RESUMEN
The effects of the antioxidant dihydroquercetin (DHQ) were studied in a model of pulmonary fibrosis. DHQ penetration into the lesion was facilitated by encapsulation into liposomes. Pulmonary fibrosis was modeled in rats by intratracheal injection of bleomycin. For the first 7 days, the rats in the treatment group received a liposomal emulsion with DHQ, while in the comparator group rats received saline. In the control group, intact rats did not receive any exposure. Thirty days after the initiation, lung function and the pathological lesion volume were assessed by 7T 1H MRI and the lungs were taken for histologic examination. The proportion of fibrous tissue was counted by Masson's trichrome staining. Both experimental groups were characterized by a significant functional pulmonary deficiency, with low mortality and a small lesion area. In the rats treated with DHQ, the distribution of fibrous tissue was significantly altered. Significantly more fibrous tissue was found in the center of the lesion, while significantly less was in the interstitial space of alveoli. Lung density at the same time was lower in the treated lungs. Dihydroquercetin encapsulated in liposomes affects the mechanisms of bleomycin-induced pulmonary fibrosis progression in rats. While accelerated fibrosis of the lesion can restrict inflammatory processes, delayed fibrosis of the interstitium can further improve the functional state of the lungs.
RESUMEN
One of the most important pathological consequences of renal ischemia/reperfusion (I/R) is kidney malfunctioning. I/R leads to oxidative stress, which affects not only nephron cells but also cells of the vascular wall, especially endothelium, resulting in its damage. Assessment of endothelial damage, its role in pathological changes in organ functioning, and approaches to normalization of endothelial and renal functions are vital problems that need to be resolved. The goal of this study was to examine functional and morphological impairments occurring in the endothelium of renal vessels after I/R and to explore the possibility of alleviation of the severity of these changes using mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decylrhodamine 19 (SkQR1). Here we demonstrate that 40-min ischemia with 10-min reperfusion results in a profound change in the structure of endothelial cells mitochondria, accompanied by vasoconstriction of renal blood vessels, reduced renal blood flow, and increased number of endothelial cells circulating in the blood. Permeability of the kidney vascular wall increased 48 h after I/R. Injection of SkQR1 improves recovery of renal blood flow and reduces vascular resistance of the kidney in the first minutes of reperfusion; it also reduces the severity of renal insufficiency and normalizes permeability of renal endothelium 48 h after I/R. In in vitro experiments, SkQR1 provided protection of endothelial cells from death provoked by oxygen-glucose deprivation. On the other hand, an inhibitor of NO-synthases, L-nitroarginine, abolished the positive effects of SkQR1 on hemodynamics and protection from renal failure. Thus, dysfunction and death of endothelial cells play an important role in the development of reperfusion injury of renal tissues. Our results indicate that the major pathogenic factors in the endothelial damage are oxidative stress and mitochondrial damage within endothelial cells, while mitochondria-targeted antioxidants could be an effective tool for the protection of tissue from negative effects of ischemia.
Asunto(s)
Antioxidantes/farmacología , Plastoquinona/análogos & derivados , Daño por Reperfusión/prevención & control , Rodaminas/farmacología , Células A549 , Animales , Antioxidantes/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Hipoxia de la Célula , Evaluación Preclínica de Medicamentos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Frecuencia Cardíaca , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Riñón/irrigación sanguínea , Riñón/patología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Plastoquinona/farmacología , Plastoquinona/uso terapéutico , Ratas , Flujo Sanguíneo Regional , Daño por Reperfusión/fisiopatología , Rodaminas/uso terapéuticoRESUMEN
We studied the influence of ischemia/reperfusion of the middle cerebral artery in the rat's brain on the deferred violation of cognitive functions of the brain which are similar to main symptoms observed in the development of Alzheimer's disease. Using 8-hose radial labyrinth we demonstrated that 6 months after incidence of cerebral ischemia a significant impairment of working memory and a decrease in animals the ability to learn are developed. 7 months after focal cerebral ischemia we could observe the accumulation of a mature amyloid peptide and hyperphosphorylated form of the Tau pro- tein in ipsilateral cerebral hemisphere and of the the beta-amyloid peptide precursor in the contralateral hemisphere. Thus, after an experimental stroke in the brain pathological chanres occur as those typical of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Isquemia Encefálica/patología , Encéfalo/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Western Blotting , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatología , Modelos Animales de Enfermedad , Imagen por Resonancia Magnética , Masculino , Aprendizaje por Laberinto/fisiología , RatasRESUMEN
A mitochondria-targeted chimeric compound consisting of a rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine, SkQR1) was studied under conditions of acute brain or kidney damage. A protective effect of this compound was demonstrated in a model of focal brain ischemia, rat kidney ischemia/reperfusion, myoglobinuria (rhabdomyolysis, or crush syndrome), and pyelonephritis. We found that a single intraperitoneal injection of SkQR1 diminishes the size of the ischemic zone in the brain and improves performance of a test characterizing neurological deficit in ischemic animals. Control substance not containing plastoquinone appeared to be not neuroprotective. The data show that SkQR1 is a nephroprotectant and neuroprotectant, which can be due to the antioxidative action of this Skulachev cation.