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Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats.

Fujita S, Ushio S, Ozawa N, Masuguchi K, Kawashiri T, Oishi R, Egashira N - PLoS ONE (2015)

Bottom Line: GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems.Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells.Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.

ABSTRACT

Background: Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.

Methods: Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.

Results: Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.

Conclusion: These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Effects of extended-release exenatide on incidence of mechanical allodynia and axonal degeneration induced by oxaliplatin.Oxaliplatin (4 mg/kg) was administered i.v. twice per week for 4 weeks (days 1, 2, 8, 9, 15, 16, 22, and 23). Extended-release exenatide (100 μg/kg) was administered s.c. once per week for 4 weeks. (A) The von Frey test was performed before the first drug administration (on day 0) and on days 7, 14, 21, and 28. Values are expressed as the mean ± standard error mean of five to six animals. (B) On day 28, the sciatic nerve was harvested, and samples were stained with toluidine blue. Images were captured at 800× magnification. Scale bar = 60 μm. (C) The area of axon was calculated by image analysis software (Image J 1.36) from approximately 3000 to 6000 axons per group. Values are expressed as the mean ± standard error mean of four animals. **P < 0.01 compared with vehicle.
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pone.0141921.g003: Effects of extended-release exenatide on incidence of mechanical allodynia and axonal degeneration induced by oxaliplatin.Oxaliplatin (4 mg/kg) was administered i.v. twice per week for 4 weeks (days 1, 2, 8, 9, 15, 16, 22, and 23). Extended-release exenatide (100 μg/kg) was administered s.c. once per week for 4 weeks. (A) The von Frey test was performed before the first drug administration (on day 0) and on days 7, 14, 21, and 28. Values are expressed as the mean ± standard error mean of five to six animals. (B) On day 28, the sciatic nerve was harvested, and samples were stained with toluidine blue. Images were captured at 800× magnification. Scale bar = 60 μm. (C) The area of axon was calculated by image analysis software (Image J 1.36) from approximately 3000 to 6000 axons per group. Values are expressed as the mean ± standard error mean of four animals. **P < 0.01 compared with vehicle.

Mentions: Animals were injected twice weekly with oxaliplatin for 4 weeks and once weekly with extended-release exenatide for 4 weeks. Oxaliplatin (4 mg/kg, i.v., twice per week) significantly lowered the withdrawal threshold compared with the vehicle on days 14, 21, and 28 (P < 0.01 by the Tukey-Kramer test, Fig 3A). Co-administration of extended-release exenatide (100 μg/kg, s.c.) had no effect on the oxaliplatin-induced reduction in withdrawal threshold. Histological studies revealed atrophy of myelinated fibers in the rat sciatic nerve of oxaliplatin-treated animals and rats co-administered oxaliplatin and exenatide for 4 weeks (Fig 3B). The quantification analysis showed that oxaliplatin significantly decreased area of axon (P < 0.01 by the Tukey-Kramer test, Fig 3C), and co-treatment with exenatide had no effect on the oxaliplatin-induced decrease in area of axon.


Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats.

Fujita S, Ushio S, Ozawa N, Masuguchi K, Kawashiri T, Oishi R, Egashira N - PLoS ONE (2015)

Effects of extended-release exenatide on incidence of mechanical allodynia and axonal degeneration induced by oxaliplatin.Oxaliplatin (4 mg/kg) was administered i.v. twice per week for 4 weeks (days 1, 2, 8, 9, 15, 16, 22, and 23). Extended-release exenatide (100 μg/kg) was administered s.c. once per week for 4 weeks. (A) The von Frey test was performed before the first drug administration (on day 0) and on days 7, 14, 21, and 28. Values are expressed as the mean ± standard error mean of five to six animals. (B) On day 28, the sciatic nerve was harvested, and samples were stained with toluidine blue. Images were captured at 800× magnification. Scale bar = 60 μm. (C) The area of axon was calculated by image analysis software (Image J 1.36) from approximately 3000 to 6000 axons per group. Values are expressed as the mean ± standard error mean of four animals. **P < 0.01 compared with vehicle.
© Copyright Policy
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pone.0141921.g003: Effects of extended-release exenatide on incidence of mechanical allodynia and axonal degeneration induced by oxaliplatin.Oxaliplatin (4 mg/kg) was administered i.v. twice per week for 4 weeks (days 1, 2, 8, 9, 15, 16, 22, and 23). Extended-release exenatide (100 μg/kg) was administered s.c. once per week for 4 weeks. (A) The von Frey test was performed before the first drug administration (on day 0) and on days 7, 14, 21, and 28. Values are expressed as the mean ± standard error mean of five to six animals. (B) On day 28, the sciatic nerve was harvested, and samples were stained with toluidine blue. Images were captured at 800× magnification. Scale bar = 60 μm. (C) The area of axon was calculated by image analysis software (Image J 1.36) from approximately 3000 to 6000 axons per group. Values are expressed as the mean ± standard error mean of four animals. **P < 0.01 compared with vehicle.
Mentions: Animals were injected twice weekly with oxaliplatin for 4 weeks and once weekly with extended-release exenatide for 4 weeks. Oxaliplatin (4 mg/kg, i.v., twice per week) significantly lowered the withdrawal threshold compared with the vehicle on days 14, 21, and 28 (P < 0.01 by the Tukey-Kramer test, Fig 3A). Co-administration of extended-release exenatide (100 μg/kg, s.c.) had no effect on the oxaliplatin-induced reduction in withdrawal threshold. Histological studies revealed atrophy of myelinated fibers in the rat sciatic nerve of oxaliplatin-treated animals and rats co-administered oxaliplatin and exenatide for 4 weeks (Fig 3B). The quantification analysis showed that oxaliplatin significantly decreased area of axon (P < 0.01 by the Tukey-Kramer test, Fig 3C), and co-treatment with exenatide had no effect on the oxaliplatin-induced decrease in area of axon.

Bottom Line: GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems.Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells.Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.

ABSTRACT

Background: Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.

Methods: Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.

Results: Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.

Conclusion: These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus