The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 2011
Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-δ.
Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-δ (PI3Kδ). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. ⋯ In addition, nortriptyline inhibited PI3Kδ activity, but had no effect on the PI3Kα and PI3Kγ isoforms. Although CSE reduced the effects of budesonide on TNFα-induced IL-8 production in U937 cells, nortriptyline reversed CSE-induced corticosteroid insensitivity. Nortriptyline restores corticosteroid sensitivity induced by oxidative stress via direct inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD and severe asthma.
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J. Pharmacol. Exp. Ther. · May 2011
Improved cerebrovascular function and reduced histological damage with darbepoietin alfa administration after cortical impact injury in rats.
Darbepoetin alfa (darbEpo) is an erythropoietic glycoprotein that activates the erythropoietin receptor. The aim of our study was to determine whether darbEpo is neuroprotective in a cortical impact injury (CII) model and to determine the characteristics of dose response and time window. To better understand the vascular mechanism of darbEpo neuroprotection, the reactivity of cerebral blood flow (CBF) to l-arginine administration was also studied. ⋯ In the time window study, darbEpo reduced contusion volume when given in a dose of 25 μg/kg at 5 min to 6 h after the impact injury. In animals pretreated with darbEpo, the CBF response to l-arginine was significantly greater than in the animals pretreated with saline. These data demonstrate that darbEpo has neuroprotective effects in traumatic brain injury in a dose- and time-dependent manner and that vascular effects of darbEpo may have a role in neuroprotection.