Pioglitazone ameliorates methotrexate-induced renal endothelial dysfunction via amending detrimental changes in some antioxidant parameters, systemic cytokines and Fas production

El‐Gowilly, Sahar M.; Helmy, Mai M.; El‐Gowelli, Hanan M.

doi:10.1016/j.vph.2015.07.002

Cited by 12 publications

(9 citation statements)

References 87 publications

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“…We have previously shown that MTX induces caspase 3 in rat kidney . It was also reported that MTX upregulates fas in renal tissue , which is in line with the results of the present study. Here, RES showed renal anti‐apoptotic activity, as it reversed renal upregulation of both fas ligand and caspase 3 when given prior to MTX administration.…”

Section: Discussionsupporting

confidence: 93%

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

El-Sheikh

Morsy

Al‐Taher

2016

Fundamemntal Clinical Pharma

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Resveratrol (RES) is a well-known polyphenol antioxidant. We have previously shown that testicular protective effect of RES against the anticancer drug methotrexate (MTX)-induced toxicity involves transporter-mediated mechanisms. Here, we investigated the effect of RES on MTX-induced nephrotoxicity. Rats were administered RES (10 mg/kg/day) for 8 days, with or without a single MTX dose (20 mg/kg i.p.) at day 4 of the experiment. MTX induced nephrotoxicity, as evidenced by a significant increase in serum blood urea nitrogen and creatinine compared to the control, as well as distortion of kidney microscopic structure. MTX also significantly increased renal nitric oxide level along with inducible nitric oxide synthase, fas ligand, and caspase 3 expressions. Administering RES prior to MTX significantly improved kidney function and microscopic picture and also significantly decreased nitrosative and apoptotic markers compared to MTX alone. RES, but not MTX, caused a significant increase in expression of breast cancer resistance protein (BCRP), an apical efflux renal transporter that participates in urinary elimination of both MTX and RES. Interestingly, concomitant MTX and RES caused further upregulation of renal BCRP compared to RES alone. Using Human BCRP ATPase assay, both RES and MTX exhibited a dose-dependent increase in ATPase activity, with Km values of 0.52 ± 0.03 and 30.9 ± 4.2 μm, respectively. Furthermore, combined RES and MTX caused ATPase activity which was significantly less than maximum ATPase activity attained by the positive control, sulfasalazine (12.5 μm). In conclusion, RES exerted nephroprotection against MTX-induced toxicity through antinitrosative and anti-apoptotic effects, as well as via upregulation of renal BCRP.

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Section: Discussionsupporting

confidence: 93%

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

El-Sheikh

Morsy

Al‐Taher

2016

Fundamemntal Clinical Pharma

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“…4 and 5 ). A relatively large body of evidence has suggested that the PPARγ agonist pioglitazone can regulate the inflammatory response and oxidative stress [ 55 , 56 ]. After pioglitazone treatment of the CMS mice, the expression of pro-inflammatory molecules was reduced and the levels of anti-inflammatory cytokines were increased.…”

Section: Discussionmentioning

confidence: 99%

The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes

Zhao

Yan

et al. 2016

J Neuroinflammation

118

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BackgroundDiscoveries that microglia-mediated neuroinflammation is involved in the pathological process of depression provided a new strategy for novel antidepressant therapy. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor regulating inflammation and microglial polarization and, therefore, a potential target for resolving depressive disorders. Our hypothesis was that antidepressant effects could be achieved through anti-inflammatory and neuroprotective activities by PPARγ-dependent microglia-modulating agents.MethodsChronic mild stress (CMS) treatment was performed on C57BL/6 mice for 6 weeks. After 3 weeks with the CMS procedure, depressive-like behaviors were evaluated by sucrose preference (SP), tail suspension test (TST), forced swimming test (FST), and locomotor activity. Pioglitazone was administered intragastrically once per day for 3 weeks at different doses. Neuroinflammatory cytokines were determined by real time-PCR (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. The activated microglial state was confirmed by immunohistochemistry. N9 microglial cells were subjected to lipopolysaccharide, pioglitazone, and GW9662 to discuss the phenotype of activated microglia by RT-PCR, ELISA, and western blot.ResultsIt was demonstrated that the PPARγ agonist pioglitazone (2.5 mg/kg) ameliorated depression-like behaviors in CMS-treated mice, as indicated by body weight (BW), the SP test, the FST, and the TST. The amelioration of the depression was blocked by the PPARγ antagonist GW9662. The expression of M1 markers (IL-1β, IL-6, TNFα, iNOS, and CCL2) increased, and the gene expression of M2 markers (Ym1, Arg1, IL-4, IL-10, and TGFβ) decreased in the hippocampus of the stress-treated mice. Pioglitazone significantly inhibited the increased numbers and morphological alterations of microglia in the hippocampus, reduced the elevated expression of microglial M1 markers, and increased the downgraded expression of microglial M2 markers in C57BL/6 mice exposed to CMS. In an in vitro experiment, pioglitazone reversed the imbalance of M1 and M2 inflammatory cytokines, which is correlated with the inhibition of nuclear factor kB activation and is expressed in LPS-stimulated N9 microglial cells.ConclusionsWe showed that pioglitazone administration induce the neuroprotective phenotype of microglia and ameliorate depression-like behaviors in CMS-treated C57BL/6 mice. These data suggested that the microglia-modulating agent pioglitazone present a beneficial choice for depression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0728-y) contains supplementary material, which is available to authorized users.

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“…Animal studies have shown conflicting results on the effects of methotrexate on endothelial function. Some studies reported negative effects [95,96], whereas others described a significant improvement in endothelial function [97,98]. However, the doses of methotrexate administered in these studies, between 24 and 490mg/day, are considerably higher than the doses typically prescribed in patients with autoimmune disorders, between 1 and 4mg/day.…”

Section: Methotrexate Endothelial Function Arterial Stiffness and mentioning

confidence: 91%

Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age

Mangoni

Tommasi

Zinellu

et al. 2019

CPD

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Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

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Pioglitazone ameliorates methotrexate-induced renal endothelial dysfunction via amending detrimental changes in some antioxidant parameters, systemic cytokines and Fas production

Cited by 12 publications

References 87 publications

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes

Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age

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