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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 given orally increases wakefulness.A. Polygraphic recording (EEG and EMG) and corresponding hypnograms showing the effect of UDCA given at 7 p.m. B. Changes in sleep-wake duration after UDCA application relative to control (vehicle application) in wild type (HDC +/+) and histidine decarboxylase deficient (HDC−/−) mice. In both mouse genotypes UDCA given during the sleepy period of the day (10 a.m.) does not affect sleep-wake states, but does so during the active period of the day. Given at 7 p.m. UDCA increases waking (W) and decreases slow wave sleep (SWS) and paradoxical sleep (PS) in the HDC+/+ mice. In HDC−/− mice UDCA decreases waking. The significant difference between time spent in a given vigilance state in control and under UDCA is indicated with stars near the corresponding bars. Significant difference between genotypes is indicated with stars on top of brackets. * p<0.05; ** p<0.01; *** p<0.005.
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pone-0042512-g001: UDCA given orally increases wakefulness.A. Polygraphic recording (EEG and EMG) and corresponding hypnograms showing the effect of UDCA given at 7 p.m. B. Changes in sleep-wake duration after UDCA application relative to control (vehicle application) in wild type (HDC +/+) and histidine decarboxylase deficient (HDC−/−) mice. In both mouse genotypes UDCA given during the sleepy period of the day (10 a.m.) does not affect sleep-wake states, but does so during the active period of the day. Given at 7 p.m. UDCA increases waking (W) and decreases slow wave sleep (SWS) and paradoxical sleep (PS) in the HDC+/+ mice. In HDC−/− mice UDCA decreases waking. The significant difference between time spent in a given vigilance state in control and under UDCA is indicated with stars near the corresponding bars. Significant difference between genotypes is indicated with stars on top of brackets. * p<0.05; ** p<0.01; *** p<0.005.

Mentions: Given during the active period of the day (7 p.m.) in HDC+/+ mice (n = 11) UDCA significantly increased waking (starting from the third hour after application, p<0.05) and decreased the amount of slow wave sleep (SWS, p<0.05) and paradoxical sleep (PS, p<0.01). In contrast, in histamine-deficient mice waking was significantly decreased by UDCA (p<0.01), whereas total sleep was increased (p<0.01). Slow wave sleep (SWS) and paradoxical sleep (PS) tended to be increased by UDCA in HDC−/− mice in comparison with vehicle control. The change in SWS under UDCA differed significantly between HDC−/− and HDC+/+ mice (Fig. 1B, p<0.01). At 32 mg/kg (maximal clinical dose) UDCA did not affect sleep wake states when given orally during the “quiet period” of the day (10 a.m.) either in wild type (HDC+/+, n = 11)) or histamine-deficient mice (HDC−/−, n = 7) (Fig. 1).


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 given orally increases wakefulness.A. Polygraphic recording (EEG and EMG) and corresponding hypnograms showing the effect of UDCA given at 7 p.m. B. Changes in sleep-wake duration after UDCA application relative to control (vehicle application) in wild type (HDC +/+) and histidine decarboxylase deficient (HDC−/−) mice. In both mouse genotypes UDCA given during the sleepy period of the day (10 a.m.) does not affect sleep-wake states, but does so during the active period of the day. Given at 7 p.m. UDCA increases waking (W) and decreases slow wave sleep (SWS) and paradoxical sleep (PS) in the HDC+/+ mice. In HDC−/− mice UDCA decreases waking. The significant difference between time spent in a given vigilance state in control and under UDCA is indicated with stars near the corresponding bars. Significant difference between genotypes is indicated with stars on top of brackets. * p<0.05; ** p<0.01; *** p<0.005.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042512-g001: UDCA given orally increases wakefulness.A. Polygraphic recording (EEG and EMG) and corresponding hypnograms showing the effect of UDCA given at 7 p.m. B. Changes in sleep-wake duration after UDCA application relative to control (vehicle application) in wild type (HDC +/+) and histidine decarboxylase deficient (HDC−/−) mice. In both mouse genotypes UDCA given during the sleepy period of the day (10 a.m.) does not affect sleep-wake states, but does so during the active period of the day. Given at 7 p.m. UDCA increases waking (W) and decreases slow wave sleep (SWS) and paradoxical sleep (PS) in the HDC+/+ mice. In HDC−/− mice UDCA decreases waking. The significant difference between time spent in a given vigilance state in control and under UDCA is indicated with stars near the corresponding bars. Significant difference between genotypes is indicated with stars on top of brackets. * p<0.05; ** p<0.01; *** p<0.005.
Mentions: Given during the active period of the day (7 p.m.) in HDC+/+ mice (n = 11) UDCA significantly increased waking (starting from the third hour after application, p<0.05) and decreased the amount of slow wave sleep (SWS, p<0.05) and paradoxical sleep (PS, p<0.01). In contrast, in histamine-deficient mice waking was significantly decreased by UDCA (p<0.01), whereas total sleep was increased (p<0.01). Slow wave sleep (SWS) and paradoxical sleep (PS) tended to be increased by UDCA in HDC−/− mice in comparison with vehicle control. The change in SWS under UDCA differed significantly between HDC−/− and HDC+/+ mice (Fig. 1B, p<0.01). At 32 mg/kg (maximal clinical dose) UDCA did not affect sleep wake states when given orally during the “quiet period” of the day (10 a.m.) either in wild type (HDC+/+, n = 11)) or histamine-deficient mice (HDC−/−, n = 7) (Fig. 1).

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