Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (17)

Search Parameters:
Keywords = Deprenyl

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
20 pages, 5945 KiB  
Article
Aging-Associated Amyloid-β Plaques and Neuroinflammation in Bottlenose Dolphins (Tursiops truncatus) and Novel Cognitive Health-Supporting Roles of Pentadecanoic Acid (C15:0)
by Stephanie Venn-Watson and Eric D. Jensen
Int. J. Mol. Sci. 2025, 26(8), 3746; https://doi.org/10.3390/ijms26083746 - 16 Apr 2025
Cited by 1 | Viewed by 4691
Abstract
There is an urgent need to identify interventions that broadly target aging-related cognitive decline and progression to Alzheimer’s disease (AD). Bottlenose dolphins (Tursiops truncatus) have histologic changes similar to AD in humans, and they also develop shared age-associated co-morbidities identified as [...] Read more.
There is an urgent need to identify interventions that broadly target aging-related cognitive decline and progression to Alzheimer’s disease (AD). Bottlenose dolphins (Tursiops truncatus) have histologic changes similar to AD in humans, and they also develop shared age-associated co-morbidities identified as risk factors for AD in humans, including type 2 diabetes, ferroptosis, and iron overload, which can be driven by nutritional C15:0 deficiency. We hypothesized that (1) dolphins would have amyloid beta (Aβ) plaques and neuroinflammation that paralleled that of humans in relation to age-related progression, quantitative concentration, and brain region; and (2) C15:0 would have dose-dependent activities relevant to protecting cognitive health. Quantitative immunohistochemistry staining was used to assess 68 tissues from archived brains of 19 Navy dolphins to evaluate associations among amyloid beta (Aβ) plaques and neuroinflammation by brain region, sex, and age group. Further, dose-dependent C15:0 activities, using a third-party panel intended to screen for potential AD therapeutics, were evaluated. Similar to humans, dolphins had the highest Aβ plaque density variation in the hippocampus (90th percentile of 4.95 plaques/mm2), where plaque density increased with age (p = 0.05). All measured markers of neuroinflammation were detected, including the highest concentrations of activated microglia (CD68+) in the hippocampus (0.46 ± 0.38 cells/mm2). C15:0 was a dose-dependent inhibitor of two targets, fatty acid amide hydrolase (FAAH) (IC50 2.5 µM, 89% maximum inhibition at 50 µM relative to URB597) and monoamine oxidase B (MAO-B) (IC50 19.4 µM, 70% maximum inhibition at 50 µM relative to R(-)-Deprenyl). These activities have demonstrated efficacy against Aβ formation and neuroinflammation, including protection of cognitive function in the hippocampus. These findings suggest that, in addition to protecting against AD co-morbidities, C15:0 may play a distinct role in supporting cognitive health, especially at higher concentrations. Full article
Show Figures

Figure 1

22 pages, 4098 KiB  
Article
Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers
by John J. Reiners, Patricia A. Mathieu, Mary Gargano, Irene George, Yimin Shen, John F. Callaghan, Richard F. Borch and Raymond R. Mattingly
Cancers 2024, 16(1), 89; https://doi.org/10.3390/cancers16010089 - 23 Dec 2023
Viewed by 1674
Abstract
Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties [...] Read more.
Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e., IG 2) exhibited improved aqueous solubility. Concentrations of IG 2 and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
Show Figures

Graphical abstract

12 pages, 861 KiB  
Article
Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease
by Rawan Khashab, Naama Gutman-Sharabi, Zehava Shabtai, Regev Landau, Reut Halperin, Tsviya Fay-Karmon, Avshalom Leibowitz and Yehonatan Sharabi
Int. J. Mol. Sci. 2023, 24(15), 12522; https://doi.org/10.3390/ijms241512522 - 7 Aug 2023
Cited by 1 | Viewed by 2273
Abstract
The catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the [...] Read more.
The catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson’s disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson’s disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson’s disease treatment. Full article
Show Figures

Figure 1

13 pages, 2616 KiB  
Article
[125I]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer’s Disease Brain
by Roz R. Limpengco, Christopher Liang, Yasmin K. Sandhu and Jogeshwar Mukherjee
Molecules 2023, 28(15), 5769; https://doi.org/10.3390/molecules28155769 - 31 Jul 2023
Cited by 4 | Viewed by 1905
Abstract
Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer’s disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[125I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([125I]INFT), for binding to [...] Read more.
Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer’s disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[125I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([125I]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [125I]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically. Computational modeling of INFT binding on Tau fibril was compared with IPPI. In vitro, autoradiography studies were conducted with [125I]INFT for Tau in AD and cognitively normal (CN) brains. [125I]INFT was produced in >95% purity. Molecular modeling of INFT revealed comparable binding energies to IPPI at site-1 of the Tau fibril with an affinity of IC50 = 7.3 × 10−8 M. Binding of [125I]INFT correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. The ratio of average grey matter (GM) [125I]INFT in AD versus CN was found to be 5.9, and AD GM/white matter (WM) = 2.5. Specifically bound [125I]INFT to Tau in AD brains was displaced by IPPI (>90%). Monoamine oxidase inhibitor deprenyl had no effect and clorgyline had little effect on [125I]INFT binding. [125I]INFT is a less lipophilic imaging agent for Tau in AD. Full article
(This article belongs to the Section Bioorganic Chemistry)
Show Figures

Figure 1

18 pages, 4768 KiB  
Article
Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer’s Disease Brain
by Amina U. Syed, Christopher Liang, Krystal K. Patel, Rommani Mondal, Vallabhi M. Kamalia, Taylor R. Moran, Shamiha T. Ahmed and Jogeshwar Mukherjee
Int. J. Mol. Sci. 2023, 24(13), 10808; https://doi.org/10.3390/ijms241310808 - 28 Jun 2023
Cited by 17 | Viewed by 2427
Abstract
Increased monoamine oxidase-A (MAO-A) activity in Alzheimer’s disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 [...] Read more.
Increased monoamine oxidase-A (MAO-A) activity in Alzheimer’s disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aβ plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aβ plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aβ plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region. Full article
(This article belongs to the Special Issue Molecular Aspects of the Neurodegenerative Brain Diseases)
Show Figures

Figure 1

12 pages, 922 KiB  
Review
Astrocyte Signature in Alzheimer’s Disease Continuum through a Multi-PET Tracer Imaging Perspective
by Igor C. Fontana, Miriam Scarpa, Mona-Lisa Malarte, Filipa M. Rocha, Sira Ausellé-Bosch, Marina Bluma, Marco Bucci, Konstantinos Chiotis, Amit Kumar and Agneta Nordberg
Cells 2023, 12(11), 1469; https://doi.org/10.3390/cells12111469 - 24 May 2023
Cited by 14 | Viewed by 4210
Abstract
Reactive astrogliosis is an early event in the continuum of Alzheimer’s disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings [...] Read more.
Reactive astrogliosis is an early event in the continuum of Alzheimer’s disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity—more than one subtype of astrocyte involved—in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
Show Figures

Figure 1

14 pages, 2974 KiB  
Article
Production of [11C]Carbon Labelled Flumazenil and L-Deprenyl Using the iMiDEV™ Automated Microfluidic Radiosynthesizer
by Hemantha Mallapura, Laurent Tanguy, Bengt Långström, Ludovic Le Meunier, Christer Halldin and Sangram Nag
Molecules 2022, 27(24), 8843; https://doi.org/10.3390/molecules27248843 - 13 Dec 2022
Cited by 9 | Viewed by 2827
Abstract
In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV™ microfluidic radiosynthesizer [...] Read more.
In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV™ microfluidic radiosynthesizer has been introduced and this study is aimed at using of the iMiDEV™ radiosynthesizer with a microfluidic cassette to produce [11C]flumazenil and [11C]L-deprenyl. These two are known PET radioligands for benzodiazepine receptors and monoamine oxidase-B (MAO-B), respectively. Methods were successfully developed to produce [11C]flumazenil and [11C]L-deprenyl using [11C]methyl iodide and [11C]methyl triflate, respectively. The final products 1644 ± 504 MBq (n = 7) and 533 ± 20 MBq (n = 3) of [11C]flumazenil and [11C]L-deprenyl were produced with radiochemical purities were over 98% and the molar activity for [11C]flumazenil and [11C]L-deprenyl was 1912 ± 552 GBq/µmol, and 1463 ± 439 GBq/µmol, respectively, at the end of synthesis. All the QC tests complied with the European Pharmacopeia. Different parameters, such as solvents, bases, methylating agents, precursor concentration, and different batches of cassettes, were explored to increase the radiochemical yield. Synthesis methods were developed using 3–5 times less precursor than conventional methods. The fully automated iMiDEV™ microfluidic radiosynthesizer was successfully applied to prepare [11C]flumazenil and [11C]L-deprenyl. Full article
(This article belongs to the Special Issue Advance in Radiochemistry)
Show Figures

Figure 1

20 pages, 3275 KiB  
Article
The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson’s Disease Model
by Juan Chen, Yixuan Chen, Yangfan Zheng, Jiawen Zhao, Huilin Yu and Jiajin Zhu
Molecules 2022, 27(15), 5007; https://doi.org/10.3390/molecules27155007 - 6 Aug 2022
Cited by 13 | Viewed by 3088
Abstract
This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson’s disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then [...] Read more.
This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson’s disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then exposed to 1.5 mm 1-methyl-4-phenylpyridinium (MPP+) for 24 h. Zebrafish larvae (AB strain) 3 days post-fertilization were incubated with deprenyl or grape seed-derived procyanidins in 400 µM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. The results showed that the procyanidin dimers procyanidin B1 (B1), procyanidin B2 (B2), procyanidin B3 (B3), procyanidin B4 (B4), procyanidin B1-3-O-gallate (B1-G), procyanidin B2-3-O-gallate (B2-G), and the procyanidin trimer procyanidin C1 (C1) had a protective effect on PC12 cells, decreasing the damaged dopaminergic neurons and motor impairment in zebrafish. In PC12 cells and the zebrafish PD model, procyanidin (B1, B2, B3, B4, B1-G, B2-G, C1) treatment decreased the content of reactive oxygen species (ROS) and malondialdehyde (MDA), increased the activity of antioxidant enzymes glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), and upregulated the expression of nuclear factor-erythroid 2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1). These results suggest that in PC12 cells and the zebrafish PD model, the neuroprotective effects of the procyanidins were positively correlated with their degree of polymerization. Full article
Show Figures

Figure 1

21 pages, 5055 KiB  
Article
Protective Effects and Mechanisms of Procyanidins on Parkinson’s Disease In Vivo and In Vitro
by Juan Chen, Yixuan Chen, Yangfan Zheng, Jiawen Zhao, Huilin Yu, Jiajin Zhu and Duo Li
Molecules 2021, 26(18), 5558; https://doi.org/10.3390/molecules26185558 - 13 Sep 2021
Cited by 15 | Viewed by 3305
Abstract
This research assessed the molecular mechanism of procyanidins (PCs) against neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridinium (MPP+) induced Parkinson’s disease (PD) models. In vitro, PC12 cells were incubated with PCs or deprenyl for 24 h, and then exposed to 1.5 [...] Read more.
This research assessed the molecular mechanism of procyanidins (PCs) against neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridinium (MPP+) induced Parkinson’s disease (PD) models. In vitro, PC12 cells were incubated with PCs or deprenyl for 24 h, and then exposed to 1.5 mM MPP+ for 24 h. In vivo, zebrafish larvae (AB strain) 3 days post-fertilization (dpf) were incubated with deprenyl or PCs in 400 μM MPTP for 4 days. Compared with MPP+/MPTP alone, PCs significantly improved antioxidant activities (e.g., glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT)), and decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Furthermore, PCs significantly increased nuclear Nrf2 accumulation in PC12 cells and raised the expression of NQO1, HO-1, GCLM, and GCLC in both PC12 cells and zebrafish compared to MPP+/MPTP alone. The current study shows that PCs have neuroprotective effects, activate the nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and alleviate oxidative damage in MPP+/MPTP-induced PD models. Full article
Show Figures

Figure 1

10 pages, 841 KiB  
Article
Pharmacological Modulation of Behaviour, Serotonin and Dopamine Levels in Daphnia magna Exposed to the Monoamine Oxidase Inhibitor Deprenyl
by Marina Bellot, Melissa Faria, Cristian Gómez-Canela, Demetrio Raldúa and Carlos Barata
Toxics 2021, 9(8), 187; https://doi.org/10.3390/toxics9080187 - 9 Aug 2021
Cited by 14 | Viewed by 3536
Abstract
This study assessed the effects of the monoamine oxidase (MAO) inhibitor deprenyl in Daphnia magna locomotor activity. The mechanisms of action of deprenyl were also determined by studying the relationship between behaviour, MAO activity and neurotransmitter levels. Modulation of the D. magna monoamine [...] Read more.
This study assessed the effects of the monoamine oxidase (MAO) inhibitor deprenyl in Daphnia magna locomotor activity. The mechanisms of action of deprenyl were also determined by studying the relationship between behaviour, MAO activity and neurotransmitter levels. Modulation of the D. magna monoamine system was accomplished by 24 h exposure to two model psychotropic pharmaceuticals with antagonistic and agonistic serotonin signalling properties: 10 mg/L of 4-chloro-DL-phenylalanine (PCPA) and 1 mg/L of deprenyl, respectively. Contrasting behavioural outcomes were observed for deprenyl and PCPA reflected in decreased basal locomotor activity and enhanced habituation for the former compound and delayed habituation for the latter one. Deprenyl exposure inhibited monoamine oxidase (MAO) activity and increased the concentrations of serotonin, dopamine and the dopamine metabolite 3-methoxytyramine in whole D. magna extracts. Our findings indicate that D. magna is a sensitive and useful nonvertebrate model for assessing the effects of short-term exposure to chemicals that alter monoamine signalling changes. Full article
Show Figures

Graphical abstract

14 pages, 3267 KiB  
Article
Pharmacological Modulation of Serotonin Levels in Zebrafish Larvae: Lessons for Identifying Environmental Neurotoxicants Targeting the Serotonergic System
by Melissa Faria, Eva Prats, Marina Bellot, Cristian Gomez-Canela and Demetrio Raldúa
Toxics 2021, 9(6), 118; https://doi.org/10.3390/toxics9060118 - 25 May 2021
Cited by 23 | Viewed by 4555
Abstract
This study examines the effects of acute pharmacological modulation of the serotonergic system over zebrafish larvae’s cognitive, basic, and defense locomotor behaviors, using a medium to high throughput screening assay. Furthermore, the relationship between behavior, enzyme activity related to neurotransmitter metabolism, neurotransmitter levels, [...] Read more.
This study examines the effects of acute pharmacological modulation of the serotonergic system over zebrafish larvae’s cognitive, basic, and defense locomotor behaviors, using a medium to high throughput screening assay. Furthermore, the relationship between behavior, enzyme activity related to neurotransmitter metabolism, neurotransmitter levels, and gene expression was also determined. Modulation of larvae serotonergic system was accomplished by 24 h exposure to single and opposite pharmacodynamics co-exposure to three model psychopharmaceuticals with antagonistic and agonistic serotonin signaling properties: 2.5 mM 4-Chloro-DL-phenylalanine (PCPA) and 5 µM deprenyl and 0.5 µM fluoxetine, respectively. Similar behavioral outcome was observed for deprenyl and fluoxetine, which was reflected as hypolocomotion, decrease in larvae defensive responses, and cognitive impairment. Contrarily, PCPA induced hyperlocomotion and increase in larvae escape response. Deprenyl exposure effects were more pronounced at a lower level of organization than fluoxetine, with complete inhibition of monoamine oxidase (MAO) activity, dramatic increase of 5-HT and dopamine (DA) levels, and downregulation of serotonin synthesis and transporter genes. PCPA showed mainly effects over serotonin and dopamine’s main degradation metabolites. Finally, co-exposure between agonistic and antagonist serotonin signaling drugs reviled full recovery of zebrafish impaired locomotor and defense responses, 5-HT synthesis gene expression, and partial recovery of 5-HT levels. The findings of this study suggest that zebrafish larvae can be highly sensitive and a useful vertebrate model for short-term exposure to serotonin signaling changes. Full article
Show Figures

Figure 1

11 pages, 1785 KiB  
Article
Differential Modulation of the Central and Peripheral Monoaminergic Neurochemicals by Deprenyl in Zebrafish Larvae
by Marina Bellot, Helena Bartolomé, Melissa Faria, Cristian Gómez-Canela and Demetrio Raldúa
Toxics 2021, 9(6), 116; https://doi.org/10.3390/toxics9060116 - 23 May 2021
Cited by 9 | Viewed by 3467
Abstract
Zebrafish embryos and larvae are vertebrate models increasingly used in translational neuroscience research. Behavioral impairment induced by the exposure to neuroactive or neurotoxic compounds is commonly linked to changes in modulatory neurotransmitters in the brain. Although different analytical methods for determining monoaminergic neurochemicals [...] Read more.
Zebrafish embryos and larvae are vertebrate models increasingly used in translational neuroscience research. Behavioral impairment induced by the exposure to neuroactive or neurotoxic compounds is commonly linked to changes in modulatory neurotransmitters in the brain. Although different analytical methods for determining monoaminergic neurochemicals in zebrafish larvae have been developed, these methods have been used only on whole larvae, as the dissection of the brain of hundreds of larvae is not feasible. This raises a key question: Are the changes in the monoaminergic profile of the whole larvae predictive of the changes in the brain? In this study, the levels of ten monoaminergic neurotransmitters were determined in the head, trunk, and the whole body of zebrafish larvae in a control group and in those treated for 24 h with 5 M deprenyl, a prototypic monoamine-oxidase B inhibitor, eight days post-fertilization. In control larvae, most of the monoaminergic neurochemicals were found at higher levels in the head than in the trunk. Significant changes were found in the distribution of some neurochemicals after deprenyl-treatment, with serotonin and norepinephrine increasing in both the head and the trunk, whereas dopamine, L-DOPA, and homovanillic acid levels were only modulated in the head. In fact, the highly significant increase in dopamine levels observed in the head after deprenyl-treatment was not detected in the whole-body analysis. These results indicate that the analysis of neurotransmitters in the zebrafish larvae whole-body should not be used as a general surrogate of the brain. Full article
(This article belongs to the Special Issue Fish Models for Human Toxicology)
Show Figures

Figure 1

14 pages, 1496 KiB  
Communication
Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding
by Ivana I. Jevtić, Thu Hang Lai, Jelena Z. Penjišević, Sladjana Dukić-Stefanović, Deana B. Andrić, Peter Brust, Sladjana V. Kostić-Rajačić and Rodrigo Teodoro
Molecules 2020, 25(21), 4941; https://doi.org/10.3390/molecules25214941 - 26 Oct 2020
Cited by 5 | Viewed by 3900
Abstract
Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded [...] Read more.
Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 817 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 817 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands. Full article
(This article belongs to the Special Issue Radiolabelled Molecules for Brain Imaging with PET and SPECT II)
Show Figures

Figure 1

11 pages, 1179 KiB  
Article
Methylated Xanthones from the Rootlets of Metaxya rostrata Display Cytotoxic Activity in Colorectal Cancer Cells
by Eva Mittermair, Hanspeter Kählig, Ammar Tahir, Stefanie Rindler, Xenia Hudec, Hemma Schueffl, Petra Heffeter, Brigitte Marian and Liselotte Krenn
Molecules 2020, 25(19), 4449; https://doi.org/10.3390/molecules25194449 - 28 Sep 2020
Cited by 2 | Viewed by 2353
Abstract
The tree fern Metaxya rostrata (Kunth) C. Presl is common in the rainforests of Central and South America, where suspensions of the dried rhizome are traditionally used to treat intestinal diseases. Two compounds from this plant, 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB), [...] Read more.
The tree fern Metaxya rostrata (Kunth) C. Presl is common in the rainforests of Central and South America, where suspensions of the dried rhizome are traditionally used to treat intestinal diseases. Two compounds from this plant, 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB), have been shown to be biologically highly active against colorectal cancer (CRC) cells in previous studies. The current investigation resulted in the isolation of the previously undescribed methylated xanthones 2-deprenyl-6-O-methyl-7-hydroxy-rheediaxanthone B, 2-deprenyl-5-O-methyl-7-methoxy-rheediaxanthone B, 2-deprenyl-5-O-methyl- 7-hydroxy-rheediaxanthone B and 2-deprenyl-7-methoxy-rheediaxanthone B. All compounds were isolated by column chromatography, structures were elucidated by one- and two-dimensional NMR-experiments and the identities of the compounds were confirmed by LC-HRMS. In logarithmically growing SW480 CRC cell cultures, cytotoxicity by neutral red uptake and MTT assays as well as caspase activation was analyzed. Cellular targets were examined by Western blot, and topoisomerase I (topo I) inhibition potential was tested. Comparing the structure-activity relationship with XB and OH-XB, the monomethylated derivatives showed qualitatively similar effects/mechanisms to their nonmethylated analogues, while dimethylation almost abolished the activity. Inhibition of topo I was dependent on the presence of an unmethylated 7-OH group. Full article
Show Figures

Graphical abstract

12 pages, 1898 KiB  
Article
Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression
by Ipsit Srivastava, Erika Vazquez-Juarez, Lukas Henning, Marta Gómez-Galán and Maria Lindskog
Cells 2020, 9(7), 1705; https://doi.org/10.3390/cells9071705 - 16 Jul 2020
Cited by 18 | Viewed by 4652
Abstract
A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these [...] Read more.
A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline. Full article
(This article belongs to the Special Issue Neuron-Glia Interactions)
Show Figures

Graphical abstract

Back to TopTop