Waking Action of Ursodeoxycholic Acid (UDCA) Involves Histamine and GABAA Receptor Block

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.

Bile in the Brain? A Role for Bile Acids in the Central Nervous System

“…This raises the possibility of cross talk between neurosteroids and bile acids, possibly to alter neurotransmission. Neurosteroids classically act to modulate GABAergic tone [16], and in fact, the bile acids ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) has been shown recently to antagonize GABA A receptors [17,18] and CDCA was shown to antagonize NMDA receptors [18]. This is further evidence supporting the idea that bile acids could be playing an endogenous role in the CNS.…”

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

“…This versatility is attributed to its multiple mechanisms of action [13]. Besides, clinical [14] and experimental [15] studies verified that the drug crosses the blood-brain barrier. It is now well established that inhibition of hepatocellular apoptosis is one of the main routes for the protective effect of UDCA [16,17].…”

Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy

“…Ursodeoxycholic acid (UDCA) inhibits, through a mechanism similar to that of pregnenolone sulfate, GABAA receptors in histaminergic neurons in slices from hypothalamus as well as recombinant GABAA receptors expressed in HEK 293 cells (Yanovsky et al, 2012). UDCA promotes waking in vivo and enhances alertness through disinhibition, at least partially of the histaminergic system via GABAA receptors and could be useful in the treatment of hepatic encephalopathy (Yanovsky et al, 2012;Sergeeva, 2013).…”

“…UDCA promotes waking in vivo and enhances alertness through disinhibition, at least partially of the histaminergic system via GABAA receptors and could be useful in the treatment of hepatic encephalopathy (Yanovsky et al, 2012;Sergeeva, 2013).…”