Background & Aims

Many of the antineoplastic drugs currently used cause peripheral neuropathy and neuropathic pain as the main dose-limiting adverse effect. The organoplatinum compound oxaliplatin (OXA) used for the treatment of colorectal and other cancers is one of the agents more prone to induce painful symptoms.
The severe impact of chemotherapy-induced peripheral neuropathy (CIPN) often needs dose reduction or drug suspension due to its harmful effects on patients’ overall health. Unfortunately, there are no currently available strategies for the prevention or long-lasting suppression of CIPN.
The aim of our work was to assess the development of mechanical allodynia, cold allodynia and locomotor impairments in an experimental model of OXA-induced neuropathy, analyzing the underlying mechanisms such as neuroinflammatory processes and the existence of sex-related differences. We also aimed to evaluate the use of resveratrol in the prevention and treatment of CIPN-associated symptoms.

Methods

Young adult rats of both genders received intraperitoneal (ip) injections of oxaliplatin (OXA) at a dosage of 4 mg/kg/day, administered on 3 alternate days for a total cumulative dose of 12 mg/kg, while control animals (CTL) were injected with vehicle (saline solution). Mechanical and thermal hypersensitivity and allodynia were evaluated over a 4-week period using von Frey and Choi Tests, respectively. Locomotor function was assessed through the open field test. Resveratrol was administered daily and orally, starting either before (preventative strategy, RESVp) or after (therapeutic strategy, RESVt) the chemotherapy regimen. Seven days after initiating OXA/saline administration, animals were deeply anesthetized with isoflurane and killed by decapitation or perfusion. Bilateral sciatic nerves and lumbar dorsal root ganglia (L3-L5) were immediately removed. Tissues were frozen and stored at -70°C until immunofluorescence assays or gene expression studies were performed.

Results

Male and female rats treated with OXA exhibited mechanical and thermal hypersensitivity and allodynia. Females displayed a more robust response to cold stimulation. RESVp prevented these functional impairments in both. No differences were detected between genders or among the different experimental groups in relation to locomotor function, particularly traveled distance, average speed, and immobility time.
OXA-treated males and females showed increased ATF-3, GFAP and IBA-1 mRNA levels. Higher GFAP fluorescence intensity, as well as higher TRPM8 mRNA levels, were detected in female DRGs. The expression of HMGB1 was only increased in male DRGs.
RESVp administration resulted in increased GSH levels, restored GSH/GSSG ratio. Decreased TBARS levels were detected in sciatic nerves and DRG. RESVp also increased the DRG expression of SIRT-1, NRF-2, and NQO-1 and resulted in lower ATF-3, NF-?B and TNF-? and mRNA levels, suggesting a protective effect against OXA-induced neuronal damage.

Conclusions

Patients exposed to OXA can develop an acute neuropathy, during or shortly after the first few infusions, and a chronic neuropathy in the long term. In our study, OXA induced mechanical and cold hypersensitivity and allodynia in male and female rats. Notably, cold stimulation was more robust in females, correlating with increased expression of TRPM8. Remarkable, resveratrol administration effectively prevented OXA induced pain behaviors.
The neurotoxic actions of chemotherapy drugs compromise mainly the peripheral nervous system. OXA induced neuronal damage in both genders (ATF-3), as well as glial activation (GFAP and IBA-1) and the production of pro-inflammatory mediators (HMGB1, NFkB and TNF-?).
RESVp was able to increase the antioxidant reserves and diminish lipid peroxidation levels within the peripheral nerve. Besides RESVp administration enhanced the antioxidant defense system and lessened the neuroinflammatory processes.

References

Bakogeorgos, M. and V. Georgoulias (2017). Risk-reduction and treatment of chemotherapy-induced peripheral neuropathy. Expert Rev Anticancer Ther 17(11): 1045-1060.
Staff, N. P., A. Grisold, W. Grisold and A. J. Windebank (2017). Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 81(6): 772-781.
Hershman, D. L., C. Lacchetti and C. L. Loprinzi (2014). Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract 10(6): 421-424.
Majithia, N., S. M. Temkin, K. J. Ruddy, A. S. Beutler, D. L. Hershman and C. L. Loprinzi (2016). National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons. Support Care Cancer 24(3): 1439-1447.

Presenting Author

Constanza Agata Miguel

Poster Authors

Constanza Miguel

Bsc in biology

IIMT

Lead Author

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Constanza Agata Miguel

Bsc

Lead Author

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Mariel Fusco,BSC

Lead Author

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Tobias Giovannetti

Tec

Lead Author

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Flavia Valeria Piccioni

PhD

Lead Author

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Mariana Malvicini,PhD

Lead Author

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Marcelo Villar

Universidad Austral, Faculty of Biomedical Sciences

Lead Author

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Maria Florencia Coronel

Instituto de Investigaciones en Medicina Traslacional Austral - CONICET

Lead Author

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Topics

  • Gender/Sex Differences