Dibutyryl-cAMP, sodium salt

Bucladesine is a membrane permeable selective activator of PKA. Target: PKA Bucladesine (bilateral infusion of 10 mM or 100 mM) leads to a significant reduction in escape latency and travel distance (showing an improvement in spatial memory) compared to the control, as assesed by Morris water maze task in male rats. Bucladesine at 1 mM and 5 mM concentrations infused within minutes after 0.5 mg nicotine infusion improves spatial memory retention in male rats [1]. Bucladesine (10 mM/side) combined with Nicotine (0.5 mM/side) results in a significant increase in the ChAT and VAChT immunoreactivity in CA1 regions, and increase in the optical density and amount of ChAT and VAChT immunostaining correlates with the decrease in escape latency and traveled distance in rats treated with Nicotine and low dose of Bucladesine [2]. Bucladesine is absorbed very rapidly and almost completely when the aqueous solution is applied to the site where the skin has been excised. Bucladesine is absorbed rapidly but slower than in the full-thickness abrasion rat model in the case of stripped skin [3]. Bucladesine (single or multiple administration of an emulsion containing 1.5%) is capable of significantly reducing the inflammatory oedema in the arachidonic acid induced ear oedema model in mice [4].

References:
[1]. Sharifzadeh, M., et al., Post-training intrahippocampal infusion of nicotine-bucladesine combination causes a synergistic enhancement effect on spatial memory retention in rats. Eur J Pharmacol, 2007. 562(3): p. 212-20. [2]. Azami, K., et al., The quantitative evaluation of cholinergic markers in spatial memory improvement induced by nicotine-bucladesine combination in rats. Eur J Pharmacol, 2010. 636(1-3): p. 102-7. [3]. Mafune, E., M. Takahashi, and N. Takasugi, Effect of vehicles on percutaneous absorption of bucladesine (dibutyryl cyclic AMP) in normal and damaged rat skin. Biol Pharm Bull, 1995. 18(11): p. 1539-43. [4]. Rundfeldt, C., et al., The stable cyclic adenosine monophosphate analogue, dibutyryl cyclo-adenosine monophosphate (bucladesine), is active in a model of acute skin inflammation. Arch Dermatol Res, 2012.

Protein kinase A induces recruitment of active Na+,K+-ATPase units to the plasma membrane of rat proximal convoluted tubule cells.[Pubmed:9679177]

J Physiol. 1998 Aug 15;511 ( Pt 1):235-43.

1. The aim of this study was to investigate the mechanism of control of Na+,K+-ATPase activity by the cAMP-protein kinase A (PKA) pathway in rat proximal convoluted tubules. For this purpose, we studied the in vitro action of exogenous cAMP (10-3 M dibutyryl-cAMP (db-cAMP) or 8-bromo-cAMP) and endogenous cAMP (direct activation of adenylyl cyclases by 10-5 M forskolin) on Na+,K+-ATPase activity and membrane trafficking. 2. PKA activation stimulated both the cation transport and hydrolytic activity of Na+,K+-ATPase by about 40%. Transport activity stimulation was specific to the PKA signalling pathway since (1) db-cAMP stimulated the ouabain-sensitive 86Rb+ uptake in a time- and dose-dependent fashion; (2) this effect was abolished by addition of H-89 or Rp-cAMPS, two structurally different PKA inhibitors; and (3) this stimulation was not affected by inhibition of protein kinase C (PKC) by GF109203X. The stimulatory effect of db-cAMP on the hydrolytic activity of Na+,K+-ATPase was accounted for by an increased maximal ATPase rate (Vmax) without alteration of the efficiency of the pump, suggesting that cAMP-PKA pathway was implicated in membrane redistribution control. 3. To test this hypothesis, we used two different approaches: (1) cell surface protein biotinylation and (2) subcellular fractionation. Both approaches confirmed that the cAMP-PKA pathway was implicated in membrane trafficking regulation. The stimulation of Na+,K+-ATPase activity by db-cAMP was associated with an increase (+40%) in Na+, K+-ATPase units expressed at the cell surface which was assessed by Western blotting after streptavidin precipitation of biotinylated cell surface proteins. Subcellular fractionation confirmed the increased expression in pump units at the cell surface which was accompanied by a decrease (-30%) in pump units located in the subcellular fraction corresponding to early endosomes. 4. In conclusion, PKA stimulates Na+,K+-ATPase activity, at least in part, by increasing the number of Na+-K+ pumps in the plasma membrane in proximal convoluted tubule cells.

Differential expression of dystrophin isoforms and utrophin during dibutyryl-cAMP-induced morphological differentiation of rat brain astrocytes.[Pubmed:9600931]

Proc Natl Acad Sci U S A. 1998 May 26;95(11):6139-44.

We have identified isoforms of dystrophin and utrophin, a dystrophin homologue, expressed in astrocytes and examined their expression patterns during dibutyryl-cAMP (dBcAMP)-induced morphological differentiation of astrocytes. Immunoblot and immunocytochemical analyses showed that full-length-type dystrophin (427 kDa), utrophin (395 kDa), and Dp71 (75 kDa), a small-type dystrophin isoform, were coexpressed in cultured nondifferentiated rat brain astrocytes and were found to be located in the cell membrane. During morphological differentiation of the astrocytes induced by 1 mM dBcAMP, the amount of Dp71 markedly increased, whereas that of dystrophin and utrophin decreased. Northern blot analyses revealed that dBcAMP regulates the mRNA levels of Dp71 and dystrophin but not that of utrophin. dBcAMP slightly increased the amount of the beta-dystroglycan responsible for anchoring dystrophin isoforms and utrophin to the cell membrane. Immunocytochemical analyses showed that most utrophin was observed in the cytoplasmic area during astrocyte differentiation, whereas Dp71 was found along the cell membrane of the differentiated astrocytes. These findings suggest that most of the dystrophin/utrophin-dystroglycan complex on cell membrane in cultured astrocytes was replaced by the Dp71-dystroglycan complex during morphological differentiation. The cell biological roles of Dp71 are discussed.

Lack of correlation between activation of cyclic AMP-dependent protein kinase and inhibition of contraction of rat vas deferens by cyclic AMP analogs.[Pubmed:1847496]

Mol Pharmacol. 1991 Feb;39(2):233-8.

The effects of N6,O2-dibutyrl-adenosine-3',5'-cyclic monophosphate (db-cAMP) and 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP) on tension and cAMP-dependent protein kinase (PKA) activities in rat vas deferens were investigated. A soluble enzyme fraction obtained from the vas deferens was found to contain both type I and type II isozymes of PKA, whereas a particulate fraction contained only the type II isozyme. Exposure of the vas deferens to db-cAMP (1-100 microM) for 30 min caused a concentration-dependent inhibition of phenylephrine-induced contractions, with an EC50 of less than 10 microM. 8-Br-cAMP had no significant effect on contractions over a similar concentration range. Both of the analogs were able to activate PKA significantly at a concentration of 10 microM, and the magnitude of the PKA activation was greater with 8-Br-cAMP than with db-cAMP. Charcoal was added to the homogenization buffer in these experiments to prevent the artifactual activation of PKA by cAMP analogs trapped in the extracellular space. The ability of db-cAMP, but not 8-Br-cAMP, to inhibit the contraction of vas deferens could not be explained on the basis of differential activation of soluble or particulate PKA or of specific isozymes of the enzyme. It is, therefore, concluded that activation of PKA is not responsible for the relaxant effects of cAMP analogs in some smooth muscle.

Bucladesine sodium salt (Dibutyryl-cAMP sodium salt) is a stabilized cyclic AMP (cAMP) analog and a selective PKA activator. Bucladesine sodium salt raises the intracellular levels of cAMP. Bucladesine sodium salt is also a phosphodiesterase (PDE) inhibitor. Bucladesine sodium salt has anti-inflammatory activity and can be used for impaired wound healing.

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