The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity.

Fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease after stem cell transplantation, a microangiopathy characterized by sinusoidal endothelial cell injury. Defibrotide is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties. Numerous clinical studies have shown promising activity of defibrotide in the treatment and prevention of veno-occlusive disease, with minimal toxicity.

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

Purpose Of The Study: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents.

Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease.

Defibrotide (DF) is a mixture of porcine-derived single-stranded phosphodiester oligonucleotides (9-80-mer; average, 50-mer) that has been successfully used to treat severe hepatic veno-occlusive disease (sVOD) with multiorgan failure (MOF) in patients who have received cytotoxic chemotherapy in preparation for bone marrow transplantation. However, its mechanism of action is unknown. Herein, we show that DF and phosphodiester oligonucleotides can bind to heparin-binding proteins (eg, basic fibroblast growth factor [bFGF] but not vascular endothelial growth factor [VEGF] 165) with low nanomolar affinity.

Acute hypertension induces oxidative stress in brain tissues.

Arterial hypertension is not only a major risk factor for cerebrovascular accidents, such as stroke and cerebral hemorrhage, but is also associated to milder forms of brain injury. One of the main causes of neurodegeneration is the increase in reactive oxygen species (ROS) that is also a common trait of hypertensive conditions, thus suggesting that such a mechanism could play a role even in the onset of hypertension-evoked brain injury. To investigate this issue, we have explored the effect of acute-induced hypertensive conditions on cerebral oxidative stress.

The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia.

Rai (Shc C or N-Shc) is a neuron-specific member of the family of Shc-like adaptor proteins. Rai functions in the cytoplasmic propagation of Ret-dependent survival signals and regulates, in vivo, the number of sympathetic neurons. We report here a function of Rai, i.

The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q.

C1-inhibitor (C1-INH) is a major regulator of the complement classical pathway. Besides this action, it may also inhibit other related inflammatory systems. We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery.