sirolimus and cordycepin

Chronic pain is extremely difficult to manage, in part due to lack of progress in reversing the underlying pathophysiology. Since translation of messenger ribonucleic acids (mRNAs) in the peripheral terminal of the nociceptor plays a role in the transition from acute to chronic pain, we tested the hypothesis that transient inhibition of translation in the peripheral terminal of the nociceptor could reverse hyperalgesic priming, a model of transition from acute to chronic pain. We report that injection of translation inhibitors rapamycin and cordycepin, which inhibit translation by different mechanisms, at the peripheral terminal of the primed nociceptor produces reversal of priming in the rat that outlasted the duration of action of these drugs to prevent the development of priming. These data support the suggestion that interruption of translation in the nociceptor can reverse a preclinical model of at least 1 form of chronic pain.. This study provides evidence that ongoing protein translation in the sensory neuron terminals is involved in pain chronification, and local treatment that transiently interrupts this translation may be a useful therapy to chronic pain.

Topics: Animals; Chronic Pain; Deoxyadenosines; Disease Models, Animal; Hyperalgesia; Male; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Sirolimus

Cordycepin (3'-deoxyadenosine) is one of the major bioactive substances produced by Cordyceps militaris, a traditional medicinal mushroom. Cordycepin possesses several biological activities, including both pro-apoptotic and anti-apoptotic properties. In the present report, we investigated an effect of cordycepin on the survival of cells exposed to tumour necrosis factor (TNF)-α. We found that subtoxic doses of cordycepin increased susceptibility of cells to TNF-α-induced apoptosis. It was associated with suppression of nuclear factor-κB (NF-κB), a major prosurvival component involved in TNF-α signalling. The adenosine transporter and A₃ adenosine receptor, but not A₁ and A₂ adenosine receptors, mediated both anti-NF-κB and pro-apoptotic effects. We found that cordycepin had the potential to phosphorylate eukaryotic translation initiation factor 2α (eIF2α) and that activation of eIF2α mimicked the suppressive effect of cordycepin on the NF-κB pathway. Furthermore, activation of eIF2α sensitized cells to TNF-α-induced apoptosis. To identify molecular events downstream of eIF2α, the role of mammalian target of rapamycin complex 1 (mTORC1) was examined. Selective activation of ₃eIF2α, as well as treatment with cordycepin, caused phosphorylation of mTORC1. Rapamycin, an inhibitor of mTORC1, significantly reversed the suppressive effects of eIF2α on NF-κB. These results suggest that cordycepin sensitizes cells to TNF-α-induced apoptosis, at least in part, via induction of the eIF2α-mTORC1 pathway and consequent suppression of NF-κB.

Topics: Animals; Apoptosis; Cell Line; Cell Survival; Cordyceps; Deoxyadenosines; eIF-2 Kinase; Epithelial Cells; Kidney Tubules; NF-kappa B; Nucleoside Transport Proteins; Phosphorylation; Rats; Receptor, Adenosine A3; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha