Protective effect of pyrrolidine dithiocarbamate against methotrexate-induced testicular damage

Delen, Özlem; Uz, Yeşim Hülya

doi:10.1177/09603271211035674

Cited by 9 publications

(7 citation statements)

References 54 publications

(135 reference statements)

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“…Anywise, it was twigged that co-administration of pyrrolidine dithiocarbamate along with tramadol significantly elevated these hormonal parameters in the tramadoltreated group. Similar results have been declared by Delen et al (2021).…”

Section: Discussionsupporting

confidence: 90%

“…Consequently, according to previous literature search, PDTC treatment significantly improved serum FSH, LH, and testosterone hormone levels and had antioxidant and anti-inflammatory with a protective impact on testicular tissue by decreasing prokineticins and NFkB expressions and elevating expressions of Nrf2. So, it was thought that PDTC can participate in the management of methotrexate-induced testicular injury and infertility (Delen and Uz 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Rats were randomly divided into four equal groups, 10 rats in each group based on previous researches (El Bana et al 2019 andRamadan et al 2020): group I, the control group, in which rats were intraperitoneally (IP) administered saline twice daily for 4 successive weeks; group II, the pyrrolidine dithiocarbamate (PDTC) group, in which rats received 100 mg/kg PDTC dissolved in saline (divided into two equal doses and administered intraperitoneally daily) for 4 successive weeks (Delen and Uz 2021); group III, the tramadol (Tr) group, in which rats received 40 mg/kg/day tramadol dissolved in distilled water orally by gastric gavage for 4 successive weeks; this dose is equivalent to human effective therapeutic dose (Ramadan et al 2020); and group (IV), the Tr + PDTC group, in which rats had been concomitantly treated daily with the previous doses of PDTC and tramadol for 4 successive weeks (Delen and Uz 2021).…”

Section: Experimental Designmentioning

confidence: 99%

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The possible protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate on tramadol-induced testicular damage in rats

Mahmoud

Moursi

Esmaeel

et al. 2023

Egypt J Forensic Sci

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Background Tramadol provokes oxidative stress that gives rise to apoptosis with alterations in the cellular structure and adversely influences male fertility. A specific inhibitor of nuclear factor kappa B (NF-κB), pyrrolidine dithiocarbamate (PDTC), has observable antioxidant and anti-inflammatory characteristics and enhances the improvement of organs damage caused by various agents. The impact of PDTC on testicular damage caused by tramadol has not been previously examined. Objective This study was designed to investigate the potential impact of pyrrolidine dithiocarbamate on testicular damage provoked by chronic tramadol usage. Materials and methods Forty healthy adult male albino rats were included in this study. Rats were randomly and equally divided into 4 groups: group (I), control group; group (II), pyrrolidine dithiocarbamate (PDTC) group; group (III), tramadol (Tr) group; and group (IV), Tr + PDTC group. This study measured serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and free testosterone levels. Testicular malondialdehyde (MDA), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and superoxide dismutase (SOD), glutathione peroxidase (GPX), and caspase-8 and caspase-3 activities were also detected. Immuno-histochemical evaluation of inducible NOS (iNOS) expression in testicular tissue along with histopathological examination of testicular tissue has been studied. Results Tramadol caused a significant reduction in serum FSH, LH and testosterone levels, epididymal sperm count, and motility, as well as testicular GPX and SOD activities. On the other hand, a significant elevation of testicular MDA, IL-1β, IL-6, and TNF-α levels and caspase-8 and caspase-3 activities were found. However, PDTC administration with tramadol showed significantly increased sperm production and motility and alleviated tramadol-induced disturbance in other measured parameters in the Tr + PDTC group compared to the Tr group. Moreover, co-administration of PDTC with tramadol significantly alleviated the histopathological structure of testicular tissue and the increased iNOS expressions noticed in the tramadol-treated group. Conclusion Considering the protective effects of PDTC against the reproductive toxicity induced by tramadol, this compound can be used as a possible protective and treating target for tramadol-induced reproductive toxicity.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

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The possible protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate on tramadol-induced testicular damage in rats

Mahmoud

Moursi

Esmaeel

et al. 2023

Egypt J Forensic Sci

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“…It inhibits oxidative stress, decreases lipid peroxidation, and exerts neuroprotection via the activation of NRF2 signaling pathway in astrocytes. Delen and co-workers [ 37 ] reported that in addition to reducing the expressions of NF-ĸB and Prokineticin 2 (PK2) levels, pyrrolidine dithiocarbamate ( I ) exerts a protective effect against methotrexate-induced testicular damage via upregulating the expression level of NRF2. Contrarily, it has been reported that while pyrrolidine dithiocarbamate deactivates NF-ĸB and upregulates some antioxidant enzymes, its administration has no effect on NRF2/KEAP pathway in dextran sodium sulfate (DSS)-induced colitis [ 38 ].…”

Section: Nitrogen Heterocycles As Modulators Of the Nrf2 Pathwaymentioning

confidence: 99%

NRF2 Activation by Nitrogen Heterocycles: A Review

et al. 2023

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Several nitrogen heterocyclic analogues have been applied to clinical practice, and about 75% of drugs approved by the FDA contain at least a heterocyclic moiety. Thus, nitrogen heterocycles are beneficial scaffolds that occupy a central position in the development of new drugs. The fact that certain nitrogen heterocyclic compounds significantly activate the NRF2/ARE signaling pathway and upregulate the expression of NRF2-dependent genes, especially HO-1 and NQO1, underscores the need to study the roles and pharmacological effects of N-based heterocyclic moieties in NRF2 activation. Furthermore, nitrogen heterocycles exhibit significant antioxidant and anti-inflammatory activities. NRF2-activating molecules have been of tremendous research interest in recent times due to their therapeutic roles in neuroinflammation and oxidative stress-mediated diseases. A comprehensive review of the NRF2-inducing activities of N-based heterocycles and their derivatives will broaden their therapeutic prospects in a wide range of diseases. Thus, the present review, as the first of its kind, provides an overview of the roles and effects of nitrogen heterocyclic moieties in the activation of the NRF2 signaling pathway underpinning their antioxidant and anti-inflammatory actions in several diseases, their pharmacological properties and structural–activity relationship are also discussed with the aim of making new discoveries that will stimulate innovative research in this area.

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“…Even though this mechanism may contribute to the mechanism by which MTX suppresses in ammation, other mechanisms of action including increased adenosine release, inhibition of transmethylation reactions essential for some cellular functions, decreased polyamine accumulation and NO synthase uncoupling have been proposed (3). Despite its bene cial effects, MTX has several major side effects and can cause toxicities in organs such as the liver, kidneys, testes and brain (4)(5)(6)(7). Protecting the organs from undesired side effects could be one way to mitigate the negative consequences of MTX in therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective effect of morin against methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways

Kızıl

Çağlayan

Darendelioğlu

et al. 2022

Preprint

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Background Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling. Methods Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. Results MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes. Conclusions According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.

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Protective effect of pyrrolidine dithiocarbamate against methotrexate-induced testicular damage

Cited by 9 publications

References 54 publications

The possible protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate on tramadol-induced testicular damage in rats

The possible protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate on tramadol-induced testicular damage in rats

NRF2 Activation by Nitrogen Heterocycles: A Review

Hepatoprotective effect of morin against methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways

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