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Evid Based Complement Alternat Med
2016 Jan 01;2016:1215393. doi: 10.1155/2016/1215393.
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GABA-A Receptor Modulation and Anticonvulsant, Anxiolytic, and Antidepressant Activities of Constituents from Artemisia indica Linn.
Khan I
,
Karim N
,
Ahmad W
,
Abdelhalim A
,
Chebib M
.
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Artemisia indica, also known as "Mugwort," has been widely used in traditional medicines. However, few studies have investigated the effects of nonvolatile components of Artemisia indica on central nervous system's function. Fractionation of Artemisia indica led to the isolation of carnosol, ursolic acid, and oleanolic acid which were evaluated for their effects on GABA-A receptors in electrophysiological studies in Xenopus oocytes and were subsequently investigated in mouse models of acute toxicity, convulsions (pentylenetetrazole induced seizures), depression (tail suspension and forced swim tests), and anxiety (elevated plus maze and light/dark box paradigms). Carnosol, ursolic acid, and oleanolic acid were found to be positive modulators of α1β2γ2L GABA-A receptors and the modulation was antagonized by flumazenil. Carnosol, ursolic acid, and oleanolic acid were found to be devoid of any signs of acute toxicity (50-200 mg/kg) but elicited anticonvulsant, antidepressant, and anxiolytic activities. Thus carnosol, ursolic acid, and oleanolic acid demonstrated CNS activity in mouse models of anticonvulsant, antidepressant, and anxiolysis. The anxiolytic activity of all three compounds was ameliorated by flumazenil suggesting a mode of action via the benzodiazepine binding site of GABA-A receptors.
Figure 1. Chemical structure of the compounds isolated from Artemisia indica Linn.
Figure 2. Carnosol, ursolic acid, and oleanolic acid are positive modulators of α1-containing GABA-A receptors expressed in Xenopus oocytes. Representative current trace showing the potentiation of GABA-EC5 by various concentrations of carnosol, ursolic acid, and oleanolic acid (1, 10, 30, 100, and 300 μM) at human recombinant α1β2γ2L GABA-A receptors ((a)–(c)). The potentiating effect of carnosol, ursolic acid, and oleanolic acid was attenuated by flumazenil (10 μM) similar to that of diazepam (d). Horizontal bars show the duration of drug application.
Figure 3. Effect of carnosol, oleanolic acid, ursolic acid, and diazepam on the behavior of mice in the elevated plus maze. (a) % of open-arm entries (left panel) and % of time spent in open arms (right panel) registered over a session of 5 min after 20 min of an i.p. injection of carnosol (1, 10, 30, and 100 mg/kg). (b) % of open-arm entries (left panel) and % of time spent in open arms (right panel) registered over a session of 5 min after 20 min of an i.p. injection of oleanolic acid (1, 10, 30, and 100 mg/kg), diazepam (1 mg/kg), or vehicle. (c) % of open-arm entries (left panel) and % of time spent in open arms (right panel) registered over a session of 5 min after 20 min of an i.p. injection of ursolic acid (1, 10, 30, and 100 mg/kg). Columns represent mean ± SEM (n = 6/group). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 compared with vehicle group using one-way ANOVA followed by Dunnett's test.
Figure 4. Effect of flumazenil on the anxiolytic activity of carnosol, oleanolic acid, and ursolic acid in the elevated plus maze. (a) % of open-arm entries and (b) % of time spent in open arms registered over a session of 5 min after 20 min of an i.p. injection of vehicle, diazepam (1 mg/kg), carnosol, oleanolic acid, and ursolic acid (10 mg/kg) in the presence of flumazenil (2.5 mg/kg). Columns express mean ± SEM (n = 6/group). ∗∗P < 0.01 and ∗∗∗P < 0.001 compared with vehicle control group using one-way ANOVA followed by Dunnett's test.
Figure 5. Effect of carnosol, oleanolic acid, ursolic acid, and diazepam on the behavior of mice in the light dark box test. (a) Time spent in lit area (left panel) and number of transitions (right panel), recorded over a session of 5 min, after 20 min of an i.p. injection of carnosol (1, 10, 30, and 100 mg/kg), diazepam (0.5, 1, and 3 mg/kg), or vehicle. (b) Time spent in lit area (left panel) and number of transitions (right panel), recorded over a session of 5 min, after 20 min of an i.p. injection of oleanolic acid (1, 10, 30, and 100 mg/kg), diazepam (0.5, 1, and 3 mg/kg), or vehicle. (c) Time spent in lit area (left panel) and number of transitions (right panel), recorded over a session of 5 min, after 20 min of an i.p. injection of ursolic acid (1, 10, 30, and 100 mg/kg), diazepam (0.5, 1, and 3 mg/kg), or vehicle. Values are expressed as mean ± SEM (n = 6/group). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 compared with vehicle group using one-way ANOVA followed by Dunnett's test.
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