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

Abstract

BackgroundOlprinone 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 FindingsTraumatic 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-κB 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/SignificanceTaken together, our results clearly demonstrate that olprinone treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Melatonin treatment protects against spinal cord injury induced functional and biochemical changes in rat urinary bladder

“…Spinal cord injury is a highly debilitating pathology; although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of limiting neuronal injury and promoting regeneration have been limited. Traumatic SCI causes severe and permanent functional deficits because of the primary mechanical insult followed by secondary tissue degeneration that may take place over a period of weeks or even months [30]. In recent years, much attention has been given to secondary injury because this appears to be susceptible for therapeutic intervention [15].…”

Spatial and temporal activation of spinal glial cells: Role of gliopathy in central neuropathic pain following spinal cord injury in rats

“…The activation of immune cells, more specifically infiltrating immune cells, such as polymorphonuclear leukocytes (PMN, neutrophils), macrophages and T-cells, develop at least 2 hours after injury and last over 6 months (Beck et al, 2010; Esposito et al, 2010; Nguyen et al, 2011). Activated and infiltrating neutrophils release proinflammatory cytokines, chemokines and reactive oxygen species (ROS) that contribute to lipid peroxidation and breakdown of blood-brain barrier (BBB) following SCI (Bao et al, 2004; Taoka and Okajima, 2000), suggesting that oxidative stress produced as a consequence of SCI plays a role in the breakdown of the BBB followed by infiltration of neutrophils from blood near the injury site (Lin et al, 2007; Schnell et al, 1999).…”

A pathophysiological role of PDE3 in allergic airway inflammation

“…However, clinical data suggest that PDE3 inhibition therapy given via infusion in heart failure, bypass operations, and enterovirus 71 infection did show antiinflammatory effects (37)(38)(39). During the last decade, a growing number of studies suggest that PDE3 inhibition might be involved in immunosuppression (40)(41)(42)(43)(44)(45)(46)(47)(48), although there is no definitive proof. There have been concerns that PDE3 inhibitors were associated with increased cardiovascular mortality in previous clinical trials (49,50).…”