Molybdenum bupropion combined neurotoxicity in rats

Helaly, Ahmed M.N.; Mokhtar, Naglaa; Firgany, Alaa El-Din L.; Hazem, Noha M.; Morsi, E. El; Ghorab, Doaa

doi:10.1016/j.yrtph.2018.08.001

Cited by 11 publications

(5 citation statements)

References 33 publications

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“…Furthermore, no histological alterations were observed in the brain of rats and mice exposed to Mo via inhalation of ≤67 mg Mo/m 3 as molybdenum trioxide for 13 weeks or 2 years (National Toxicology Program, 1997) or in rats exposed to ≤60 mg Mo/kg/day as sodium molybdate in the diet for 90 days (Murray et al, 2014). In contrast, Helaly et al (2018) reported inflammation and neuronal degeneration in the cerebral cortex and hippocampus of rats receiving daily gavage doses of 30 mg molybdenum/kg/day as molybdenum dihydrate for 30 days. In support of the findings of accumulation of Mo in the CNS, elevated levels of Mo (range 21–76 μg/L) have also been found in the cerebrospinal fluid of rats given similar doses of TTM to those used in the current study–data not shown.…”

Section: Discussionmentioning

confidence: 91%

“…Furthermore, no histological alterations were observed in the brain of rats and mice exposed to Mo via inhalation of ≤67 mg Mo/m 3 as molybdenum trioxide for 13 weeks or 2 years (National Toxicology Program, 1997) or in rats exposed to ≤60 mg Mo/kg/day as sodium molybdate in the diet for 90 days (Murray et al, 2014). In contrast, Helaly et al (2018) and an adverse event as a result of exposure to the therapy, implementation of a therapeutic formulation that results in accumulation of molybdenum may make the safe monitoring of patients challenging.…”

Section: Discussionmentioning

confidence: 99%

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Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Foster¹,

Billimoria

Busto

et al. 2022

J of Applied Toxicology

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Molybdenum is an essential dietary trace element required for several critical enzyme systems. High intake is associated with toxicity in ruminants and animal studies. The proposed therapeutic use of molybdenum-based drugs poses a potential risk for accumulation through chronic administration of therapeutic doses of this element.The current experiment was designed to study the effect of daily dosing of a molybdenum compound, bis-choline tetrathiomolybdate (TTM), in Sprague Dawley rats using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-ToF-MS) and two dosing levels of TTM for up to 3 months. To investigate if molybdenum accumulation was associated with tissue toxicity, histopathology, haematology and clinical biochemistry markers of toxicity were incorporated into the study design. There were no behavioural signs of toxicity to the rats, and no clinical or anatomic pathology was associated with treatment. The current data did show a progressive accumulation of molybdenum within the adrenal gland, kidneys, liver, spleen, brain and testes. Although this was not associated with tissue toxicity within the 3-month study design, greater exposure over a longer period of time has the potential for producing adverse pathophysiological cellular function. Tissue toxicity, as a result of local excessive accumulation of molybdenum over time, has clear implications for the therapeutic use of molybdenum in humans and demands sensitive monitoring of tissue molybdenum levels to avoid toxicity. The current study highlights the shortcomings of conventional biomonitoring approaches to detect molybdenum accumulation with the goal of avoiding molybdenum-associated toxicity.

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Section: Discussionmentioning

confidence: 91%

“…Furthermore, no histological alterations were observed in the brain of rats and mice exposed to Mo via inhalation of ≤67 mg Mo/m 3 as molybdenum trioxide for 13 weeks or 2 years (National Toxicology Program, 1997) or in rats exposed to ≤60 mg Mo/kg/day as sodium molybdate in the diet for 90 days (Murray et al, 2014). In contrast, Helaly et al (2018) and an adverse event as a result of exposure to the therapy, implementation of a therapeutic formulation that results in accumulation of molybdenum may make the safe monitoring of patients challenging.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Foster¹,

Billimoria

Busto

et al. 2022

J of Applied Toxicology

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“…Surprisingly, bupropion increased mRNA levels of TNF-a, IL-1-ß, in the present study. However, in an animal study conducted by Helaly et al TNF-a gene expression reported being down-regulated by bupropion 14 . Studies concerning changes in IL-17 levels in response to bupropion are limited.…”

Section: Discussionmentioning

confidence: 95%

“…Given that bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) and a serotonin (5-HT) type 3A receptor inhibitor possessing anti-inflammatory properties 13 , it is expected to have a double point advantage as an antidepressant. Meanwhile, in an animal study conducted by Helaly et al, bupropion exerted an inflammatory effect at therapeutic doses evidenced by positive NF-κB/ p65 stained microglia and neurocytes, obvious inflammation in hippocampus along with a moderate rise in the mean of serum IL-6 levels 14 . Moreover, the association between bupropion administration and a couple of inflammatory conditions is stated in a considerable number of case reports [15][16][17][18] .…”

Section: Introductionmentioning

confidence: 98%

Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3

Karimollah,

Hemmatpur,

Vahid

2024

Preprint

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There are accumulating reports regarding poor response to the common antidepressant therapy. Antidepressant resistance has often been associated with activation of the inflammatory system. Accordingly, major depressive disorder (MDD) patients displaying inflammation prior to the treatment are less responsive to antidepressants. We hypothesized that the inefficacy of antidepressant therapy in some patients could be due to the drugs’ inflammatory mode of action that remained overshadowed by their substantial therapeutic value. Bupropion is a common-used antidepressant that is prescribed for seasonal affective disorders and smoking cessation as well. Nevertheless, there are some reports regarding inflammation induction and depressive behavior exacerbation in response to bupropion. Here, we put a spot on bupropion and investigate the alterations of innate and adaptive immunity cytokines and the influence on immune signaling pathways. Therefore, we treated LPS-stimulated human peripheral mononuclear cells (PBMCs) with different doses of bupropion. Pro-/ anti-inflammatory cytokines (TNF-ɑ, IL-1ß, IL-17, and IL-10) on both transcriptional and translational levels are assessed as well as the involvement of the JAK2 /STAT3, TLR2, and TLR4 signaling in this process. Bupropion decreased IL-17A, TNF-ɑ, and IL-1ß protein levels in the cultures. Nonetheless, the results regarding the target genes expression were controversial. Surprisingly, IL-1ß, TNF-ɑ, and IL-17A genes expression increased following bupropion treatment. TLR2, TLR4, JAK2, and STAT3 gene expression also rose in response to bupropion. Our findings suggest that bupropion possesses pro-inflammatory properties especially at concentrations of 50 and 100 and would rather be co-administrated with anti-inflammatory agents at least in patients with inflammatory conditions.

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“…Given that bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) and a serotonin (5-HT) type 3A receptor inhibitor possessing anti-in ammatory properties (Stuebler and Jansen, 2020), it is expected to have a double point advantage as an antidepressant. Meanwhile, in an animal study conducted by Helaly et al, bupropion exerted an in ammatory effect at therapeutic doses evidenced by positive NF-κB/ p65 stained microglia and neurocytes, obvious in ammation in hippocampus along with a moderate rise in the mean of serum IL-6 levels (Helaly et al, 2018). Moreover, the association between bupropion administration and a couple of in ammatory conditions is stated in a considerable number of case reports (Akpinar et al, 2013, García et al, 2013, Jumez et al, 2004, Yuan and Williams, 2011.…”

Section: Introductionmentioning

confidence: 99%

Revisiting Bupropion Anti-inflammatory Action: Involvement of the TLR2/TLR4 and JAK2/STAT3 

Karimollah

Hemmatpur

Vahid

2021

Preprint

View full text Add to dashboard Cite

There are accumulating reports regarding poor response to the common antidepressant therapy. Antidepressant resistance has often been associated with activation of the inflammatory system. Accordingly, major depressive disorder (MDD) patients displaying inflammation prior to the treatment are less responsive to antidepressants. We hypothesized that the inefficacy of antidepressant therapy in some patients could be due to the drugs’ inflammatory mode of action that remained overshadowed by their substantial therapeutic value. Bupropion is a common-used antidepressant that is prescribed for seasonal affective disorders and smoking cessation as well. Nevertheless, there are some reports regarding inflammation induction and depressive behavior exacerbation in response to bupropion. Here, we put a spot on bupropion and investigate the alterations of innate and adaptive immunity cytokines and the influence on immune signaling pathways. Therefore, we treated LPS-stimulated human peripheral mononuclear cells (PBMCs) with different doses of bupropion. Pro-/ anti-inflammatory cytokines (TNF-ɑ, IL-1ß, IL-17, and IL-10) on both transcriptional and translational levels are assessed as well as the involvement of the JAK2 /STAT3, TLR2, and TLR4 signaling in this process. Bupropion decreased IL-17A, TNF-ɑ, and IL-1ß protein levels in the cultures. Nonetheless, the results regarding the target genes expression were controversial. Surprisingly, TNF-ɑ and IL-17A genes expression increased following bupropion treatment. TLR2, TLR4, JAK2, and STAT3 gene expression also rose in response to bupropion. Our findings suggest that bupropion possesses pro-inflammatory properties especially at concentrations of 50 and 100 and would rather be co-administrated with anti-inflammatory agents at least in patients with inflammatory conditions.

show abstract

Molybdenum bupropion combined neurotoxicity in rats

Cited by 11 publications

References 33 publications

Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3

Revisiting Bupropion Anti-inflammatory Action: Involvement of the TLR2/TLR4 and JAK2/STAT3

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Molybdenum bupropion combined neurotoxicity in rats

Cited by 11 publications

References 33 publications

Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3

Revisiting Bupropion Anti-inflammatory Action: Involvement of the TLR2/TLR4&nbsp;and JAK2/STAT3&nbsp;

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Revisiting Bupropion Anti-inflammatory Action: Involvement of the TLR2/TLR4 and JAK2/STAT3