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1.
Neurotox Res ; 36(4): 688-699, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31228092

ABSTRACT

The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 µL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.


Subject(s)
Oxaliplatin/toxicity , Peripheral Nervous System Diseases/chemically induced , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Animals , Bosentan/administration & dosage , Endothelin Receptor Antagonists , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Male , Mice , Peripheral Nervous System Diseases/metabolism , Spinal Cord Dorsal Horn/drug effects , Spinal Cord Dorsal Horn/metabolism
2.
Toxicol Appl Pharmacol ; 340: 77-84, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29307816

ABSTRACT

Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.


Subject(s)
Antineoplastic Agents/toxicity , Organoplatinum Compounds/toxicity , Oxalates , Peripheral Nervous System Diseases/chemically induced , Animals , Antineoplastic Agents/chemistry , Male , Mice , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/pathology , Organoplatinum Compounds/chemistry , Oxaliplatin , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/pathology
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