Administration of CORM-2 inhibits diabetic neuropathy but does not reduce dyslipidemia in diabetic mice
Por:
Méndez-Lara K.A., Santos D., Farré N., Ruiz-Nogales S., Leánez S., Sánchez-Quesada J.L., Zapico E., Lerma E., Escola-Gil J.C., Blanco-Vaca F., Martón-Campos J.M., Julve J., Pol O.
Publicada:
1 ene 2018
Resumen:
The antinociceptive effects of the carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimer (CORM-2) during chronic pain are well documented, but most of its possible side-effects remain poorly understood. In this work, we examine the impact of CORM- 2 treatment on the lipoprotein profile and two main atheroprotective functions attributed to high-density lipoprotein (HDL) in a mouse model of type 1 diabetes while analyzing the effect of this drug on diabetic neuropathy. Streptozotocin (Stz)-induced diabetic mice treated with CORM-2 (Stz-CORM-2) or vehicle (Stz-vehicle) were used to evaluate the effect of this drug on the modulation of painful diabetic neuropathy using nociceptive behavioral tests. Plasma and tissue samples were used for chemical and functional analyses, as appropriate. Two main antiatherogenic properties of HDL, i.e., the ability of HDL to protect low-density lipoprotein (LDL) from oxidation and to promote reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT), were also assessed. Stz-induced diabetic mice displayed hyperglycemia, dyslipidemia and pain hypersensitivity. The administration of 10 mg/kg CORM-2 during five consecutive days inhibited allodynia and hyperalgesia and significantly ameliorated spinal cord markers (Cybb and Bdkrb1expression) of neuropathic pain in Stz mice, but it did not reduce the combined dyslipidemia shown in Stz-treated mice. Its administration to Stz-treated mice led to a significant increase in the plasma levels of cholesterol (*1.4-fold vs. Ctrl,*1.3- fold vs. Stz-vehicle; p < 0.05) and was attributed to significant elevations in both non-HDL (*1.8-fold vs. Ctrl;*1.6-fold vs. Stz-vehicle; p < 0.05) and HDL cholesterol (*1.3-fold vs. Ctrl,*1.2-fold vs. Stz-vehicle; p < 0.05). The increased HDL in plasma was not accompanied by a commensurate elevation in m-RCT in Stz-CORM-2 compared to Stz-vehicle mice; instead, it was worsened as revealed by decreased [3H]-tracer trafficking into the feces in vivo. Furthermore, the HDL-mediated protection against LDL oxidation ex vivo shown by the HDL isolated from Stz-CORM-2 mice did not differ from that obtained in Stz-vehicle mice. In conclusion, the antinociceptive effects produced by a high dose of CORM-2 were accompanied by antioxidative effects but were without favorable effects on the dyslipidemia manifested in diabetic mice. © 2018 Méndez-Lara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Filiaciones:
Méndez-Lara K.A.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
Santos D.:
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Farré N.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Ruiz-Nogales S.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Leánez S.:
Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
Sánchez-Quesada J.L.:
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Grup de Bioquõmica Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Zapico E.:
Departament de Bioquõmica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Lerma E.:
Departament de Patologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Departament de Ciències Morfològiques, Universitat Autònoma de Barcelona, Barcelona, Spain
Escola-Gil J.C.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Blanco-Vaca F.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Martón-Campos J.M.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Julve J.:
Grup de Bases Metabòliques de Risc Cardiovascular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain
Pol O.:
Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
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