Neeraj Gilhotra

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.

A clinical perspective on mucoadhesive buccal drug delivery systems

Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems.

Piroxicam Bioadhesive Ocular Inserts: Physicochemical Characterization and Evaluation in Prostaglandin-Induced Inflammation

Purpose: An attempt has been made in the present research to formulate piroxicam into bioadhesive ocular inserts with an objective to sustain drug release, reduce frequency of dosing, and enhance ocular bioavailability of piroxicam. Material and Methods: Drug matrices were prepared using film forming polymer, PVP and bioadhesive polymers, HPMC, CMC, and carbopol. Ocular inserts were prepared by film casting method and prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug release. The optimized formulation was tested and compared with eye drops of piroxicam for ocular anti-inflammatory activity in rabbits against PGE2-induced inflammation. Results: The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of the polymers and their combination. The above properties were found to be optimum for all films; however, formulation containing carbopol 0.5% and HPMC 1% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable drug release (99% at 12 hr). Kinetic studies indicated both diffusion and swelling as mechanism of drug release from this matrix. Further in vivo studies with this formulation indicated a significant inhibition of PGE2-induced lid closure and PMN migration as compared to eye drops formulation. Conclusion: Formulation was found promising, as it sustained the drug release and enhanced the ocular bioavailability of piroxicam as compared to piroxicam eye drops.

GABAergic and nitriergic influence in antianxiety-like Activity of Garlic in Mice

Objectives: To investigate the GABAergic and nitriergic mechanism involved in the anxiolytic-like profile of ethanolic extract of garlic (GE). Materials and Methods: Male Swiss albino mice were employed in the present study. Stress was produced in mice by immobilizing them for 6h. Elevated plus maze, light/dark box and social interaction test were used for the assessment of anxiety in mice. Concentrations of GABA in brain and nitrite level in plasma were estimated to determine the possible involvement of GABAergic and nitriergic mechanisms in the anxiolytic profile of GE. Results: The present study showed that the GE produced significant antianxiety- like activity in unstressed and stressed mice. In unstressed mice, GE significantly increased GABA levels, but could not produce any change in nitrite levels. Meanwhile, in stressed mice, GE significantly increased GABA levels along with a significant decrease in nitrite levels. Pre-treatment with aminoguanidine, an inducible nitric oxide synthase inhibitor, significantly enhanced the anxiolytic-like activity of GE, as compared to GE and aminoguanidine alone in stressed mice, but not in unstressed mice. On the other hand, pretreatment with 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, did not produce any significant change in antianxiety- like activity of GE in unstressed as well as stressed mice. Conclusion: It has been concluded that the garlic may possess anxiolytic- like activity and possess NOS inhibiting property in stressed mice, which may add to its status to be used in stress-induced anxiety conditions.

Nitriergic Influence in the Compromised Antidepressant Effect of Fluoxetine in Stressed Mice

Objective: To investigate the possible nitriergic influence in the compromised antidepressant effect of fluoxetine in stressed mice. Materials and methods: Male swiss albino mice were used in the present study. Mice were stressed by immobilization for 2hrs. Mice subjected to stress were considered as stressed mice and mice not subjected to stress were considered as unstressed mice. All the treatments were administered intraperitoneally (i.p.) at the dose of 10 ml/kg. Depression like behavioral alterations in unstressed and stressed mice was measured by TST followed by FST. To determine the possible nitriergic influence; nitrite levels were measured in brain homogenates. Results: Present study showed that the 2hrs immobilization significantly increased the immobility period of mice in both TST and FST, with the concurrent increase in the levels of nitrite in the brain homogenates as compared to the vehicle treated unstressed mice. Fluoxetine (FLX) (20 mg/kg, i.p.); pyrrolidine dithiocarbamate (PDTC) (100 mg/kg, i.p.) and methylene blue (MB) (100 mg/kg, i.p.) significantly reduced the immobility period of stressed mice in both TST and FST as compared to vehicle treated stressed mice. Pre-treatment with PDTC (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) did not significantly alter the immobility period and nitrite levels of FLX (20 mg/kg, i.p.) treated stressed mice. Pre-treatment with MB (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) did not significantly alter the immobility period of mice in TST, but significantly reduced the immobility period of mice in FST as compared to the FLX (20 mg/kg, i.p.) treated stressed mice. Also the pre-treatment with MB (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) significantly reduced the nitrite levels as compared to the FLX (20 mg/kg, i.p.) treated stressed mice. Conclusion: It has been concluded that nitriergic mechanism plays a significant role in the compromised antidepressant effect of fluoxetine in stressed mice.