Dinesh Dhingra

Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests

The present study was undertaken to investigate the effects of aqueous extract of Glycyrrhiza glabra L. (Family: Fabaceae), popularly known as liquorice, on depression in mice using forced swim test (FST) and tail suspension test (TST). The extract of G. glabra (75, 150, and 300 mg/kg) was administered orally for 7 successive days in separate groups of Swiss young male albino mice. The dose of 150 mg/kg of the extract significantly reduced the immobility times of mice in both FST and TST, without any significant effect on locomotor activity of mice. The efficacy of extract was found to be comparable to that of imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.). Liquorice extract reversed reserpine-induced extension of immobility period of mice in FST and TST. Sulpiride (50 mg/kg i.p.; a selective D2 receptor antagonist) and prazosin (62.5 microg/kg i.p.; an alpha1-adrenoceptor antagonist) significantly attenuated the extract-induced antidepressant-like effect in TST. On the other hand, p-chlorophenylalanine (100 mg/kg i.p.; an inhibitor of serotonin synthesis) did not reverse antidepressant-like effect of liquorice extract. This suggests that antidepressant-like effect of liquorice extract seems to be mediated by increase of brain norepinephrine and dopamine, but not by increase of serotonin. Monoamine oxidase inhibiting effect of liquorice may be contributing favorably to the antidepressant-like activity. Thus, it is concluded that liquorice extract may possess an antidepressant-like effect.

Improvement of mouse memory by Myristica fragrans seeds.

Memory is one of the most complex functions of the brain and involves multiple neural pathways and neurotransmitter systems. The present study was undertaken to investigate the effect of Myristica fragrans (MF) seeds on learning and memory in mice. The n-hexane extract of MF was administered orally in three doses (5, 10, and 20 mg/kg p.o.) for 3 successive days to different groups of young and aged mice. The learning and memory parameters were assessed using elevated plus-maze and passive-avoidance apparatus. The effect of MF extract on scopolamine (0.4 mg/kg i.p.)- and diazepam (1 mg/kg i.p.)-induced impairment in learning and memory was also studied. MF extract at the lowest dose of 5 mg/kg p.o. administered for 3 successive days significantly improved learning and memory of young and aged mice. This extract also reversed scopolamine- and diazepam-induced impairment in learning and memory of young mice. MF extract enhanced learning and retention capacities of both young and aged mice. The exact mechanism of the memory-improving effect of MF extract was not explored in the present study. But, the observed memory-enhancing effect may be attributed to a variety of properties (individually or in combination) the plant is reported to possess, such as antioxidant, anti-inflammatory, or perhaps procholinergic activity.

Thymoquinone produced antianxiety-like effects in mice through modulation of GABA and NO levels

The aim of the present study was to investigate the role of GABAergic and nitriergic modulation in the antianxiety effect of thymoquinone, a major constituent of Nigella sativa, in mice under unstressed and stressed conditions. Thymoquinone (10 and 20 mg/kg), methylene blue (1 mg/kg) and diazepam (2 mg/kg) were administered followed by behavioral testing using an elevated plus maze, the light/dark test and the social interaction test in both unstressed and stressed mice (mice subjected to 6 h immobilization). The effects of the above-mentioned drugs on plasma nitrite, a stable metabolite of nitric oxide (NO) and brain GABA content were also studied. Diazepam (2 mg/kg) produced significant anxiolytic-like effects only in unstressed mice. However, diazepam significantly increased the GABA content in both unstressed and stressed mice as compared with their respective control groups. Thymoquinone (10 and 20 mg/kg) produced significant antianxiety effects in unstressed mice without altering nitrite levels, but only the higher dose (20 mg/kg) of thymoquinone increased the GABA content in unstressed mice. In stressed mice, thymoquinone (20 mg/kg) showed anxiolytic effects, with a significant decrease in plasma nitrite and reversal of the decreased brain GABA content. Pre-treatment with methylene blue enhanced the antianxiety effect of thymoquinone in both unstressed and stressed mice. Therefore, the present study suggests an involvement of NO-cGMP and GABAergic pathways in the anxiolytic-like activity of thymoquinone.

GABAergic and nitriergic modulation by curcumin for its antianxiety-like activity in mice.

In the present study, effect of curcumin (10 and 20mg/kg), an active constituent of Curcuma longa was evaluated for its antianxiety-like activity in mice subjected to immobilization-induced restraint stress for 6h. The effect on anxiety was assessed by employing elevated plus maze, open field test, light/dark test and social interaction test. Only the higher dose (20mg/kg, i.p.) of curcumin produced significant antianxiety-like effect in stressed mice. Pre-treatment with aminoguanidine (50mg/kg; i.p.), an inducible nitric oxide synthase inhibitor significantly enhanced the anxiolytic-like effect of curcumin in stressed mice as compared to curcumin and aminoguanidine per se in stressed mice. Pretreatment with 7-nitroindazole (20mg/kg), a neuronal nitric oxide synthase inhibitor did not significantly affect the antianxiety-like response of curcumin in stressed mice as compared to curcumin per se. Restraint stress significantly increased plasma nitrite levels in mice. Curcumin (20mg/kg, i.p.) and aminoguanidine significantly decreased plasma nitrite levels in stressed mice. The combination of aminoguanidine and curcumin significantly decreased the plasma nitrite levels as compared to curcumin and aminoguanidine per se in stressed mice. Curcumin and aminoguanidine did not produce any significant change in brain GABA contents of the animals. Diazepam (2mg/kg) produced significant anxiolytic-like effect only in unstressed mice, but could not exert significant anxiolysis in stressed mice. However, diazepam significantly increased GABA contents in both unstressed and stressed mice as compared to respective control groups. These findings suggest the possible involvement of only inducible NOS and not neuronal NOS in antianxiety-like effect of curcumin.

Involvement of NO-cGMP pathway in anti-anxiety effect of aminoguanidine in stressed mice.

In the present study, effect of aminoguanidine (12.5, 25 and 50mg/kg, i.p.), a selective inhibitor of inducible nitric oxide synthase, was evaluated for its anti-anxiety activity in stressed mice employing elevated plus maze, open field test, light/dark test and social interaction test. Restraint stress induced by immobilizing for 6h enhanced an anxiety-like behavior and increased plasma nitrite levels in mice. Only the highest dose (50mg/kg) employed of aminoguanidine attenuated the stress-induced anxiety-like behavior and decreased plasma nitrite levels. There was no significant anxiolytic effect of aminoguanidine in unstressed mice. Sildenafil (1mg/kg i.p.), was used to explore the probable mechanism of anti-anxiety activity of aminoguanidine through NO-cGMP signaling. Aminoguanidine (50mg/kg) attenuated the anxiogenic effect of sildenafil. Aminoguanidine and sildenafil per se and in combination did not affect the locomotor activity of stressed and unstressed mice as compared to their respective control groups. Thus, aminoguanidine produced anti-anxiety activity in stressed mice through iNOS-NO-cGMP pathway.

Antidepressant-like activity of gallic acid in mice subjected to unpredictable chronic mild stress

This study was designed to evaluate antidepressant‐like activity of gallic acid in Swiss young male albino mice subjected to unpredictable chronic mild stress and to explore the possible underlying mechanisms for this activity. Gallic acid (5, 10, 20 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) per se were administered daily to unstressed mice and other groups of mice subjected to unpredictable mild stress, 30 min after the injection for 21 successive days. The antidepressant‐like activity was evaluated using forced swim test (FST) and sucrose preference test. Stress significantly increased immobility period of mice in FST. Gallic acid (10 and 20 mg/kg, i.p.) and fluoxetine significantly decreased immobility period of unstressed and stressed mice in FST and prevented the stress‐induced decrease in sucrose preference, indicating significant antidepressant‐like activity. There was no significant effect on locomotor activity of the mice by the drugs. Gallic acid (10 and 20 mg/kg, i.p.) significantly decreased Monoamine oxidase‐A (MAO‐A) activity, malondialdehyde levels, and catalase activity in unstressed mice; and significantly prevented the stress‐induced decrease in reduced glutathione and catalase activity; and also significantly prevented stress‐induced increase in MAO‐A activity, malondialdehyde levels, plasma nitrite, and corticosterone levels. Thus, gallic acid showed antidepressant‐like activity in unstressed and stressed mice probably due to its antioxidant activity and through inhibition of MAO‐A activity and decrease in plasma nitrite levels. In addition, gallic acid also showed antidepressant‐like activity in stressed mice probably through decrease in plasma corticosterone levels.

Evidences for the Involvement of Monoaminergic and GABAergic Systems in Antidepressant-like Activity of Tinospora cordifolia in Mice.

The present study was taken up to investigate the effect of petroleum ether extract of Tinospora cordifolia (Wild.) Miers, on depression in mice. The extract (50, 100 and 200 mg/kg, p.o.) was administered for 14 successive days to Swiss young albino mice (either sex) and evaluated for antidepressant-like activity using tail suspension test and forced swim test. Petroleum ether extract at all three doses produced significant antidepressant-like effect in tail suspension test as well as in forced swim test and their efficacies were found to be comparable to imipramine (15 mg/kg, p.o.) and sertraline (20 mg/kg, p.o.). The extract at a dose of 50 mg/kg showed most potent effect and did not show any significant change in locomotor functions of mice as compared to control. The antidepressant-like effect of the extract was significantly reversed by pretreatment of animals with prazosin (a α1-adrenoceptor antagonist), sulpiride (a selective dopamine D2-receptor antagonist), p-CPA (a serotonin synthesis inhibitor) and baclofen (GABA-B agonist), when tested in tail suspension test. Moreover, petroleum ether extract also reduced the mouse whole brain monoamine oxidase (MAO-A and MAO-B) activities as compared to control, resulting in increase in the levels of brain monoamines. Therefore, the extract may have potential therapeutic value for the management of depressive disorders.

Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice

BACKGROUND The aim of present study was to evaluate antidepressant-like activity of ellagic acid in Swiss young male albino mice; and to explore the possible underlying mechanisms for this activity. METHODS Mice were immobilized for 150 min once only for induction of stress. Ellagic acid (8.75, 17.5, 35 mg/kg, po) and fluoxetine (20 mg/kg, ip) per se were administered to unstressed and stressed mice; and immobility periods were recorded using tail suspension test and forced swim test. The plasma nitrite levels were also estimated in unstressed and stressed mice. Effects of 7-nitroindazole (nNOS inhibitor), aminoguanidine (iNOS inhibitor), prazosin (α(1)-adrenoceptor antagonist), sulpiride (selective D(2)-receptor antagonist), and p-chlorophenylalanine (p-CPA - tryptophan hydroxylase inhibitor) on antidepressant-like activity of ellagic acid were also evaluated. RESULTS Ellagic acid (17.5 and 35 mg/kg, po) and fluoxetine per se significantly decreased immobility periods of unstressed and stressed mice, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice. Ellagic acid significantly decreased the plasma nitrite levels in stressed mice only. Aminoguanidine significantly potentiated antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid (35 mg/kg) in stressed mice. 7-Nitroindazole did not enhance antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid in unstressed mice. Prazosin and p-CPA significantly attenuated antidepressant-like effect of ellagic acid (35 mg/kg) in unstressed mice only. CONCLUSION Thus, ellagic acid showed antidepressant-like activity in unstressed mice probably by interaction through adrenergic and serotonergic systems. On the other hand, antidepressant-like activity of ellagic acid in stressed mice might be through inhibition of inducible NOS.

Optimization and evaluation of bioactive drug-loaded polymeric nanoparticles for drug delivery

The premise of the present study was to suitably select or modify the constitution of the polymer matrix to achieve significantly high entrapment of hydrophilic drugs within polymeric nanoparticles (NPs). Glycyrrhizin (GL), the bioactive drug was selected as a representative hydrophilic drug. Ionotropic gelation technique was used for the preparation of glycyrrhizin-loaded NPs. Concentration of polymers were optimized by 3-level factorial design which affected the particle size and encapsulation efficiency. The formulation was subjected to morphological, physiochemical and in vitro drug release studies. Mean particle size of nanoparticles was around 181 nm as estimated with particle size analyzer. TEM observations revealed spherical shape and size in the range of 140-200 nm. Fourier transform-infrared analysis did not reveal any chemical interaction among the drug and polymers used for the nano-formulation. A release study conducted in vitro over a period of 24 h indicated primarily burst release after that controlled release of glycyrrhizin from the formulation. Antibacterial activities of glycyrrhizin, blank chitosan-gum arabic NPs and glycyrrhizin-loaded chitosan-gum arabic NPs were tested against two Gram negative and two Gram positive bacteria. The study demonstrates the benefit of excipient screening techniques in improving entrapment efficiency of a hydrophilic drug.

Possible Involvement of Monoaminergic Neurotransmission in Antidepressant-like activity of Emblica officinalis Fruits in Mice

Aims: In this study, antidepressant‐like activity of Emblica offcinalis Gaertn. fruits (Family: Euphorbiaceae) was evaluated in Swiss young male albino mice employing tail suspension test and forced swim test. Methods: Aqueous extract (200 and 400 mg/kg) of the fruits was administered orally for 14 successive days to mice. On day 14, 60 min after extract administration, animals were subjected to tail suspension test and forced swim test. Results: The extract significantly decreased immobility period in both tail suspension test and forced swim test, indicating significant antidepressant‐like activity. The lower dose (200 mg/kg) of the extract showed better antidepressant‐like action. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg), imipramine (15 mg/kg), and phenelzine (20 mg/kg). The extract did not show any significant effect on locomotor activity of the mice. Prazosin (alpha1‐adrenoceptor antagonist), sulpiride (selective D2‐receptor antagonist), baclofen (GABAB agonist), and p‐CPA (tryptophan hydroxylase inhibitor) significantly attenuated the extract‐induced antidepressant‐like effect. The extract also significantly decreased brain MAO‐A levels. Discussion: The aqueous extract might produce antidepressant‐like effect by interaction with α1‐adrenoceptors, dopamine D2‐ receptors, serotonergic, and GABAB receptors. In this study, aqueous extract was found to contain 2.94% of ascorbic acid. So ascorbic acid and other constituents like flavanoids, tannoid principles, and polyphenolic substances present in the aqueous extract of E. officinalis might be responsible for its antidepressant‐like activity. Conclusions: Thus, aqueous extract of E. officinalis showed antidepressant‐like activity probably by inhibiting MAO‐A and GABA; and also due to its antioxidant activity.