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Hintersteiner J
,
Haider M
,
Luger D
,
Schwarzer C
,
Reznicek G
,
Jäger W
,
Khom S
,
Mihovilovic MD
,
Hering S
.
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Valerenic acid (VA) is a β2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2-microelectrode-voltage-clamp. Anxiolytic effects of the VA-esters were studied on male C57BL/6N mice by means of the elevated plus maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1β3γ2S) receptors in vitro. in vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.
Fig. 1. Structural formulae of VA and synthesized ester derivatives.
Fig. 2. IGABA modulation by VA-ester derivatives (A) Enhancement of IGABA through GABAA receptors composed of α1β3γ2S subunits by 1 µM (white bars), 10 µM (light grey bars), 30 μM (dark grey bars) and 100 μM (black bars) of the indicated compounds. Each value represents the mean±S.E.M from at least 5 oocytes and â¥2 oocyte batches. (*) indicates significantly different from IGABA enhancement by VA at the same concentration (P<0.05, Student׳s t-test) (B) Typical traces for the potentiation of chloride currents through α1β3γ2S channels by VA-derivatives at a GABA EC3â7. Control currents (GABA, single bar) and corresponding currents elicited by co-application of GABA and the indicated compound (double bar) are shown.
Fig. 3. Effects on explorative behavior of VA-esters in the elevated plus maze test are compared to saline-treated control (white bars) mice at a dose of 3 mg/kg bodyweight. Bars display the time spent (in % of the total time) on the open arms ((A)â(C)) and the open arm distance ((D)â(F)) 15 (left column), 30 (mid column) and 60 (right column) min after i.p. application of the indicated compounds. Each bar represents a mean±S.E.M from at least 8 different mice. (â) indicates statistically significant differences with P<0.05, (ââ) with P<0.01 to control.
Fig. 4. Number of entries to the open (OA; (A)â(C)) and closed arms (CA; (D)â(F)) of the elevated plus maze 15 (left column), 30 (mid column) and 60 (right column) min after i.p. application of the indicated compound are compared to control (white bars) at a dose of 3 mg/kg bodyweight. Each bar represents a mean±S.E.M from at least 8 different mice. (â) indicates statistically significant differences with P<0.05, (ââ) with P<0.01 to control.
Fig. 5. Changes in seizure threshold upon PTZ-infusion are compared at a dose of 3 mg/kg bodyweight of VA (dotted line) and (A) VA-ME, (B) VA-EE, (C) VA-PE and (D) VA-POM. Each data point represents the mean±S.E.M from at least 3 mice; (âŽ) indicates statistically significant differences with P<0.05; (âŽâŽ) indicates statistically significant differences with P<0.01 to VA.
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