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Biochem Pharmacol
2013 Jun 15;8512:1827-36. doi: 10.1016/j.bcp.2013.04.017.
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GABAA receptor modulation by piperine and a non-TRPV1 activating derivative.
Khom S
,
Strommer B
,
Schöffmann A
,
Hintersteiner J
,
Baburin I
,
Erker T
,
Schwarz T
,
Schwarzer C
,
Zaugg J
,
Hamburger M
,
Hering S
.
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The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were investigated. GABA(A) receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (I(GABA)) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behaviour, thermoregulation and seizure threshold were analysed in mice. Piperine acted with similar potency on all GABA(A) receptor subtypes (EC₅₀ range: 42.8±7.6 μM (α₂β₂)-59.6±12.3 μM (α₃β₂). I(GABA) modulation by piperine did not require the presence of a γ(2S)-subunit, suggesting a binding site involving only α and β subunits. I(GABA) activation was slightly more efficacious on receptors formed from β(2/3) subunits (maximal I(GABA) stimulation through α₁β₃ receptors: 332±64% and α₁β₂: 271±36% vs. α₁β₁: 171±22%, p<0.05) and α₃-subunits (α₃β₂: 375±51% vs. α₅β₂:136±22%, p<0.05). Replacing the piperidine ring by a N,N-diisobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABA(A) receptor modulation. SCT-66 displayed greater efficacy on GABA(A) receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABA(A) receptor modulators.
Fig. 1. Comparison of TRPV1 activation by piperine and SCT-66. (A) The concentration–response relationship for piperine (■; 3–300 μM) and SCT-66 (●, 3–300 μM) are shown. These normalized data were generated by measuring the net currents evoked in response to a test concentration of agonist and are expressed as a percentage of a preceding 300 μM piperine control response recorded in the same cell. Data are expressed as the mean ± S.E.M with n = 3–10 individual cells. The EC50 for piperine was 33.3 ± 0.1 μM (Hill coefficient of 4.1 ± 0.1; n = 3–10 per concentration). The EC50 value of piperine agrees with [2]. (B) Typical traces showing activation of TRPV1 channels by piperine and the lack of TRPV1 activation by SCT-66 at the indicated concentrations. (C) Structural formulae of piperine and its derivative SCT-66.
Fig. 2. IGABA modulation by piperine and SCT-66 concentration–response curves for IGABA modulation through GABAA receptors of the indicated subunit combinations by piperine (A and B) and SCT-66 (D and E) at a GABA concentration eliciting 3–7% of the maximal GABA response (EC3–7). The enhancement of IGABA by piperine trough α1β2γ2S receptors (dashed line) receptors is taken from [3]. Each data point represents the mean ± S.E.M. from at least five oocytes and at least two oocyte batches. (C and F) Typical traces illustrating IGABA enhancement by 30 μM compound. Control currents (GABA, single bar) and corresponding currents elicited by co-application of GABA and 30 μM piperine/SCT-66 (double bar) are shown.
Fig. 3. Piperine and SCT-66 shift the GABA concentration–response curve towards higher GABA sensitivity GABA concentration–response curves for α3β2 GABAA receptors in the absence (control, □) and in the presence of 100 μM piperine (■), and 100 μM SCT-66 (●) are compared. The corresponding EC50 values and Hill-coefficients were 5.7 ± 1.9 μM and nH = 1.1 ± 0.1 (control) and 2.7 ± 0.8 μM and nH = 1.1 ± 0.2 (piperine), and 1.9 ± 0.4 μM and nH = 1.1 ± 0.1 (SCT-66), respectively. Each data point represents the mean ± S.E.M. from at least four oocytes and at least two oocyte batches.
Fig. 4. SCT-66 does not reduce body temperature in mice Effects of piperine and SCT-66 on body temperature 3 h after injection of (■) piperine or (●) SCT-66 at the indicated doses (mg/kg bodyweight) are illustrated. Each data point represents the mean ± S.E.M. of at least 9 mice. (**) indicates statistically significant (p < 0.01) differences to control (ANOVA with Bonferroni).
Fig. 5. Piperine and SCT-66 dose-dependently reduce locomotor activity in the OF test. Bars indicate in (A) the total distance travelled, in (B) the time spent in the centre, in (C) the number of entries to the centre and in (D) the distance travelled in the centre as % of the total distance after application of the indicated dose (mg/kg bodyweight) of piperine (black bars), SCT-66 (shaded bars) or control (white bars). Bars always represent means ± S.E.M. from at least 8 different mice. (*) indicates statistically significant differences with p < 0.05, (**) p < 0.01 to control (ANOVA with Bonferroni).
Fig. 6. Piperine and SCT-66 display anxiolytic-like effects in the EPM test. Bars indicate in (A) the time spent in the open arms (OA) in % of the total time, in (B) the number of OA entries, in (C) the number of closed arm (CA) entries and in (D) the total distance after application of the indicated dose in mg/kg bodyweight of either piperine (black bars) or SCT-66 (shaded bars), respectively. White bars illustrate the behaviour of control mice. Bars represent means ± S.E.M. from at least 9 different mice. (*) indicates statistically significant differences with p < 0.05, (**) p < 0.01 to control (ANOVA with Bonferroni).
Fig. 7. Piperine and SCT-66 affect seizure threshold differently. Changes in seizure threshold upon PTZ-infusion of the indicated dose (mg/kg bodyweight) of piperine (A) and SCT-66 (B) are depicted. Each data point represents the mean ± S.E.M. of a least 3 mice. (*) indicates statistically significant differences with p < 0.05, (**) p < 0.01 to control (ANOVA with Bonferroni).
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