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Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia.

Asano T, Aida S, Suemasu S, Tahara K, Tanaka K, Mizushima T - Sci Rep (2015)

Bottom Line: Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying.Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity.We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT
Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

No MeSH data available.


Related in: MedlinePlus

Involvement of α-2 adrenergic receptor in stimulatory effect of aldioxa on gastric emptying.SH-SY5Y cells were incubated with indicated concentration of aldioxa, yohimbine, allantoin or aluminium hydrate (Al(OH)3) in the presence of 100 μM clonidine, 5 μM forskolin and 1 mM IBMX for 30 min at 37 °C. Control cells were incubated with 5 μM forskolin and 1 mM IBMX in the presence ( + ) or absence (−) of 100 μM clonidine. Intracellular cAMP levels were determined by ELISA and expressed relative to control (a). Membrane fractions prepared from cells expressing human α-2 adrenergic receptor (b) or human muscarinic M3 receptor (c) were incubated with [3H]-clonidine (20 nM) (b) or [3H]-NMS (2 nM) (c), respectively, in the presence of indicated concentrations of aldioxa, allantoin, aluminium hydrate (Al(OH)3), L-(-)-norepinephrine or yohimbine for 2 h and clonidine- (b) or NMS- (c) binding was determined by the filter-binding assay. Effect of indicated dose of yohimbine on restraint stress (RS)- (d) or clonidine- (e) induced delayed gastric emptying was examined using the phenol red method as described in the legends of Figs 1 and 4. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). Experiments were replicated at least two times.
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f6: Involvement of α-2 adrenergic receptor in stimulatory effect of aldioxa on gastric emptying.SH-SY5Y cells were incubated with indicated concentration of aldioxa, yohimbine, allantoin or aluminium hydrate (Al(OH)3) in the presence of 100 μM clonidine, 5 μM forskolin and 1 mM IBMX for 30 min at 37 °C. Control cells were incubated with 5 μM forskolin and 1 mM IBMX in the presence ( + ) or absence (−) of 100 μM clonidine. Intracellular cAMP levels were determined by ELISA and expressed relative to control (a). Membrane fractions prepared from cells expressing human α-2 adrenergic receptor (b) or human muscarinic M3 receptor (c) were incubated with [3H]-clonidine (20 nM) (b) or [3H]-NMS (2 nM) (c), respectively, in the presence of indicated concentrations of aldioxa, allantoin, aluminium hydrate (Al(OH)3), L-(-)-norepinephrine or yohimbine for 2 h and clonidine- (b) or NMS- (c) binding was determined by the filter-binding assay. Effect of indicated dose of yohimbine on restraint stress (RS)- (d) or clonidine- (e) induced delayed gastric emptying was examined using the phenol red method as described in the legends of Figs 1 and 4. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). Experiments were replicated at least two times.

Mentions: Next, we tested involvement of the α-2 adrenergic receptor. Since activation of this receptor is coupled with a decrease in the intracellular level of cAMP31, we examined the effect of aldioxa on this receptor by monitoring intracellular cAMP levels. As shown in Fig. 6a, treatment of human neuroblastoma (SH-SY5Y) cells with clonidine decreased intracellular cAMP levels in a manner that was suppressed by simultaneous treatment with aldioxa or yohimbine hydrochloride (yohimbine, an α-2 adrenergic receptor antagonist). We also found that allantoin but not aluminium hydrate restored intracellular cAMP levels seen in the presence of clonidine, and that the level of restoration was similar to that observed with aldioxa (Fig. 6b). These results suggest that aldioxa has an antagonizing effect on α-2 adrenergic receptor activation via its allantoin moiety.


Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia.

Asano T, Aida S, Suemasu S, Tahara K, Tanaka K, Mizushima T - Sci Rep (2015)

Involvement of α-2 adrenergic receptor in stimulatory effect of aldioxa on gastric emptying.SH-SY5Y cells were incubated with indicated concentration of aldioxa, yohimbine, allantoin or aluminium hydrate (Al(OH)3) in the presence of 100 μM clonidine, 5 μM forskolin and 1 mM IBMX for 30 min at 37 °C. Control cells were incubated with 5 μM forskolin and 1 mM IBMX in the presence ( + ) or absence (−) of 100 μM clonidine. Intracellular cAMP levels were determined by ELISA and expressed relative to control (a). Membrane fractions prepared from cells expressing human α-2 adrenergic receptor (b) or human muscarinic M3 receptor (c) were incubated with [3H]-clonidine (20 nM) (b) or [3H]-NMS (2 nM) (c), respectively, in the presence of indicated concentrations of aldioxa, allantoin, aluminium hydrate (Al(OH)3), L-(-)-norepinephrine or yohimbine for 2 h and clonidine- (b) or NMS- (c) binding was determined by the filter-binding assay. Effect of indicated dose of yohimbine on restraint stress (RS)- (d) or clonidine- (e) induced delayed gastric emptying was examined using the phenol red method as described in the legends of Figs 1 and 4. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). Experiments were replicated at least two times.
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Related In: Results  -  Collection

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f6: Involvement of α-2 adrenergic receptor in stimulatory effect of aldioxa on gastric emptying.SH-SY5Y cells were incubated with indicated concentration of aldioxa, yohimbine, allantoin or aluminium hydrate (Al(OH)3) in the presence of 100 μM clonidine, 5 μM forskolin and 1 mM IBMX for 30 min at 37 °C. Control cells were incubated with 5 μM forskolin and 1 mM IBMX in the presence ( + ) or absence (−) of 100 μM clonidine. Intracellular cAMP levels were determined by ELISA and expressed relative to control (a). Membrane fractions prepared from cells expressing human α-2 adrenergic receptor (b) or human muscarinic M3 receptor (c) were incubated with [3H]-clonidine (20 nM) (b) or [3H]-NMS (2 nM) (c), respectively, in the presence of indicated concentrations of aldioxa, allantoin, aluminium hydrate (Al(OH)3), L-(-)-norepinephrine or yohimbine for 2 h and clonidine- (b) or NMS- (c) binding was determined by the filter-binding assay. Effect of indicated dose of yohimbine on restraint stress (RS)- (d) or clonidine- (e) induced delayed gastric emptying was examined using the phenol red method as described in the legends of Figs 1 and 4. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). Experiments were replicated at least two times.
Mentions: Next, we tested involvement of the α-2 adrenergic receptor. Since activation of this receptor is coupled with a decrease in the intracellular level of cAMP31, we examined the effect of aldioxa on this receptor by monitoring intracellular cAMP levels. As shown in Fig. 6a, treatment of human neuroblastoma (SH-SY5Y) cells with clonidine decreased intracellular cAMP levels in a manner that was suppressed by simultaneous treatment with aldioxa or yohimbine hydrochloride (yohimbine, an α-2 adrenergic receptor antagonist). We also found that allantoin but not aluminium hydrate restored intracellular cAMP levels seen in the presence of clonidine, and that the level of restoration was similar to that observed with aldioxa (Fig. 6b). These results suggest that aldioxa has an antagonizing effect on α-2 adrenergic receptor activation via its allantoin moiety.

Bottom Line: Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying.Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity.We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT
Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

No MeSH data available.


Related in: MedlinePlus