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Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block.

Yanovsky Y, Schubring SR, Yao Q, Zhao Y, Li S, May A, Haas HL, Lin JS, Sergeeva OA - PLoS ONE (2012)

Bottom Line: In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine.The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA.In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany.

ABSTRACT
Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50) = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A) receptors composed of α1, β1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

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UDCA synchronizes network activity like a GABAA receptor antagonist.A. Firing rate of TMN neurons (n = 10) recorded in mouse hypothalamic slices is not significantly affected by UDCA during the first 5 min of UDCA perfusion. Each filled circle represents the average firing during 5 min. Significant difference from baseline is indicated with stars (* p<0.05, Wilcoxon test). B. Summary of MEA experiments illustrates the change in spikes/min (all spikes over all active electrodes) and Cohen's kappa (synchronization index). Note that gabazine blanks the effect of UDCA and tauroursodeoxycholate (TUDC) on synchronization. Mineralocorticoid- and glucocorticoid- receptor- antagonists (mifepristone and spironolactone, respectively) did not significantly change effects of UDCA (significance of modulation compared to the control indicated with stars within bars (*: p<0.05). C. Examples of neuronal firing patterns recorded from 2 electrodes in one hypothalamic culture (one electrode in black, another in grey color) during 1 second. Note more synchronous discharge of hypothalamic neurons in the presence of UDCA.
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pone-0042512-g002: UDCA synchronizes network activity like a GABAA receptor antagonist.A. Firing rate of TMN neurons (n = 10) recorded in mouse hypothalamic slices is not significantly affected by UDCA during the first 5 min of UDCA perfusion. Each filled circle represents the average firing during 5 min. Significant difference from baseline is indicated with stars (* p<0.05, Wilcoxon test). B. Summary of MEA experiments illustrates the change in spikes/min (all spikes over all active electrodes) and Cohen's kappa (synchronization index). Note that gabazine blanks the effect of UDCA and tauroursodeoxycholate (TUDC) on synchronization. Mineralocorticoid- and glucocorticoid- receptor- antagonists (mifepristone and spironolactone, respectively) did not significantly change effects of UDCA (significance of modulation compared to the control indicated with stars within bars (*: p<0.05). C. Examples of neuronal firing patterns recorded from 2 electrodes in one hypothalamic culture (one electrode in black, another in grey color) during 1 second. Note more synchronous discharge of hypothalamic neurons in the presence of UDCA.

Mentions: Mouse TMN neurons recorded in slices either did not change their activity in response to UDCA 100 µM (n = 5), or significantly reduced their firing compared to the baseline (n = 5, paired t-test, p<0.05). Inhibition of firing showed a delayed onset and represented 86±5% of control at the end of UDCA application (n = 10, Fig. 2A). The firing frequency of cultured mouse hypothalamic neurons on microelectrode arrays (MEA) was not affected by UDCA 10, 30 or 100 µM (Fig. 2B) but UDCA increased the synchronicity of firing within the hypothalamic network (Fig. 2B,C). This effect was abolished in the presence of GABAA receptor antagonist gabazine (Fig. 2B). As conjugated or unconjugated UDCA can interact with the mineralocorticoid- and glucocorticoid- nuclear receptors preventing apoptosis [5], [20] we applied UDCA together with the mifepristone (10 µM, glucocorticoid receptor antagonist) and spironolactone (10 µM, mineralocorticoid receptor antagonist [21]): the UDCA-induced synchronization of firing was not affected (Fig. 2B).


Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block.

Yanovsky Y, Schubring SR, Yao Q, Zhao Y, Li S, May A, Haas HL, Lin JS, Sergeeva OA - PLoS ONE (2012)

UDCA synchronizes network activity like a GABAA receptor antagonist.A. Firing rate of TMN neurons (n = 10) recorded in mouse hypothalamic slices is not significantly affected by UDCA during the first 5 min of UDCA perfusion. Each filled circle represents the average firing during 5 min. Significant difference from baseline is indicated with stars (* p<0.05, Wilcoxon test). B. Summary of MEA experiments illustrates the change in spikes/min (all spikes over all active electrodes) and Cohen's kappa (synchronization index). Note that gabazine blanks the effect of UDCA and tauroursodeoxycholate (TUDC) on synchronization. Mineralocorticoid- and glucocorticoid- receptor- antagonists (mifepristone and spironolactone, respectively) did not significantly change effects of UDCA (significance of modulation compared to the control indicated with stars within bars (*: p<0.05). C. Examples of neuronal firing patterns recorded from 2 electrodes in one hypothalamic culture (one electrode in black, another in grey color) during 1 second. Note more synchronous discharge of hypothalamic neurons in the presence of UDCA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412845&req=5

pone-0042512-g002: UDCA synchronizes network activity like a GABAA receptor antagonist.A. Firing rate of TMN neurons (n = 10) recorded in mouse hypothalamic slices is not significantly affected by UDCA during the first 5 min of UDCA perfusion. Each filled circle represents the average firing during 5 min. Significant difference from baseline is indicated with stars (* p<0.05, Wilcoxon test). B. Summary of MEA experiments illustrates the change in spikes/min (all spikes over all active electrodes) and Cohen's kappa (synchronization index). Note that gabazine blanks the effect of UDCA and tauroursodeoxycholate (TUDC) on synchronization. Mineralocorticoid- and glucocorticoid- receptor- antagonists (mifepristone and spironolactone, respectively) did not significantly change effects of UDCA (significance of modulation compared to the control indicated with stars within bars (*: p<0.05). C. Examples of neuronal firing patterns recorded from 2 electrodes in one hypothalamic culture (one electrode in black, another in grey color) during 1 second. Note more synchronous discharge of hypothalamic neurons in the presence of UDCA.
Mentions: Mouse TMN neurons recorded in slices either did not change their activity in response to UDCA 100 µM (n = 5), or significantly reduced their firing compared to the baseline (n = 5, paired t-test, p<0.05). Inhibition of firing showed a delayed onset and represented 86±5% of control at the end of UDCA application (n = 10, Fig. 2A). The firing frequency of cultured mouse hypothalamic neurons on microelectrode arrays (MEA) was not affected by UDCA 10, 30 or 100 µM (Fig. 2B) but UDCA increased the synchronicity of firing within the hypothalamic network (Fig. 2B,C). This effect was abolished in the presence of GABAA receptor antagonist gabazine (Fig. 2B). As conjugated or unconjugated UDCA can interact with the mineralocorticoid- and glucocorticoid- nuclear receptors preventing apoptosis [5], [20] we applied UDCA together with the mifepristone (10 µM, glucocorticoid receptor antagonist) and spironolactone (10 µM, mineralocorticoid receptor antagonist [21]): the UDCA-induced synchronization of firing was not affected (Fig. 2B).

Bottom Line: In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine.The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA.In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany.

ABSTRACT
Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50) = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A) receptors composed of α1, β1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

Show MeSH
Related in: MedlinePlus