Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug

Yamamoto, Seigo; Ushio, Soichiro; Egashira, Nobuaki; Kawashiri, Takehiro; Mitsuyasu, Shohei; Higuchi, Hitomi; Ozawa, Nana; Masuguchi, Ken; Ono, Yuko; Masuda, Satohiro

doi:10.1038/s41598-017-08891-1

Cited by 33 publications

(38 citation statements)

References 56 publications

(66 reference statements)

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“…Our related facilities have reported many drugs that improve oxaliplatin-induced peripheral neuropathy in the rat model 5,18,[30][31][32][33][34] . In those reports, goshajinkigan, ifenprodil, and trifluoperazine have transient analgesic effects [31][32][33] , and calcium channel blockers attenuate the incidence of cold hyperalgesia in the acute neuropathy 5 .…”

Section: Discussionmentioning

confidence: 99%

“…In those reports, goshajinkigan, ifenprodil, and trifluoperazine have transient analgesic effects [31][32][33] , and calcium channel blockers attenuate the incidence of cold hyperalgesia in the acute neuropathy 5 . In contrast, riluzole, dimethyl fumarate, donepezil, and alogliptin, have the prophylactic effect on www.nature.com/scientificreports www.nature.com/scientificreports/ oxaliplatin-induced mechanical allodynia in the chronic neuropathy 18,30,34 , which is a dose-limiting toxicity in clinical. Moreover, DPP-4 inhibitors have a lower incidence of adverse events, including hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

“…C-26 cells (1.5 × 10 6 cells) were subcutaneously implanted in the right paw of BALB/c mice. We selected C26 cell line-bearing mice model because it had been used in some previous studies 19, 34 and it does not require nude mice. Three days after the implantation of the tumor cells, the drug administration began.…”

Section: Methodsmentioning

confidence: 99%

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Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro

Shigematsu

Kawashiri

Kobayashi

et al. 2020

Sci Rep

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Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.Oxaliplatin is a platinum-based chemotherapeutic agent used for the standard treatment of colorectal, gastric, and pancreatic cancer. However, it has a particularly high risk of acute and chronic neuropathies. Acute neuropathy occurs in nearly all patients within hours to days after oxaliplatin infusion. Paranesthesia in the hands, feet, and the perioral region is manifested by exposure to cold temperature but is transient and reversible in most cases 1,2 .It is believed that voltage-gated ion channels and transient receptor potential channels are involved in oxaliplatin-induced acute neurotoxicity 3-5 . Chronic neuropathy results from the repeated treatment of oxaliplatin, which is dose-limiting toxicity. Sensory and motor dysfunction occurs similar to cisplatin-induced neuropathy and may last for several months or years 2,6 . Chronic neurotoxicity is considered to be caused by morphological changes in neurons, such as axon degeneration, neuronal cell body damage, and myelin disorder 7-9 . These neuropathies remain a significant clinical problem in chemotherapy with oxaliplatin as they impact the quality of life and can lead to drug reduction or discontinuation.Although many researches have been conducted to prevent chemotherapy-induced peripheral neuropathy, an effective treatment has yet to be found 10 . According to the clinical practice guideline established by the American Society of Clinical Oncology in 2014, no agents have yet to be recommended for the prevention of chemotherapy-induced peripheral neuropathy 11 .Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is clinically used for the treatment of type 2 diabetes mellitus. It lowers the blood glucose level mainly by preventing the inactivation of glucagon-like peptide-1 (GLP-1). Recently, it has received considerable attention as DPP-4 inhibitors have pleiotropic effects in addition to hypoglycemic action 12,13 . It has been reported that ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro

Shigematsu

Kawashiri

Kobayashi

et al. 2020

Sci Rep

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“…Although DMF rarely causes serious side effects, some studies have reported that it causes lymphopenia 34,35) ; therefore, we were concerned that DMF may worsen myelosuppression during oxaliplatin treatment. However, our results showed that the co-administration of DMF during oxaliplatin treatment caused no further decrease in any blood cell count and no more weight loss than that caused by oxaliplatin treatment in rats, indicating that the co-treatment using oxaliplatin and DMF has little additional risk.…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents

Miyagi

Kawashiri

Shimizu

et al. 2019

Biological & Pharmaceutical Bulletin

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Oxaliplatin has been used as a first choice for colorectal, gastric and pancreatic cancer, but it induces peripheral neuropathies. Dimethyl fumarate (DMF) is an oral drug for multiple sclerosis with neuroprotective effects on oxidative stress. Using both in vivo and in vitro models, we investigated the effects of DMF on oxaliplatin-induced peripheral neuropathy and other side effects, as well as on the anti-tumor activity of oxaliplatin. Repeated intraperitoneal injection of 4 mg/kg oxaliplatin (twice per week for 4 weeks) caused mechanical allodynia (as revealed by the von Frey tests), cold hyperalgesia (as revealed by the acetone tests), and axonal degeneration in the sciatic nerve of rats. Co-administration of oral DMF (200 mg/kg, five times per week for 4 weeks) relieved oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and ameliorated axonal degeneration. In addition, DMF did not exacerbate oxaliplatin-induced body weight loss or bone marrow suppression, such as reduction in red blood cells, white blood cells, neutrophils and lymphocytes. Furthermore, DMF did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line (C26, mouse colon carcinoma; HCT116, human colon carcinoma; MKN45, human gastric adenocarcinoma; MIA PaCa-2, human pancreatic carcinoma) or C26-bearing mice. These results suggest that DMF prevents oxaliplatin-induced mechanical allodynia and axonal degeneration without affecting the anti-tumor activity of oxaliplatin. Therefore, DMF may be useful for managing oxaliplatin-induced chronic peripheral neuropathy.

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“…Nerve injury induces changes in the expression of glutamate transporters in the spinal cord and supraspinal brain regions (Gegelashvili & Bjerrum, ; Marcello et al, ; Putatunda, Hala, Chin, & Lepore, ; Sung et al, ; Xin, Weng, & Dougherty, ). Among the five subtypes, GLT1 expression is frequently affected in various animal models of neuropathic pain (Gegelashvili & Bjerrum, ; Marcello et al, ; Putatunda et al, ; Shi, Jiang, & Li, ; Yamamoto et al, ; Yan, Maixner, Li, & Weng, ). Downregulation of GLT1 expression in the spinal dorsal horn is associated with neuropathic pain following chronic constriction of the sciatic nerve and tight ligation of spinal nerves (Gegelashvili & Bjerrum, ; Sung et al, ; Xin et al, ).…”

Section: Introductionmentioning

confidence: 99%

Region‐specific deletions of the glutamate transporter GLT1 differentially affect nerve injury‐induced neuropathic pain in mice

Zhao

Hiraoka

Ogawa

2018

Glia

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Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG-specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.

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Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug

Cited by 33 publications

References 56 publications

Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro

Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro

Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents

Region‐specific deletions of the glutamate transporter GLT1 differentially affect nerve injury‐induced neuropathic pain in mice

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