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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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Spontaneous and evoked IPSCs in TMN neurons are inhibited by UDCA.At the left: Examples of averaged (5 min periods) spontaneous and evoked IPSCs recorded from the same neuron in a slice in control (black) and in the presence of UDCA (100 µM: green trace; 300 µM: red trace) and of averaged sIPSCs recorded in an acutely isolated neuron below (each trace represents an average of 24 to 87 events). At the right: Comparison of the relative amplitudes and decay time constants of eIPSCs and sIPSCs from different neuronal preparations. Four to ten neurons were tested with each UDCA concentration. Data obtained from the 4 acutely isolated neurons were pooled with data from 6 cultured neurons. Data points were normalized on the averaged value from control and washout. Significance of difference from control is indicated above the bars (p<0.05; **:p<0.01; ***: p<0.005).
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pone-0042512-g003: Spontaneous and evoked IPSCs in TMN neurons are inhibited by UDCA.At the left: Examples of averaged (5 min periods) spontaneous and evoked IPSCs recorded from the same neuron in a slice in control (black) and in the presence of UDCA (100 µM: green trace; 300 µM: red trace) and of averaged sIPSCs recorded in an acutely isolated neuron below (each trace represents an average of 24 to 87 events). At the right: Comparison of the relative amplitudes and decay time constants of eIPSCs and sIPSCs from different neuronal preparations. Four to ten neurons were tested with each UDCA concentration. Data obtained from the 4 acutely isolated neurons were pooled with data from 6 cultured neurons. Data points were normalized on the averaged value from control and washout. Significance of difference from control is indicated above the bars (p<0.05; **:p<0.01; ***: p<0.005).

Mentions: Amplitude and decay time of spontaneous and evoked inhibitory postsynaptic potentials were reduced in the presence of 100 and 300 µM of UDCA in rat TMN neurons (Fig. 3). Rat brain slices were used in these experiments because neuronal identification and stimulation are much more reliable than in the mouse [22]. Evoked IPSCs (eIPSCs) were obtained by stimulating the dense bundle of GABAergic axons entering TMN from VLPO (as in [22]). Gabazine (10 µM) abolished eIPSCs and sIPSCs recorded in these experiments (n = 5, Figure S1). The comparatively slow onset of the UDCA-effects in brain slices can be explained by the poor diffusion of this compound through the slice. Only at 300 µM UDCA produced significant reductions of amplitude and decay time of eIPSCs and sIPSCs in all investigated neurons (analysed with the Kolmogorov-Smirnov 2 sample test in every cell). At 100 µM UDCA significantly inhibited the amplitude of eIPSCs and sIPSCs in less than half of the neurons, 30 µM UDCA was ineffective. In TMN neurons isolated from the same rat hypothalamic slices UDCA inhibited macroscopic GABA-evoked currents with an IC50 similar to that seen in mice (Table S1). In TMN neurons recorded from adult HDC−/− mice GABA potency (EC50 = 15.6±5 µM, n = 15) and UDCA inhibition (IC50 = 90±5 µM, n = 5) of maximal GABA (0.5 mM) responses were not different from WT mice (Figure S2 and Table S1).


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)

Spontaneous and evoked IPSCs in TMN neurons are inhibited by UDCA.At the left: Examples of averaged (5 min periods) spontaneous and evoked IPSCs recorded from the same neuron in a slice in control (black) and in the presence of UDCA (100 µM: green trace; 300 µM: red trace) and of averaged sIPSCs recorded in an acutely isolated neuron below (each trace represents an average of 24 to 87 events). At the right: Comparison of the relative amplitudes and decay time constants of eIPSCs and sIPSCs from different neuronal preparations. Four to ten neurons were tested with each UDCA concentration. Data obtained from the 4 acutely isolated neurons were pooled with data from 6 cultured neurons. Data points were normalized on the averaged value from control and washout. Significance of difference from control is indicated above the bars (p<0.05; **:p<0.01; ***: p<0.005).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412845&req=5

pone-0042512-g003: Spontaneous and evoked IPSCs in TMN neurons are inhibited by UDCA.At the left: Examples of averaged (5 min periods) spontaneous and evoked IPSCs recorded from the same neuron in a slice in control (black) and in the presence of UDCA (100 µM: green trace; 300 µM: red trace) and of averaged sIPSCs recorded in an acutely isolated neuron below (each trace represents an average of 24 to 87 events). At the right: Comparison of the relative amplitudes and decay time constants of eIPSCs and sIPSCs from different neuronal preparations. Four to ten neurons were tested with each UDCA concentration. Data obtained from the 4 acutely isolated neurons were pooled with data from 6 cultured neurons. Data points were normalized on the averaged value from control and washout. Significance of difference from control is indicated above the bars (p<0.05; **:p<0.01; ***: p<0.005).
Mentions: Amplitude and decay time of spontaneous and evoked inhibitory postsynaptic potentials were reduced in the presence of 100 and 300 µM of UDCA in rat TMN neurons (Fig. 3). Rat brain slices were used in these experiments because neuronal identification and stimulation are much more reliable than in the mouse [22]. Evoked IPSCs (eIPSCs) were obtained by stimulating the dense bundle of GABAergic axons entering TMN from VLPO (as in [22]). Gabazine (10 µM) abolished eIPSCs and sIPSCs recorded in these experiments (n = 5, Figure S1). The comparatively slow onset of the UDCA-effects in brain slices can be explained by the poor diffusion of this compound through the slice. Only at 300 µM UDCA produced significant reductions of amplitude and decay time of eIPSCs and sIPSCs in all investigated neurons (analysed with the Kolmogorov-Smirnov 2 sample test in every cell). At 100 µM UDCA significantly inhibited the amplitude of eIPSCs and sIPSCs in less than half of the neurons, 30 µM UDCA was ineffective. In TMN neurons isolated from the same rat hypothalamic slices UDCA inhibited macroscopic GABA-evoked currents with an IC50 similar to that seen in mice (Table S1). In TMN neurons recorded from adult HDC−/− mice GABA potency (EC50 = 15.6±5 µM, n = 15) and UDCA inhibition (IC50 = 90±5 µM, n = 5) of maximal GABA (0.5 mM) responses were not different from WT mice (Figure S2 and Table S1).

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