Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib‐induced peripheral neuropathy

Shin, Yoon Kyung; Jang, So Young; Lee, Hyun Kyoung; Jung, Junyang; Suh, Duk Joon; Seo, Suyoung; Park, Hwan Tae

doi:10.1002/glia.21065

Cited by 53 publications

(54 citation statements)

References 46 publications

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“…1,13 Several preclinical models reproducing the features of BiPN have been reported, and they can be reliably used to investigate the molecular mechanisms underlying BiPN. 18,20,23 In this study we explored the effects of acute and protracted proteasome inhibition on the modulation of tubulin dynamics. Altered dynamics of α-tubulin polymerization has an important effect on microtubule function and may be an important pathogenic mechanism underlying peripheral neurotoxicity in addition to the proposed effects of proteasome inhibition on apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

et al. 2013

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“…In response to peripheral nerve injury, myelinating Schwann cells are activated and their myelin properties are modified, resulting in altered conduction properties of nociceptive fibers [37,38,39,40]. Apoptosis of SCs plays a primary role in the development of DPN [41,42].…”

Section: Resultsmentioning

confidence: 99%

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Ren

et al. 2013

Cell Physiol Biochem

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Background/Aims: Peripheral neuropathy is a frequent and severe diabetic complication characterized by progressive loss of peripheral nerve axons and manifested by pain and eventually complete loss of sensation. Effective therapy for diabetic peripheral neuropathy (DPN) is still lacking due to our limited understanding of the mechanisms for nerve injury. Methods: Here we tested the roles of endoplasmic reticulum (ER) stress and the ER stress-activated pro-apoptotic protein CHOP and anti-apoptotic protein ORP150 in DPN in a rat model of high-fat/streptozotocin diabetes and in cultured Schwann cells (SCs). Results: No significant DPN was seen in the early stage of diabetes (4 weeks following verification of diabetes). However, after prolonged diabetes (16 weeks following verification of diabetes), DPN was severely developed as reflected by slowed motor and sensory nerve conduction velocity, blunted thermal nociception, and decreased intraepidermal nerve fiber profiles in the hindpaw. Meanwhile, while it was not noticed in sciatic nerves of early diabetes, ER stress in prolonged diabetic rats was indicated by robust increases in H₂O₂ production and expression of the ER chaperon glucose-regulated protein 78 (GRP78). ORP150 expression was substantially upregulated, accompanied by mild increase in CHOP expression, resulting in a low CHOP/ORP150 ratio, in early diabetes. In contrast, with prolonged diabetes, CHOP expression exceeded ORP150 expression, resulting in an increased CHOP/ORP150 ratio. In vivo knockdown of ORP150 induced DPN in early diabetes and exacerbated the DPN after prolonged diabetes, whereas knockdown of CHOP ameliorated DPN in rats with prolonged diabetic. On the other hand, in vitro knockdown of ORP150 promoted high glucose-induced SC apoptosis, whereas knockdown of CHOP protected SCs from apoptosis. Conclusion: Taken together, we have provided evidence for the critical role of ER stress in the development of DN and also uncovered CHOP/ORP150 ratio as an important mechanism for determining neuronal apoptosis during ER stress. In the early stage of diabetes, CHOP/ORP150 ratio was relatively low favoring neuronal cell survival, whereas after prolonged diabetes, CHOP/ORP150 ratio increased resulting in apoptotic cell death leading to accelerated DPN.

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“…Behavioral experiments were done in a quiet, temperaturecontrolled room (20)(21)(22) C) between 9 a.m. and 5 p.m., and were conducted by an operator blinded to the genotype and the status of drug treatment. Animals were sacrificed with a high dose of intraperitoneal (i.p.)…”

Section: Animalsmentioning

confidence: 99%

“…No satisfactory explanation or effective treatment exists for bortezomib-evoked CIPN (20,21). As described for other chemotherapeutics, bortezomib has been reported to increase oxidative stress (22,23).…”

Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

et al. 2013

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Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger a-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or a-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress byproducts in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists. Cancer Res; 73(10); 3120-31. Ó2013 AACR.

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Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib‐induced peripheral neuropathy

Cited by 53 publications

References 46 publications

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

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