Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice

Bruna, Jordi; Udina, Esther; Alé, Albert; Vilches, J; Vynckier, Ann; Monbaliu, Johan; Silverman, Lee; Navarro, Xavier

doi:10.1016/j.expneurol.2010.02.006

Cited by 91 publications

(108 citation statements)

References 49 publications

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“…Second, we observed a mild impairment of neuromuscular transmission in the 4w-Bz control group (but not in the 8w-Bz Control group) in comparison with the saline-treated control group. This effect possibly indicates transient nerve damage similar to the bortezomib-induced polyneuropathy (26,40). Arguably, the weight loss in control animals was caused by an effect of proteasome inhibition on the gastrointestinal tract, which has been seen in patients (41).…”

Section: Discussionmentioning

confidence: 95%

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

124

100

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Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

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Section: Discussionmentioning

confidence: 95%

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

124

100

View full text Add to dashboard Cite

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“…Oxygen--reactive species (ORS) seem to play a relevant role in the development and maintenance of paclitaxel-induced pain 10 . For bortezomib, a proteasome inhibitor, Bruna et al 11 have described decreased myelinated and non myelinated fibers and the presence of abnormal inclusion bodies in non myelinated axons in rats treated with the drug, which would change pain threshold. An experimental study with rats has shown by electronic microscopy, that there were no significant pathological changes in the morphology of myelin sheath of animals treated with cisplatin, bortezomib and paclitaxel, although there has been decreased nervous conduction velocity 12 .…”

Section: Pathophysiology Of Chemotherapy-indu-ced Peripheral Neuropathymentioning

confidence: 99%

Chemotherapy-induced peripheral neuropathy: review for clinical practice

Simão¹,

Murad²,

Martins³

et al. 2015

Revista Dor

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“…We began by performing a dose-response analysis of proteasome inhibition after bortezomib injection into WT congenic BalbC/J mice. Previous studies from oncology-related research work have highlighted a narrow therapeutic window in vivo (0.7-1.3 mg/kg) owing to bortezomib-induced neuropathy in mouse models (16). After a single bortezomib injection (0.2-2 mg/kg i.p.…”

Section: Bortezomib Significantly Reduces Porphyrin Accumulation In Vmentioning

confidence: 99%

“…However, we also have shown that efficient and long-term proteasome inhibition is difficult to obtain in vivo, especially in the erythroid lineage, even with clinical-grade drugs. Furthermore, such long-term unspecific inhibition of abnormal protein degradation could lead to serious adverse toxic effects, especially in the central nervous system, and would not constitute a safe therapeutic choice for CEP (16,28). Recently, mutations in genes involved in the ubiquitin-proteasome system have been associated with the pathogenesis of neurodegenerative and other brain diseases (29).…”

Section: Bortezomib Significantly Reduces Porphyrin Accumulation In Vmentioning

confidence: 99%

Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria

Blouin

Duchartre

Costet

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS C73R mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS P248Q mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS C73R and UROS P248Q are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros P248Q/P248Q ) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.protein misfolding | Günther's disease | enzyme instability | heme biosynthetic pathway | pharmacological therapy

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Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice

Cited by 91 publications

References 49 publications

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Chemotherapy-induced peripheral neuropathy: review for clinical practice

Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria

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