In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity

2016 ◽  
Vol 31 (3) ◽  
pp. 365-376 ◽  
Author(s):  
Pirathiv Kugathasan ◽  
Jessica Waller ◽  
Ligia Westrich ◽  
Aicha Abdourahman ◽  
Joseph A Tamm ◽  
...  
Keyword(s):  
Protein Level ◽  
Hippocampal Neurons ◽  
Transcript Level ◽  
Middle Aged ◽  
Α Subunit ◽  
Aged Mice ◽  
Positive Effects ◽  
Brain Functions

Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca2+/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.

scholarly journals Resveratrol Ameliorates Intestinal Damage Challenged With Deoxynivalenol Through Mitophagy in vitro and in vivo

2022 ◽  
Vol 8 ◽  
Author(s):  
Yujian Huang ◽  
Changbing Zheng ◽  
Bo Song ◽  
Li Wang ◽  
Hao Xiao ◽  
...  
Keyword(s):  
Growth Performance ◽  
Protein Level ◽  
Dietary Supplementation ◽  
Protective Mechanism ◽  
Intestinal Damage ◽  
Intestinal Function ◽  
Positive Effects ◽  
Weaning Piglets

Deoxynivalenol (DON) reduces growth performance and damage intestinal function, and resveratrol (RES) has positive effects on growth performance and intestinal function. The purpose of this study was to investigate the protective mechanism of RES in vitro and vivo challenged with DON. The results showed that dietary supplementation with DON significantly increase the mRNA expression levels of mitophagy- related genes, and protein level for PINK1, Parkin, Beclin-1, Lamp, Atg5, Map1lc, Bnip3, Fundc1, Bcl2l1 and SQSTMS1 (P < 0.05), while supplementation with both RES and DON decreased those indexes in the ileum. Besides DON significantly decreased protein level for Pyruvate Dehydrogenase, Cytochrome c, MFN1, OPA1, and PHB1 (P < 0.05), while supplementation with both RES and DON increased protein level for PHB1, SDHA, and VDAC in the ileum. Moreover, in vitro, we found that DON significantly decreased mitochondrial respiration (P < 0.05), while RES + DON increased the rate of spare respiratory capacity. Also, DON significantly decreased total NAD and ATP (P < 0.05), while RES + DON increased the total NAD and ATP. These results indicate that RES may ameliorates the intestinal damage challenged with deoxynivalenol through mitophagy in weaning piglets.

scholarly journals Interleukin 3 Prevents Delayed Neuronal Death in the Hippocampal CA1 Field

1998 ◽  
Vol 188 (4) ◽  
pp. 635-649 ◽  
Author(s):  
Tong-Chun Wen ◽  
Junya Tanaka ◽  
Hui Peng ◽  
Junzo Desaki ◽  
Seiji Matsuda ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Delayed Neuronal Death ◽  
Α Subunit ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Field

In the central nervous system, interleukin (IL)-3 has been shown to exert a trophic action only on septal cholinergic neurons in vitro and in vivo, but a widespread distribution of IL-3 receptor (IL-3R) in the brain does not conform to such a selective central action of the ligand. Moreover, the mechanism(s) underlying the neurotrophic action of IL-3 has not been elucidated, although an erythroleukemic cell line is known to enter apoptosis after IL-3 starvation possibly due to a rapid decrease in Bcl-2 expression. This in vivo study focused on whether IL-3 rescued noncholinergic hippocampal neurons from lethal ischemic damage by modulating the expression of Bcl-xL, a Bcl-2 family protein produced in the mature brain. 7-d IL-3 infusion into the lateral ventricle of gerbils with transient forebrain ischemia prevented significantly hippocampal CA1 neuron death and ischemia-induced learning disability. TUNEL (terminal deoxynucleotidyltransferase–mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling) staining revealed that IL-3 infusion caused a significant reduction in the number of CA1 neurons exhibiting DNA fragmentation 7 d after ischemia. The neuroprotective action of IL-3 appeared to be mediated by a postischemic transient upregulation of the IL-3R α subunit in the hippocampal CA1 field where IL-3Rα was barely detectable under normal conditions. In situ hybridization histochemistry and immunoblot analysis demonstrated that Bcl-xL mRNA expression, even though upregulated transiently in CA1 pyramidal neurons after ischemia, did not lead to the production of Bcl-xL protein in ischemic gerbils infused with vehicle. However, IL-3 infusion prevented the decrease in Bcl-xL protein expression in the CA1 field of ischemic gerbils. Subsequent in vitro experiments showed that IL-3 induced the expression of Bcl-xL mRNA and protein in cultured neurons with IL-3Rα and attenuated neuronal damage caused by a free radical–producing agent FeSO4. These findings suggest that IL-3 prevents delayed neuronal death in the hippocampal CA1 field through a receptor-mediated expression of Bcl-xL protein, which is known to facilitate neuron survival. Since IL-3Rα in the hippocampal CA1 region, even though upregulated in response to ischemic insult, is much less intensely expressed than that in the CA3 region tolerant to ischemia, the paucity of IL-3R interacting with the ligand may account for the vulnerability of CA1 neurons to ischemia.

scholarly journals Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e67419 ◽  
Author(s):  
Rami A. Namas ◽  
John Bartels ◽  
Rosemary Hoffman ◽  
Derek Barclay ◽  
Timothy R. Billiar ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
In Silico ◽  
In Vitro Studies ◽  
Acute Inflammatory Response ◽  
Middle Aged ◽  
Aged Mice

Metabolomics of Healthy Berry Fruits

2019 ◽  
Vol 25 (37) ◽  
pp. 4888-4902 ◽  
Author(s):  
Gilda D'Urso ◽  
Sonia Piacente ◽  
Cosimo Pizza ◽  
Paola Montoro
Keyword(s):  
Biological Activities ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Bioactive Metabolites ◽  
Active Metabolites ◽  
Positive Effects ◽  
Cell Functions ◽  
Berry Fruits

The consumption of berry-type fruits has become very popular in recent years because of their positive effects on human health. Berries are in fact widely known for their health-promoting benefits, including prevention of chronic disease, cardiovascular disease and cancer. Berries are a rich source of bioactive metabolites, such as vitamins, minerals, and phenolic compounds, mainly anthocyanins. Numerous in vitro and in vivo studies recognized the health effects of berries and their function as bioactive modulators of various cell functions associated with oxidative stress. Plants have one of the largest metabolome databases, with over 1200 papers on plant metabolomics published only in the last decade. Mass spectrometry (MS) and NMR (Nuclear Magnetic Resonance) are the most important analytical technologies on which the emerging ''omics'' approaches are based. They may provide detection and quantization of thousands of biologically active metabolites from a tissue, working in a ''global'' or ''targeted'' manner, down to ultra-trace levels. In the present review, we highlighted the use of MS and NMR-based strategies and Multivariate Data Analysis for the valorization of berries known for their biological activities, important as food and often used in the preparation of nutraceutical formulations.

scholarly journals Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

2021 ◽  
Author(s):  
Naresh Damuka ◽  
Miranda Orr ◽  
Paul W. Czoty ◽  
Jeffrey L. Weiner ◽  
Thomas J. Martin ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Ex Vivo ◽  
Neuroblastoma Cells ◽  
Proper Function ◽  
Brain Functions ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
Vitro Binding

AbstractMicrotubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

2020 ◽  
Vol 54 (01) ◽  
pp. 37-46
Author(s):  
Kristina Friedland ◽  
Giacomo Silani ◽  
Anita Schuwald ◽  
Carola Stockburger ◽  
Egon Koch ◽  
...  
Keyword(s):  
Essential Oil ◽  
Hippocampal Neurons ◽  
Day Treatment ◽  
Neuronal Cell ◽  
Antidepressant Activity ◽  
In Vivo Models ◽  
Antidepressant Effects ◽  
Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

scholarly journals Strong Antimicrobial and Healing Effects of Beta-Acids from Hops in Methicillin-Resistant Staphylococcus aureus-Infected External Wounds In Vivo

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 708
Author(s):  
Radek Sleha ◽  
Vera Radochova ◽  
Jiri Malis ◽  
Alexander Mikyska ◽  
Milan Houska ◽  
...  
Keyword(s):  
Wound Healing ◽  
Porcine Model ◽  
Therapeutic Effects ◽  
Methicillin Resistant ◽  
Antimicrobial Effects ◽  
Therapeutic Modalities ◽  
Positive Effects ◽  
Inflammatory Parameters

Staphylococcus (S.) aureus is an important causative agent of wound infections with increasing incidence in the past decades. Specifically, the emergence of methicillin-resistant S. aureus (MRSA) causes serious problems, especially in nosocomial infections. Therefore, there is an urgent need to develop of alternative or supportive antimicrobial therapeutic modalities to meet these challenges. Purified compounds from hops have previously shown promising antimicrobial effects against MRSA isolates in vitro. In this study, purified beta-acids from hops were tested for their potential antimicrobial and healing properties using a porcine model of wounds infected by MRSA. The results show highly significant antimicrobial effects of the active substance in both the powder and Ambiderman-based application forms compared to both no-treatment control and treatment with Framycoin. Moreover, the macroscopic evaluation of the wounds during the treatment using the standardized Wound Healing Continuum indicated positive effects of the beta-acids on the overall wound healing. This is further supported by the microscopic data, which showed a clear improvement of the inflammatory parameters in the wounds treated by beta-acids. Thus, using the porcine model, we demonstrate significant therapeutic effects of hops compounds in the management of wounds infected by MRSA. Beta-acids from hops, therefore, represent a suitable candidate for the treatment of non-responsive nosocomial tissue infections by MRSA.

scholarly journals Emergence Of Consciousness And Qualia From A Complex Brain

Folia Medica ◽  
2014 ◽  
Vol 56 (4) ◽  
pp. 289-296
Author(s):  
Jakob Korf
Keyword(s):  
System Theory ◽  
General System ◽  
Resolution Power ◽  
Brain Functions ◽  
Scientific Exploration ◽  
Brain Changes ◽  
Higher Brain Functions ◽  
The Brain

Abstract Qualia are private conscious experiences of which the associated feelings can be reported to other people. Whether qualia are amenable to scientific exploration has often been questioned, which is challenged by the present article. The following arguments are given: 1. the configuration of the brain changes continuously and irreversibly, because of genetic and environmental influences and interhuman communication; 2. qualia and consciousness are processes, rather than states; 3. private feelings, including those associated with qualia, should be positioned in the context of a personal brain as being developed during life; 4. consciousness and qualia should be understood in the context of general system theory, thus concluding that isolated, in vitro, properties of neurons and other brain constituents might marginally contribute to the understanding of higher brain functions, mind or qualia; 5. current in vivo approaches have too little resolution power - in terms of space and time - to delineate individual and subjective brain processes. When subtle personalized properties of the nervous system can be assessed in vivo or in vitro, qualia can scientifically be investigated. We discuss some approaches to overcome these barriers.

scholarly journals Hsp90 Binds and Regulates the Ligand-Inducible α Subunit of Eukaryotic Translation Initiation Factor Kinase Gcn2

1999 ◽  
Vol 19 (12) ◽  
pp. 8422-8432 ◽  
Author(s):  
Olivier Donzé ◽  
Didier Picard
Keyword(s):  
Amino Acid ◽  
Constitutive Expression ◽  
Amino Acid Starvation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Restrictive Temperature ◽  
Α Subunit ◽  
Macbecin I

ABSTRACT The protein kinase Gcn2 stimulates translation of the yeast transcription factor Gcn4 upon amino acid starvation. Using genetic and biochemical approaches, we show that Gcn2 is regulated by the molecular chaperone Hsp90 in budding yeast Saccharomyces cerevisiae. Specifically, we found that (i) several Hsp90 mutant strains exhibit constitutive expression of a GCN4-lacZ reporter plasmid; (ii) Gcn2 and Hsp90 form a complex in vitro as well as in vivo; (iii) the specific inhibitors of Hsp90, geldanamycin and macbecin I, enhance the association of Gcn2 with Hsp90 and inhibit its kinase activity in vitro; (iv) in vivo, macbecin I strongly reduces the levels of Gcn2; (v) in a strain expressing the temperature-sensitive Hsp90 mutant G170D, both the accumulation and activity of Gcn2 are abolished at the restrictive temperature; and (vi) the Hsp90 cochaperones Cdc37, Sti1, and Sba1 are required for the response to amino acid starvation. Taken together, these data identify Gcn2 as a novel target for Hsp90, which plays a crucial role for the maturation and regulation of Gcn2.

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