ABSTRACT
Pressure ulcers are necrotic lesions mainly due to capillary hypoperfusion. It is well known that hypoxia and also subsequent oxygenation at reperfusion provoke the formation of reactive oxygen species (ROS) responsible for cell death. The hypothesis of their participation in the pathogenesis of pressure ulcers has already been tested; several antioxidants have the capacity to inhibit skin necrosis in animal models but their efficiency in preventing bedsores has never been demonstrated in patients. The failure of clinical trials to show the protective activity of some antioxidants does not rule out the involvement of ROS in ischemic ulcers and the potential efficacy of other antioxidants in preventing their formation remains possible.
Subject(s)
Antioxidants/therapeutic use , Pressure Ulcer/prevention & control , Animals , Cell Death , Clinical Trials as Topic , Disease Models, Animal , Humans , Hypoxia , Ischemia , Models, Theoretical , Necrosis , Oxidative Stress , Reactive Oxygen Species/metabolism , Risk Factors , Skin/pathologyABSTRACT
The purpose of this study was to investigate the mechanism of the neuroprotective activity of trimetazidine in animal retina stressed by ischemia or kainate. Flash electroretinograms were recorded in guinea pigs after ischemia, induced by an acute increase in the intraocular pressure (IOP), or after an intravitreal injection of kainate. Treatment with trimetazidine per os afforded a significant protection of the electroretinogram against the ischemic as well as the excitotoxic insult as an antioxidant (dimethylthiourea) and a nitric oxide synthase inhibitor (nitroarginine) did. The effect of the drug on the extracellular accumulation of glutamate induced by chemical ischemia was studied by incubating rat retina in vitro. Trimetazidine was able to inhibit the extracellular glutamate accumulation, which represents the first step of the excitotoxic phenomenon. Then the compound activity on the glial uptake of glutamate was studied in a rat Müller cell line (rMC-1) in culture. Chemical ischemia inhibited the active 3H-glutamate transport, an effect that was reversed by trimetazidine, at micromolar concentrations. These results demonstrate that trimetazidine which is recognized as an efficient drug against ischemic injuries, is also capable of protecting the retina against excitotoxicity by reducing ischemia-induced accumulation of glutamate due in particular to glial transporter inhibition.
Subject(s)
Excitatory Amino Acid Antagonists/therapeutic use , Glutamic Acid/metabolism , Ischemia/prevention & control , Retina/drug effects , Retinal Diseases/prevention & control , Trimetazidine/therapeutic use , Administration, Oral , Animals , Cell Line , Disease Models, Animal , Electroretinography , Female , Guinea Pigs , Ischemia/metabolism , Ischemia/pathology , Kainic Acid/toxicity , Rats , Rats, Wistar , Retina/metabolism , Retina/pathology , Retinal Diseases/metabolism , Retinal Diseases/pathologyABSTRACT
Glutamate uptake in neurons and glial cells is essential to prevent the persistence of excitotoxic levels of glutamate observed during ischemia. We demonstrated that a short period of hypoxia stimulated the apparent glutamate transport rate in isolated rat retinal cells. The observed increase in glutamate uptake was not affected by glutamate receptor antagonists, protein kinase inhibitors, antioxidant or neo-synthesis inhibitors. However, inhibition of actin polymerization reversed the hypoxia-induced increase in glutamate uptake, suggesting a mobilization of transporters to the cell membrane. Moreover, the depletion in cell glutathione stimulated in the same manner the glutamate uptake and emphasized the key role of glutamate in the control of the level of this antioxidant. This rapid up-regulation of glutamate transport could be considered as an adaptative mechanism of neuroprotection.
