ABSTRACT
Cardiovascular diseases (CVDs) are one of the leading causes of death in patients over 60years with Huntington's disease (HD). Here, we investigated if age-related oxidative stress (OS) is a relevant factor to develop cardiac damage in an in vivo model of striatal neurodegeneration induced by 3-nitropropionic acid (3-NP). We also evaluated the potential effect of tert-butylhydroquinone (tBHQ) to increase the Nrf2-regulated antioxidant response in hearts from adult and aged rats intoxicated with 3-NP. Our results showed that 3-NP-treatment did not induce cardiac dysfunction, neither in adult nor in aged rats. However, at the cellular level, adult animals showed higher susceptibility to 3-NP-induced damage than aged rats, which suggest that chronic oxidative stress ongoing during aging might have induced an hormetic response that probably prevented from further 3-NP damage. We also found that the oxidative unbalance concurs with unresponsiveness of the Nrf2-mediated antioxidant response in old animals.
Subject(s)
Huntington Disease/chemically induced , NF-E2-Related Factor 2/metabolism , Neuroprotective Agents/pharmacology , Nitro Compounds/toxicity , Propionates/toxicity , Animals , Antihypertensive Agents , Antioxidants/pharmacology , Female , Heart Diseases/chemically induced , Hydroquinones/pharmacology , NF-E2-Related Factor 2/drug effects , Oxidative Stress/physiology , Rats, WistarABSTRACT
Acute myocardial infarction is a frequent and disabling disease. Paradoxically, reperfusion, the most effective treatment to reduce infarct size, can both protect and kill. Although reperfusion protects by preventing lesions occurring during prolonged ischemia, it causes damage because reflow is associated with an unbalance between oxygen availability and metabolic demand, altered ionic homeostasis, and reactive oxygen species (ROS) generation. Recently, more players in myocardial reperfusion injury have been described: protein kinase C (PKC) and members of the MAP kinase, which activate downstream cascades that may activate intricate processes compromising cardiac recovery after ischemia. All together, such mechanisms promote endothelial and vascular dysfunction, sequels of impaired blood flow, metabolic and contractile dysfunction, dysrhythmia, cellular necrosis and apoptosis. Different pharmacological agents, as well as mechanical strategies, have been used to challenge the outcome of the complex interactions among these mechanisms and with others. In this review, we focused on the potential of different compounds used in animal models and in the clinical practice to improve the prognosis after post-ischemic reperfusion. We also review mechanisms activated during reperfusion injury and the structure-activity relationship between some of the cardioprotective chemicals and their cellular targets.
Subject(s)
Myocardial Reperfusion Injury/drug therapy , Adrenergic beta-Antagonists/therapeutic use , Animals , Apoptosis , Calcium Channel Blockers/therapeutic use , Disease Models, Animal , Free Radical Scavengers/therapeutic use , Myocardial Reperfusion Injury/prevention & control , Oxidative Stress , Protease Inhibitors/therapeutic use , Protein Kinase Inhibitors/therapeutic useABSTRACT
Although alpha-mangostin prevents from toxicity associated to oxidative stress, it also promotes apoptotic cell death in cancer cells. Such effects have been associated with mitochondrial membrane depolarization and cytochrome c release. Therefore, the aim of this work was to analyze the potentially harmful effect of this natural compound on relevant parameters of mitochondrial function from normal tissue. Our results showed that alpha-mangostin protected mitochondria from peroxidative damage, but at high concentration, it acted as an uncoupler, reduced dramatically ADP-stimulated respiration and inhibited the activity of respiratory complex IV, making mitochondria prone to permeability transition, which is a mitochondrial player on cell fate.
