The NAMPT inhibitor FK866 reverts the damage in spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.</p> <p>Methods</p> <p>We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.</p> <p>Results</p> <p>Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.</p> <p>We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.</p> <p>Conclusions</p> <p>Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.</p

Olprinone Attenuates the Acute Inflammatory Response and Apoptosis after Spinal Cord Trauma in Mice

BACKGROUND: Olprinone hydrochloride is a newly developed compound that selectively inhibits PDE type III and is characterized by several properties, including positive inotropic effects, peripheral vasodilatory effects, and a bronchodilator effect. In clinical settings, olprinone is commonly used to treat congestive cardiac failure, due to its inotropic and vasodilating effects. The mechanism of these cardiac effects is attributed to increased cellular concentrations of cAMP. The aim of the present study was to evaluate the pharmacological action of olprinone on the secondary damage in experimental spinal cord injury (SCI) in mice. METHODOLOGY/PRINCIPAL FINDINGS: Traumatic SCI is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should be preventable, no effective treatment options currently exist for patients with SCI. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, apoptosis, and locomotor disturbance. Olprinone treatment (0.2 mg/kg, i.p.) 1 and 6 h after the SCI significantly reduced: (1) the degree of spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation, (4) pro-inflammatory cytokines, (5) NF-kappaB expression, (6) p-ERK1/2 and p38 expression and (7) apoptosis (TUNEL staining, FAS ligand, Bax and Bcl-2 expression). Moreover, olprinone significantly ameliorated the recovery of hind-limb function (evaluated by motor recovery score). CONCLUSIONS/SIGNIFICANCE: Taken together, our results clearly demonstrate that olprinone treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI

THORACIC AND CARDIOVASCULAR SURGEON

We present a case of a 16-year-old girl who underwent infundibular myectomy for right ventricular outflow tract obstruction complicated by biventricular non-compaction. The pathogenesis of this condition remains unknown. In pediatric patients non-compaction cardiomyopathy is associated with other cardiac abnormalities and carries a high mortality as a result of heart failure. In view of her improved cardiac performance after operation, we believe that a cardiac repair procedure should be performed based on the usual indications if left ventricular function is preserved

ACTA CARDIOLOGICA

Objective - Paraplegia remains a devastating complication after thoracic and thoracoabdominal aortic surgery for coarctations, dissections or aneurysms. Since the advent of ischaemic preconditioning of the myocardium, attention has been directed to the nervous system. This study was designed to evaluate the acute protective effect of ischaemic preconditioning on the spinal cord. Methods and results - Thirty-six New Zealand white rabbits were randomly assigned to one of three groups. The preconditioning group had 5 minutes of aortic occlusion, 25 minutes reperfusion and 20 minutes of ischaemia, whereas the controls had only 20 minutes of ischaemia. The sham group was anaesthetized and subjected to laparotomy without aortic occlusion. Physiological parameters and somatosensory evoked potentials were monitored during the experiment. Neurological outcome was clinically evaluated up to 48 hour after ischaemia and motor function was scored. Then the animals were sacrificed. Their spinal cord, abdominal aorta and its branches were removed and processed for histopathological examination. Histhopathological changes of the gray matter in the lumbosacral segments were scored from 0 to 6 according to a semi-quantitative scala. The changes in amplitudes of evoked potentials during ischaemia and recovery periods were similar in preconditioning and control groups. The average motor function score was significantly higher in the preconditioning group than the control group at 24 and 48 hours after the ischaemic event (p < 0.05). Histological observations were consistent with the neurological findings. The histopathological scores in the control group and the preconditioning group were 3.2 (1.4-5.2) and 2.4 (0.8-4.4), respectively (p < 0.05). Conclusions - The results suggest that ischaemic preconditioning reduces the spinal cord injury and improves neurological outcome in transient ischaemia in rabbits. This protective mechanism is rapidly invoked within only 25 minutes interval between the preconditioning stimulus and the ischaemic insult

ANNALI ITALIANI DI CHIRURGIA

A 49-year-old man admitted with a 3 weeks history of stomachache and without any cardiac symptoms and diagnosed as pseudoaneurysm of the left ventricle is reported. The repair was performed with the aid of cardiopulmonary bypass, defect was repaired with Gore-tex patch and myocardial tissues were approximated and closed by using two Teflon stripes. BioGlue was applied on the sutures and between the stripes. We report this unusual case because rarity and high clinical index of suspicion is needed to make correct diagnosis in such patients. Although there is a significantly high mortality of the pseudoaneurysm cases their repair can and should be performed as an urgent procedure

ACTA CARDIOLOGICA

Annular calcifications carry some technical difficulties for success in conventional valve surgery. In this paper we present an easy alternative mitral valve replacement method applied for a patient with a heavily calcified mitral annulus. Excision of both leaflets and partial resection of the annular calcification with an ultrasonic dissector allowed the intra-atrial insertion of a 33-mm Omnicarbon monoleaflet prosthetic valve through a smaller opening of the left posterior atrium. The technical difficulties in inserting a prosthetic valve in a patient with a heavily calcified mitral annulus are discussed

THORACIC AND CARDIOVASCULAR SURGEON

We describe a case of congenitally corrected transposition of the great arteries plus dextrocardia and normal anatomical abdominal viscera. Systemic (tricuspid) valve replacement was performed due to moderately severe valve regurgitation. An unusual operative technique Was used because of the patient's rare morphology. On cardipopulmonary bypass, the systemic valve was approached via a left atriotomy anterior to the left pulmonary veins, whereby the surgeon was positioned on the patient's left side. As the surgeon had excellent exposure from the opposite side of the table, he was able to perforin a tricuspid valve replacement through the left atrium. Our aim is to share our limited experience of such cardiac morphology, which may oblige the Surgeon to be positioned on the left side of the table to perform systemic valve surgery

ANNALI ITALIANI DI CHIRURGIA

A 70 years old man affected by clinical findings of congestive heart failure eight months after aneurysmectomy of a true left ventricular aneurysm, presented with actual pseudoaneurysm of the left ventricle. There was a 5 x 5 cm soft tissue mass on the left side of the chest, synchronously pulsating with heart beating. The repair was performed with the aid of cardiopulmonary bypass. Myocardial tissues were approximated and closed by using two Teflon stripes. BioGlue was applied on the sutures and between the stripes. Although there is a significantly high mortality of the pseudoaneurysm cases their repair can and should be performed in an urgent procedure