Leflunomide-induced liver injury in mice: Involvement of TLR4 mediated activation of PI3K/mTOR/NFκB pathway

Elshaer, Rabie E.; Tawfik, Mona K.; Nosseir, Nermine; El-Ghaiesh, Sabah; Toraih, Eman A.; Elsherbiny, Nehal M.; Zaitone, Sawsan A.

doi:10.1016/j.lfs.2019.116824

Cited by 20 publications

(17 citation statements)

References 64 publications

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“…The low dose was mainly 10 mg/day, while the high dose was mainly 20 mg/day. LEF dose was positively correlated with liver enzyme elevation and adverse events 14,33 , so low dose LEF was worth considering within the same efficacy.…”

Section: Discussionmentioning

confidence: 99%

Leflunomide monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a retrospective study

Deng

Zhou

et al. 2020

Sci Rep

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Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of rheumatoid arthritis. However, there are few reports on the comparison of efficacy between LEF alone and combined with other csDMARDs. Here, the efficacy and safety of LEF monotherapy (88) and combination (361) therapy groups were evaluated. After 3 months, there were no significant differences in 28-joint disease activity score (DAS28), health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) between the monotherapy and combination groups (all P > 0.05). According to the European League Against Rheumatism (EULAR) response criteria, it was found that the DAS28 response rates were similar in the two groups (P > 0.05). Besides, the two groups presented similar safety profiles. Subgroup analysis found that there was no difference in efficacy among the three combined therapies (LEF + methotrexate (MTX), LEF + hydroxychloroquine (HCQ), and LEF + MTX + HCQ) and LEF monotherapy. Furthermore, when the dose of LEF was less than 40 mg/day, no significant difference in efficacy was observed between low and high doses. Overall, these results indicated that low dose LEF monotherapy was not inferior to the combination therapy. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovitis, and its primary clinical manifestations is symmetric arthritis affecting multiple joints. Inflammation and joint erosion cause physical function disorder, which severely reduces the quality of life. The global prevalence of RA is 0.5-1% 1,2 , the incidence of RA among females is 2 to 3 times than of males, and the incidence in females shows an increasing trend 3,4. Although multiple studies have reported that the occurrence of RA is related to environmental, hormonal and genetic factors 5-7 , the specific pathogenesis of RA remains unclear, which is difficult to achieve radical cure. The main goal of treating RA at present is to control and alleviate the disease. Currently, drugs for treating RA mainly include conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), targeted synthetic DMARDs (tsDMARDs), biological DMARDs (bDMARDs), biosimilar DMARDs (bsDMARDs), and glucocorticoids (GCs) 8. Economical and effective csDMARDs are the first treatment strategy recommended by the European League Against Rheumatism (EULAR) 8 , including leflunomide (LEF), methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), cyclosporine, azathioprine and gold salts. Among them, LEF was approved by the Food and Drug Administration for the treatment of RA in 1998 and plays a role in controlling and relieving the condition of the disease through acting on dihydroorotate

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Section: Discussionmentioning

confidence: 99%

Leflunomide monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a retrospective study

Deng

Zhou

et al. 2020

Sci Rep

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“…For quantification of NGF, PI3K and Akt genes, qRT-PCR technique was applied. Taqman Universal PCR master mix II, No UNG (2×) [Applied Biosystems] and Taqman assays [Applied Biosystems], assay ID [Mm01282781_m1 for PIK3R1 (Chen et al, 2012; Elshaer et al, 2019) Mm01331626_m1 for Akt1, Mm00443039_m1 for NGF, and Mm99999915_g1 for GAPDH, the endogenous control gene] were utilized (Kanwar and Kowluru, 2009; Qiu et al, 2017) to run reactions in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation

et al. 2019

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Aim: Diabetic retinopathy causes loss of vision in adults at working-age. Few therapeutic options are available for treatment of diabetic retinopathy. Carbamazepine (CARB), a widely used antiepileptic drug, was recently accounted for its neuroprotective effect. Nerve growth factor (NGF) activates various cascades among which, PI3K/Akt/mTOR pathway has a vital action in NGF-mediated neuronal differentiation and survival. This study evaluated the effect of CARB in the treatment of diabetic retina and unveiled some of the underlying molecular mechanisms.Main Methods: Alloxan diabetes model was induced in 36 albino well-acclimatized mice. After establishment of the diabetic model in 9 weeks, mice were assigned to treatment groups: (1) saline, (2) alloxan-diabetic, (3 and 4) alloxan+CARB (25 or 50 mg per kg p.o) for 4 weeks. After completion of the therapeutic period, mice were sacrificed and eyeballs were enucleated. Retinal levels of NGF and PI3K/Akt were assessed using real-time polymerase chain reaction. Further, total and phosphorylated TrKA, PI3K, Akt, mTOR as well as Caspase-3 were measured by Western blot analysis.Key Findings: Histopathological examination demonstrated that CARB attenuated vacuolization and restored normal thickness and organization of retinal cell layers. In addition, CARB increased pTrKA/TrKA ratio and ameliorated diabetes-induced reduction of NGF mRNA and immunostaining in retina. Additionally, it augmented the mRNA expression of PI3K and Akt, as well as the protein level of the phosphorylated PI3/Akt/mTOR.Significance: Results highlighted, for the first time, the neuronal protective effect for CARB in diabetic retina, which is mediated, at least in part, by activation of the NGF/PI3K/Akt/mTOR pathway.

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“… Endoplasmic reticulum stress MAPK signaling cascade, through inhibiting JNK and enhancing ERK1/2 pathways [130] . Metabolic stress and inflammatory pathway TLR4-induced apoptosis through activation of PI3K/mTOR/NFκB pathway [129] . Hepatic fibrosis Increased hepatic expression of TGF-β [127] , [129] .…”

Section: Clinical Importance Of Lfmentioning

confidence: 99%

“… Metabolic stress and inflammatory pathway TLR4-induced apoptosis through activation of PI3K/mTOR/NFκB pathway [129] . Hepatic fibrosis Increased hepatic expression of TGF-β [127] , [129] . CYP450 polymorphism CYP2C9*3 allele may be associated with hepatic toxicity of LF in rheumatoid arthritis patients [16] , [138] .…”

Section: Clinical Importance Of Lfmentioning

confidence: 99%

“…Clinical studies and basic research reported on the hepatotoxicity of LF, which was found to be dose and time-dependent [129] , [130] , [131] , [132] . For the former, the use of LF doses of higher than 20 mg/day is associated with a higher incidence of hepatic injury, which may be asymptomatic or of a fulminating nature with a life-threatening hazard [1] , [16] , [126] .…”

Section: Studies Reporting the Drawbacks Of Leflunomide On The Livermentioning

confidence: 99%

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Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Alamri

Elmeligy

Albalawi

et al. 2021

International Immunopharmacology

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Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients’ mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.

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Leflunomide-induced liver injury in mice: Involvement of TLR4 mediated activation of PI3K/mTOR/NFκB pathway

Cited by 20 publications

References 64 publications

Leflunomide monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a retrospective study

Leflunomide monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a retrospective study

Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation

Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

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