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 GABAAR 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 (IC50 = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABAA receptors composed of α1, β1–3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABAA receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABAAR potentiation by several neurosteroids, had no effect on GABAAR inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABAA receptors.
Highlights
Ursodeoxycholic acid (UDCA) and its taurine conjugate tauroursodeoxycholate (TUDC), major constituents of black bear bile, are used for over 3000 years to treat liver disorders [1] and visual system disorders [2,3]
We discovered a wake-promoting action of UDCA in mice at a dose used for the standard treatment of primary biliary cirrhosis
Cortical EEG and sleep-wake monitoring showed a difference between wild type and histamine-deficient mice in response to UDCA, indicating that recruitment of histamine is necessary in the wake-promoting effect
Summary
Ursodeoxycholic acid (UDCA) and its taurine conjugate tauroursodeoxycholate (TUDC), major constituents of black bear bile, are used for over 3000 years to treat liver disorders (such as cholesterol gallstones, cholestasis, sclerotic cholangitis, primary biliary cirrhosis) [1] and visual system disorders [2,3]. UDCA represents a minor fraction of the human bile acid pool (2–5%), but after several month of UDCA therapy (up to 35 mg/kg) it substitutes for the so called ‘‘bad’’ pro-apoptotic bile acids, such as chenodeoxycholate and deoxycholate and comprises 58–69% of the total bile acid pool exerting a choleretic action and improving liver function [7,8]. We have recently shown that common BS which are synthesized in the brain, such as cholate and chenodeoxycholate, antagonize GABAA and NMDA receptors [12] and can by this way influence hypothalamic control of energy homeostasis
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