Neuroscience letters
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Neuroscience letters · Mar 2006
Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI 3-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells.
Adenosine is an endogenous nucleoside that regulates many processes, including inflammatory responses, through activation of its receptors. Adenosine receptors have been reported to be expressed in microglia, which are major immune cells of brain, yet little is known about the role of adenosine receptors in microglial cytokine production. Thus, we investigated the effect of adenosine and adenosine A3 receptor ligands on LPS-induced tumor necrosis factor (TNF-alpha) production and its molecular mechanism in mouse BV2 microglial cells. ⋯ Adenosine inhibited LPS-induced phosphatidylinositol (PI) 3-kinase activation and Akt phosphorylation, whereas it had no effect on the phosphorylation of p38 and ERK1/2. We also found that adenosine as well as Cl-IB-MECA inhibited LPS-induced NF-kappaB DNA binding and luciferase reporter activity. Taken together, these results suggest that adenosine A3 receptor activation suppresses TNF-alpha production by inhibiting PI 3-kinase/Akt and NF-kappaB activation in LPS-treated BV2 microglial cells.
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Neuroscience letters · Mar 2006
Comparative StudyComparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels.
Na(+) channel blockers are highly effective analgesics. Among the neuronal Na(+) channel subtypes, Nav1.8 is discussed to be of importance for certain pain states, and Nav1.8-preferring Na(+) channel blockers should be able to relief pain without causing severe effects (due to the restricted expression of this channel type). In this study, the effects of four Na(+) channel blockers on rat tetrodotoxin-resistant (TTX-r) Na(+) channels (representing mostly Nav1.8) in sensory neurons were investigated using the patch-clamp technique in the voltage-clamp configuration, and compared with those on cells heterologously expressing Nav1.2 alpha subunits. ⋯ All compounds shifted steady-state inactivation curves to more negative values. Ambroxol blocked resting TTX-r channels more potently than Nav1.2, the opposite was the case for lidocaine, mexiletine and benzocaine. Based on the drugs' potencies found in this study, and the published information on clinically achievable plasma levels, the amount of Na(+) channel block to induce analgesia after systemic administration was estimated.