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1.
Sci Rep ; 10(1): 6734, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317735

RESUMO

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.


Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Hiperalgesia/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Piperidinas/farmacologia , Uracila/análogos & derivados , Aloenxertos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuritos/efeitos dos fármacos , Neuritos/patologia , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Carga Tumoral/efeitos dos fármacos , Uracila/farmacologia
2.
J Pharmacol Sci ; 140(3): 291-294, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31377017

RESUMO

Oxaliplatin induces severe peripheral neuropathy. The effect of donepezil, a drug used for treatment of Alzheimer's disease, on oxaliplatin-induced peripheral neuropathy was investigated using both in vivo and in vitro models. Donepezil effectively attenuated oxaliplatin- and cisplatin-induced inhibition of neurite outgrowth in cultured PC12 cells. In a rat model, repeated oral administration of donepezil (5 times/week for 4 weeks) ameliorated oxaliplatin-induced mechanical allodynia (von Frey test) and sciatic nerve axonal degeneration. Moreover, donepezil did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line. Therefore, donepezil may be useful for managing oxaliplatin-induced peripheral neuropathy.


Assuntos
Donepezila/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Masculino , Camundongos , Células PC12 , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos
3.
Biol Pharm Bull ; 42(4): 638-644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930422

RESUMO

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.


Assuntos
Antineoplásicos , Fumarato de Dimetilo/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Oxaliplatina , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Fumarato de Dimetilo/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fármacos Neuroprotetores/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Carga Tumoral/efeitos dos fármacos
4.
J Pharmacol Sci ; 137(2): 202-211, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30042024

RESUMO

Chemotherapy agents such as oxaliplatin, cisplatin, paclitaxel, and bortezomib frequently cause severe peripheral neuropathy and there is currently no effective strategy to prevent this. Dimethyl fumarate (DMF) is a new oral drug for the treatment of multiple sclerosis, and has neuroprotective effects via up-regulation of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response. In this study, we investigated the effect of DMF on chemotherapy agent-induced neurodegenerations in cultured cells. We found that DMF and its metabolite monomethyl fumarate (MMF) attenuated oxaliplatin-, cisplatin-, and bortezomib- (but not paclitaxel-) induced inhibition of neurite outgrowth, but had no effect on cell death as a result of these agents in cultured PC12 cells and primary cultured rat dorsal root ganglion (DRG) neurons. Furthermore, Nrf2 DNA binding activity was increased by DMF and MMF in PC12 cells. These findings suggest that DMF, which activates Nrf2 pathway, has a potential protective action against chemotherapy-induced neurotoxicity, particularly neurite impairments.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/prevenção & controle , Crescimento Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores , Animais , DNA/metabolismo , Gânglios Espinais/efeitos dos fármacos , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ligação Proteica/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
J Agric Food Chem ; 62(13): 2845-52, 2014 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-24617642

RESUMO

Gliadin is the principal allergen of wheat-dependent exercise-induced anaphylaxis (WDEIA). The primary structure of IgE-binding epitopes in wheat gliadin includes tandem sequencing sites of glutamine residues. Therefore, deamidation would be an effective approach to reduce the allergenicity of wheat proteins. In our previous study, we deamidated wheat gliadin without causing peptide-bond hydrolysis or polymerization by use of carboxylated cation-exchange resins, and we found that the deamidated gliadin scarcely reacted with the sera of patients radioallergosorbent test (RAST)-positive to wheat. In this study, we examined the allergenicity of deamidated gliadin in a mouse model of wheat-gliadin allergy. Oral administration of deamidated gliadin to gliadin-sensitized mice suppressed enhancement in intestinal permeability, serum allergen level, serum allergen-specific IgE level, mast-cell-surface expression of FcεRI, and serum and intestinal histamine levels. Our results indicate that gliadin deamidated with no peptide-bond hydrolysis by cation-exchange resins has low allergenicity even under in vivo conditions.


Assuntos
Anafilaxia/prevenção & controle , Epitopos/química , Epitopos/imunologia , Gliadina/química , Gliadina/imunologia , Imunoglobulina E/imunologia , Triticum/imunologia , Hipersensibilidade a Trigo/prevenção & controle , Anafilaxia/imunologia , Animais , Desaminação , Humanos , Hidrólise , Imunoglobulina E/sangue , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Triticum/química , Hipersensibilidade a Trigo/imunologia
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