Background and aim
The FOLFOX family of chemotherapy regimens are hampered by the development of a painful neuropathy. Current clinical treatments are inadequate, and furthermore, the research of innovative drugs is strongly disadvantaged by the absence of a preclinical model based on the complete mixture of FOLFOX components. The aim of this study was to set up a rat model of FOLFOX-induced neuropathy in rats, validate its predictability by reference drugs, and evaluate the effectiveness of the new anti-neuropathic compound dimiracetam.
Male Sprague–Dawley rats were treated intraperitoneally with the FOLFOX components (6 mg kg−1 oxaliplatin, 50 mg kg−1 5-FU, 90 mg kg−1 leucovorin calcium salt) or oxaliplatin alone (6 mg kg−1) on days 0, 7, 14, and 21, whereas a separate group received one more injection of FOLFOX on day 28. Pain behavioural measurements (paw pressure, cold plate, and electronic Von Frey tests) and motor coordination (Rota-rod test) were assessed before and after treatments. Behavioural, motor, neurological, and autonomic parameters (open field and Irwin tests) were evaluated.
FOLFOX reduced the pain threshold in response to mechanical noxious and thermal (cold) non-noxious stimuli beginning from day 14 up to day 42 comparably to oxaliplatin alone. A fifth FOLFOX injection enhanced the severity but not the duration of painful alterations. Spontaneous activity, behavioural, autonomic, and neurological functions were also affected, whereas the motor coordination was not altered. On day 22, duloxetine (15 mg kg−1, per os), morphine (10 mg kg−1, subcutaneously), or pregabalin (20 mg kg−1, per os), acutely administered, reduced the FOLFOX-dependent hypersensitivity. Repeated treatments with dimiracetam (150 mg kg−1, per os, twice daily, from day 22) significantly protected rats from FOLFOX-induced alterations of pain threshold as well as from autonomic and neurological impairments taking effect after 7 days treatment. Pregabalin repeatedly administered (20 mg kg−1, per os, twice daily, from day 22) was less effective in reducing mechanical hypersensitivity.
A clinically consistent model of FOLFOX-induced neurotoxicity has been developed in rats. Dimiracetam fully reduced hypersensitivity and neurological alterations showing a relevant profile as anti-neuropathic resource.
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This research was funded by the Italian Ministry of Instruction, University and Research (MIUR), University of Florence and Metys Pharmaceuticals.
Conflict of interest
CG, MS, and CF have a patent (patent n. EP2857017) issued. MS and CF report personal fees, outside the submitted work, from Metys Pharma as CEO and as employee, respectively. LDCM, MM, and LM declare that have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Procedures were approved by the Italian Ministry of Health, decree No. 54/2014B.
Electronic supplementary material
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Supplementary Figure S1. Body weight. Oxaliplatin (6.0 mg kg-1 i.p.) or FOLFOX (oxaliplatin 6.0 mg kg-1 i.p/5-FU 50 mg kg-1 i.p./leucovorin 90 mg kg-1 i.p.) were injected on days 0, 7, 14, and 21 after the behavioural measurements. On day 28, animals were divided into two groups, one was treated once again on the same day with FOLFOX [FOLFOX(5)]. Control rats were treated with vehicle. Each value represents the mean ± S.E.M. of at least ten rats per group, performed in two different experimental sets (TIF 504 KB)
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Di Cesare Mannelli, L., Maresca, M., Micheli, L. et al. A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin. Cancer Chemother Pharmacol 80, 1091–1103 (2017). https://doi.org/10.1007/s00280-017-3449-8
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