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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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Time courses of GABA-response-block by UDCA and picrotoxin.Picrotoxin (PTX) continuously present in the recording solution shows use-dependent block of GABA (10 µM, 1 s) - currents: block is not fully reversible after PTX withdrawal. In contrast, the UDCA-block is fully reversible and achieves maximum with the first GABA/UDCA co-application.
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pone-0042512-g005: Time courses of GABA-response-block by UDCA and picrotoxin.Picrotoxin (PTX) continuously present in the recording solution shows use-dependent block of GABA (10 µM, 1 s) - currents: block is not fully reversible after PTX withdrawal. In contrast, the UDCA-block is fully reversible and achieves maximum with the first GABA/UDCA co-application.

Mentions: Similar to chenodeoxycholate [12], UDCA concentration-dependently enhanced macroscopic apparent desensitization of current responses to saturating GABA concentration by decreasing the fast exponential decay time constant and the ratio of steady-state current to peak current. The deactivation time constant (τoff) was prolonged by UDCA (Fig. 4). In contrast to the block by picrotoxin, the UDCA-mediated inhibition of GABA currents (taken near EC50) was not use dependent (Fig. 5). To determine the voltage dependence of BS antagonism, we investigated the block of the response to GABA at different membrane potentials (Figure S3). The GABA current-voltage relationship was roughly linear from −70 to +30 mV (reversal potential 0.7±2 mV, n = 5, close to the predicted reversal potential for chloride ions: −2.9 mV), but exhibited an outward rectification at more positive potentials (at +50 mV 153±20% of control (−50 mV)). In the presence of UDCA the current-voltage relationship was nearly linear with a slight inward rectification. At +50 mV the current amplitude was 69±5% of control (−50 mV) without a significant change in the reversal potential (3.1±2.2 mV, p = 0.14). Thus, the inhibition of GABA-induced currents was greatest at the most positive holding potentials. In the presence of UDCA, stationary GABA current represented 59±2% and 28±2% of corresponding unblocked currents at −50 and at +50 mV, respectively (the difference in the amount of block at these two membrane potentials was significant, p = 0.012). At positive holding potentials co-application of GABA and UDCA was associated with the appearance of a tail current following cessation of the application. According to the Woodhull model, two sets of GABA currents (steady-state currents in the absence and presence of UDCA) measured at different membrane potentials were organized in a (Iblocked/Icontrol)/Voltage plot and fitted with the equation (3). The results of fitting and experimental data are shown in Figure S3. The best fitted values for the fraction of the transmembrane field sensed at the acceptor site (f) was 0.29±0.03 (n = 5), which did not differ significantly from cholate, chenodeoxycholate and dehydrocholate, indicating the same mechanism of their interaction with the GABAA receptor.


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)

Time courses of GABA-response-block by UDCA and picrotoxin.Picrotoxin (PTX) continuously present in the recording solution shows use-dependent block of GABA (10 µM, 1 s) - currents: block is not fully reversible after PTX withdrawal. In contrast, the UDCA-block is fully reversible and achieves maximum with the first GABA/UDCA co-application.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042512-g005: Time courses of GABA-response-block by UDCA and picrotoxin.Picrotoxin (PTX) continuously present in the recording solution shows use-dependent block of GABA (10 µM, 1 s) - currents: block is not fully reversible after PTX withdrawal. In contrast, the UDCA-block is fully reversible and achieves maximum with the first GABA/UDCA co-application.
Mentions: Similar to chenodeoxycholate [12], UDCA concentration-dependently enhanced macroscopic apparent desensitization of current responses to saturating GABA concentration by decreasing the fast exponential decay time constant and the ratio of steady-state current to peak current. The deactivation time constant (τoff) was prolonged by UDCA (Fig. 4). In contrast to the block by picrotoxin, the UDCA-mediated inhibition of GABA currents (taken near EC50) was not use dependent (Fig. 5). To determine the voltage dependence of BS antagonism, we investigated the block of the response to GABA at different membrane potentials (Figure S3). The GABA current-voltage relationship was roughly linear from −70 to +30 mV (reversal potential 0.7±2 mV, n = 5, close to the predicted reversal potential for chloride ions: −2.9 mV), but exhibited an outward rectification at more positive potentials (at +50 mV 153±20% of control (−50 mV)). In the presence of UDCA the current-voltage relationship was nearly linear with a slight inward rectification. At +50 mV the current amplitude was 69±5% of control (−50 mV) without a significant change in the reversal potential (3.1±2.2 mV, p = 0.14). Thus, the inhibition of GABA-induced currents was greatest at the most positive holding potentials. In the presence of UDCA, stationary GABA current represented 59±2% and 28±2% of corresponding unblocked currents at −50 and at +50 mV, respectively (the difference in the amount of block at these two membrane potentials was significant, p = 0.012). At positive holding potentials co-application of GABA and UDCA was associated with the appearance of a tail current following cessation of the application. According to the Woodhull model, two sets of GABA currents (steady-state currents in the absence and presence of UDCA) measured at different membrane potentials were organized in a (Iblocked/Icontrol)/Voltage plot and fitted with the equation (3). The results of fitting and experimental data are shown in Figure S3. The best fitted values for the fraction of the transmembrane field sensed at the acceptor site (f) was 0.29±0.03 (n = 5), which did not differ significantly from cholate, chenodeoxycholate and dehydrocholate, indicating the same mechanism of their interaction with the GABAA receptor.

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