounds and an Informatics Approach to Predict the Mechanism of Action

Biomolecules ◽

10.3390/biom10010091 ◽

2020 ◽

Vol 10 (1) ◽

pp. 91 ◽

Cited By ~ 3

Author(s):

Hyun Gyu Choi ◽

Ji Hoon Song ◽

Musun Park ◽

Soonok Kim ◽

Chang-Eop Kim ◽

...

Keyword(s):

Cell Death ◽

Fusarium Solani ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuroprotective Activity ◽

Glutamate Toxicity ◽

Protective Effects ◽

Cns Injury ◽

Ht22 Cells

Glutamate toxicity has been implicated in neuronal cell death in both acute CNS injury and in chronic diseases. In our search for neuroprotective agents obtained from natural sources that inhibit glutamate toxicity, an endophytic fungus, Fusarium solani JS-0169 isolated from the leaves of Morus alba, was found to show potent inhibitory activity. Chemical investigation of the cultures of the fungus JS-0169 afforded isolation of six compounds, including one new γ-pyrone (1), a known γ-pyrone, fusarester D (2), and four known naphthoquinones: karuquinone B (3), javanicin (4), solaniol (5), and fusarubin (6). To identify the protective effects of the isolated compounds (1–6), we assessed their inhibitory effect against glutamate-induced cytotoxicity in HT22 cells. Among the isolates, compound 6 showed significant neuroprotective activity on glutamate-mediated HT22 cell death. In addition, the informatics approach using in silico systems pharmacology identified that compound 6 may exert its neuroprotective effect by controlling the amount of ubiquinone. The results suggest that the metabolites produced by the endophyte Fusarium solani JS-0169 might be related to the neuroprotective activity of its host plant, M. alba.

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