The Impact of Timing of Microglial Activation by Inflammation and Hypoxia Regarding Additive Neurotoxic Effects

ABSTRACTIt has long been considered that psychosocial stress plays a role in the expression of symptoms in schizophrenia (SZ), as it interacts with latent neural vulnerability that stems from genetic liability and early environmental insult. Advances in the understanding of the neurobiology of the stress cascade in both animal and human studies lead to a plausible model by which this interaction may occur: through neurotoxic effects on the hippocampus that may involve synaptic remodeling. Of late, the neurodevelopmental model of SZ etiology has been favored. But an elaboration of this schema that credits the impact of postnatal events and considers a role for neurodegenerative changes may be more plausible, given the evidence for gene-environment interaction in SZ expression and progressive structural changes observed with magnetic resonance imaging. Furthermore, new insights into nongliotic neurotoxic effects such as apoptosis, failure of neurogenesis, and changes in circuitry lead to an expansion of the time frame in which environmental effects may mediate expression of SZ symptoms.

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Adverse Effects of Methylene Blue on the Central Nervous System

Anesthesiology ◽

10.1097/aln.0b013e3181684be4 ◽

2008 ◽

Vol 108 (4) ◽

pp. 684-692 ◽

Cited By ~ 83

Author(s):

Laszlo Vutskits ◽

Adrian Briner ◽

Paul Klauser ◽

Eduardo Gascon ◽

Alexandre G. Dayer ◽

...

Keyword(s):

Methylene Blue ◽

Cell Death ◽

Neuronal Cultures ◽

Dendritic Arbor ◽

Field Potentials ◽

Neurotoxic Effects ◽

The Central Nervous System ◽

The Impact

Background An increasing number of clinical observations suggest adverse neurologic outcome after methylene blue (MB) infusion in the setting of parathyroid surgery. Hence, the aim of the current study was to investigate the potentially neurotoxic effects of MB using a combination of in vivo and in vitro experimental approaches. Methods Isoflurane-anesthetized adult rats were used to evaluate the impact of a single bolus intravascular administration of MB on systemic hemodynamic responses and on the minimum alveolar concentration (MAC) of isoflurane using the tail clamp test. In vivo, MB-induced cell death was evaluated 24 h after MB administration using Fluoro-Jade B staining and activated caspase-3 immunohistochemistry. In vitro, neurotoxic effects of MB were examined in hippocampal slice cultures by measuring excitatory field potentials as well as propidium iodide incorporation after MB exposure. The impact of MB on dendritic arbor was evaluated in differentiated single cell neuronal cultures. Results Bolus injections of MB significantly reduced isoflurane MAC and initiated widespread neuronal apoptosis. Electrophysiologic recordings in hippocampal slices revealed a rapid suppression of evoked excitatory field potentials by MB, and this was associated with a dose-dependent effect of this drug on cell death. Dose-response experiments in single cell neuronal cultures revealed that a 2-h-long exposure to MB at non-cell-death-inducing concentrations could still induce significant retraction of dendritic arbor. Conclusions These results suggest that MB exerts neurotoxic effects on the central nervous system and raise questions regarding the safety of using this drug at high doses during parathyroid gland surgery.

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C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation

Journal of Neuroinflammation ◽

10.1186/s12974-021-02167-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Liu Ye ◽

Gongwei Jia ◽

Yuejie Li ◽

Ying Wang ◽

Hong Chen ◽

...

Keyword(s):

Food Intake ◽

Microglial Activation ◽

Obese Mice ◽

Related Protein ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

Tnf Α ◽

Hypothalamic Inflammation ◽

The Impact

Abstract Objective C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. Methods Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. Results We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. Conclusions Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

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The impact of microglial activation on blood-brain barrier in brain diseases

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2014.00362 ◽

2014 ◽

Vol 8 ◽

Cited By ~ 218

Author(s):

Anna Carolina Carvalho da Fonseca ◽

Diana Matias ◽

Celina Garcia ◽

Rackele Amaral ◽

Luiz Henrique Geraldo ◽

...

Keyword(s):

Blood Brain Barrier ◽

Microglial Activation ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain ◽

The Impact

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Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity

Biomolecules ◽

10.3390/biom11091292 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1292

Author(s):

Alexey A. Tinkov ◽

Airton C. Martins ◽

Daiana Silva Avila ◽

Victor A. Gritsenko ◽

Anatoly V. Skalny ◽

...

Keyword(s):

Gut Microbiota ◽

Biological Effects ◽

Mn Toxicity ◽

Bacterial Phyla ◽

Neurotoxic Effects ◽

Wall Permeability ◽

High Doses ◽

The Impact ◽

Existing Data

Manganese (Mn) is an essential metal, which at high exposures causes neurotoxic effects and neurodegeneration. The neurotoxic effects of Mn are mediated by neuroinflammation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, and other mechanisms. Recent findings have demonstrated the potential impact of Mn overexposure on gut microbiota dysbiosis, which is known to contribute to neurodegeneration via secretion of neuroactive and proinflammatory metabolites. Therefore, in this review, we discuss the existing data on the impact of Mn exposure on gut microbiota biodiversity, bacterial metabolite production, and gut wall permeability regulating systemic levels. Recent data have demonstrated that Mn exposure may affect gut microbiota biodiversity by altering the abundance of Shiegella, Ruminococcus, Dorea, Fusicatenibacter, Roseburia, Parabacteroides, Bacteroidetes, Firmicutes, Ruminococcaceae, Streptococcaceae, and other bacterial phyla. A Mn-induced increase in Bacteroidetes abundance and a reduced Firmicutes/Bacteroidetes ratio may increase lipopolysaccharide levels. Moreover, in addition to increased systemic lipopolysaccharide (LPS) levels, Mn is capable of potentiating LPS neurotoxicity. Due to the high metabolic activity of intestinal microflora, Mn-induced perturbations in gut microbiota result in a significant alteration in the gut metabolome that has the potential to at least partially mediate the biological effects of Mn overexposure. At the same time, a recent study demonstrated that healthy microbiome transplantation alleviates Mn-induced neurotoxicity, which is indicative of the significant role of gut microflora in the cascade of Mn-mediated neurotoxicity. High doses of Mn may cause enterocyte toxicity and affect gut wall integrity through disruption of tight junctions. The resulting increase in gut wall permeability further promotes increased translocation of LPS and neuroactive bacterial metabolites to the systemic blood flow, ultimately gaining access to the brain and leading to neuroinflammation and neurotransmitter imbalance. Therefore, the existing data lead us to hypothesize that gut microbiota should be considered as a potential target of Mn toxicity, although more detailed studies are required to characterize the interplay between Mn exposure and the gut, as well as its role in the pathogenesis of neurodegeneration and other diseases.

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TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

10.21203/rs.3.rs-1124682/v1 ◽

2021 ◽

Author(s):

Giulia Di Benedetto ◽

Chiara Burgaletto ◽

Maria Francesca Serapide ◽

Antonio Munafò ◽

Carlo Maria Bellanca ◽

...

Keyword(s):

Substantial Reduction ◽

Death Receptor ◽

Amyloid Β ◽

Potent Inducer ◽

P53 Expression ◽

Akt Phosphorylation ◽

Tnf Superfamily ◽

Neurotoxic Effects ◽

The Impact ◽

Deficient Mice

Abstract TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells undergone treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β protein. Likewise, TRAIL-R2 appears essential to both TRAIL-Aβ mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice, challenged with Aβ1-42, showed a scanty expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-a, iNOS and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

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Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.691648 ◽

2021 ◽

Vol 9 ◽

Author(s):

Donald H. Penning ◽

Simona Cazacu ◽

Aharon Brodie ◽

Vesna Jevtovic-Todorovic ◽

Steve N. Kalkanis ◽

...

Keyword(s):

Cell Death ◽

Extracellular Vesicles ◽

Neuronal Cells ◽

Neural Cells ◽

General Anesthetics ◽

Rt Pcr ◽

Neurotoxic Effects ◽

The Impact ◽

Bdnf Pathway

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

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Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

10.21203/rs.2.24503/v4 ◽

2020 ◽

Author(s):

Xiaowei Sun ◽

Peng Sun ◽

Limei Liu ◽

Pengfei Jiang ◽

YUANBIN LI

Keyword(s):

Ferulic Acid ◽

Retinal Degeneration ◽

Microglial Activation ◽

Inflammatory Factors ◽

Immunomodulatory Activity ◽

Retinal Structure ◽

The Impact ◽

Optimal Protection

Abstract Background: Retinal degeneration is often accompanied by microglia-mediated neuroinflammation. Ferulic acid (FA), an active ingredient of traditional Chinese medicines (TCMs), has been reported to have anti-inflammatory effects. This study explores the impact of FA on microglia-mediated neuroinflammation and associated retinal degeneration in rd10 mice. Methods: Rd10 mice received different concentrations of FA every day from postnatal day (P)4 to P24. On P25, the visual function of the mice was evaluated by electroretinogram, and retinae were collected for further investigation. Microglial activation and the expression of relevant cytokines in the retina were evaluated by qPCR, western blotting and immunofluorescence staining. Retinal structure was assessed by haematoxylin and eosin (HE) staining.Results: Supplementation with 50 mg/kg FA provided optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as greater wave amplitude amplification on electroretinogram than untreated mice. FA suppressed microglial activation both in vivo and in vitro, and inhibited the expression of pro-inflammatory factors Tnfα, IL1β, and Ccl2 in the retinae of rd10 mice. Furthermore, FA suppressed the activation of STAT1 and subsequently inhibited IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions: Attenuation of neuroinflammation by FA may be beneficial for retarding retinal degeneration.

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Sepsis-Associated Encephalopathy

10.1093/med/9780199653461.003.0032 ◽

2014 ◽

Author(s):

Eric Magalhaes ◽

Angelo Polito ◽

Andréa Polito ◽

Tarek Sharshar

Keyword(s):

Microglial Activation ◽

Specific Treatment ◽

Major Complication ◽

Endothelial Activation ◽

Brain Dysfunction ◽

Biological Mechanisms ◽

Neurotoxic Effects ◽

The Central Nervous System ◽

Alteration Of Consciousness

Brain dysfunction is a major complication of sepsis and is characterized by alteration of consciousness, ranging from delirium to coma and marked electroencephalographic changes. It reflects a constellation of dynamic biological mechanisms, including neurotransmitter imbalance, macro- and microcirculatory dysfunction resulting in ischaemia, endothelial activation, alteration of the blood-brain barrier impairment with passage of neurotoxic mediators, activation of microglial cells within the central nervous system, cumulatively resulting in a neuroinflammatory state. Sepsis-associated brain dysfunction is associated with increased mortality and long-term cognitive decline, whose mechanisms might include microglial activation, axonopathy, or cerebral microinfarction. There is no specific treatment, other than the management of the underlying septic source, correction of physiological and metabolic abnormalities, and limiting the use of medications with neurotoxic effects.

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Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

Cephalalgia ◽

10.1177/0333102417703764 ◽

2017 ◽

Vol 38 (4) ◽

pp. 674-689 ◽

Cited By ~ 15

Author(s):

Nathan T Fried ◽

Christina R Maxwell ◽

Melanie B Elliott ◽

Michael L Oshinsky

Keyword(s):

Blood Brain Barrier ◽

Rat Model ◽

Microglial Activation ◽

Brain Regions ◽

Brain Barrier ◽

Sodium Fluorescein ◽

Blood Brain ◽

Bbb Permeability ◽

The Impact ◽

Trigeminal Sensitivity

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

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