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Preclinical evaluation of Boswellia serrata for anxiolytic activity

Decreased levels of GABA, an inhibitory neurotransmitter in the central nervous system is responsible for causing anxiety. Most of the anxiolytics achieve their goal by modulating the GABA receptors.4-6 Benzodiazepines are the most commonly used, safe and effective drug in the short term management of anxiety.7 Long-term use of benzodiazepine has psychological and physical adverse effects. They are also associated with tolerance, physical dependence and withdrawal syndrome on sudden discontinuation.8,9 Hence, the requirement for newer, well-tolerated and efficacious treatment remains high.

the gum resin of Boswellia, inhibits the synthesis of pro-inflammatory 5-lipoxygenase products, including 5 hydroxyeicosatetraenoic acid and leukotriene B4, which are responsible for bronchoconstriction, chemotaxis, and increased vascular permeability. 13 Boswellic acid is also a specific inhibitor of 5-lipoxygenase. 14,15 It was found that BS helps in surging of GABA levels in mice brain. Mice pretreated with BS exhibited down-regulation of xanthine oxidase enzymatic activity, showing that BS has the ability to arm the cellular components against oxidative stress. 16 So, the present study is done to elucidate the possible anxiolytic activity of BS in Swiss albino mice. A total of 60 mice (n=60) were used. They were divided into ten groups of six mice in each.

Drugs
The test drug, BS was purchased from Natural Remedies, Bangalore, India. The standard antianxiety drug -diazepam and control -normal saline (NS) were purchased from our institutional pharmacy.

Acute oral toxicity test
Acute oral toxicity was carried out in male Swiss albino mice according to Organization of Economic Co-operation and Development (OECD) guidelines, ANNEX-423. 17 Animals were administered BS in a dose of 5, 50, 300 and 2000 mg/kg per orally to find out safe dose range in animals. Animals were observed for 48 hrs from the time of drug administration. Mice were looked for general behavior and mortality. As the highest dose of BS (2000 mg/kg) did not cause mortality in mice, the dose range of 50, 100, 200 mg/ kg of BS were used in the present study.
Anxiolytic activity of BS was evaluated by using two modelslight and dark arena (LDA) and elevated plus maze (EPM). The experiment was conducted in Ethanopharmacology laboratory of the Department of Pharmacology, Yenepoya Medical College, Yenepoya University, between 8:00 A.M. and 2:00 P.M. The food but not water was withdrawn 6 hrs prior to study period. Animals were weighed and appropriate dose of the drug was administered per orally (p.o.) to the different groups of animals. The standard drug -diazepam and test drug BS were dissolved in NS before administration to animals. The experiment was conducted 60 mins after the oral administration of the drug.

Light and dark arena
The apparatus consists of a rectangular box (45 cm × 27 cm × 27 cm), partitioned into two equal compartments, which are connected by a 7.5 cm × 7.5 cm opening in the wall between compartments. One light compartment painted white on all four sides and illuminated with 40 W white light source, which was placed 25 cm above the open compartment. The dark compartment painted black on all four sides and top covered with black plywood. Mouse was placed in the center of the light compartment and observed for 5 mins for the time spent and number of entries in light and dark boxes. 18 The animals were divided as follows for LDA model:

Data analysis
Results are represented as mean ± standard deviation. Statistical analysis was performed by using one-way Analysis of Variance and Dunnett's test for multiple comparisons.

RESULTS
The experiment was conducted in 60 (n=60) male Swiss albino mice after 60 mins of oral drug administration. Mice were divided into ten groups of six mice in each. Mice in the first five groups were evaluated for anxiolytic action by LDA model. Table 1 shows the number of entries and time spent in light and dark boxes. Remaining five groups of mice were evaluated for anxiolytic action by EPM model. Table 2

DISCUSSION
Feel worried and anxious are the common symptoms in day today life. However, some persons fail to control their worries and ultimately their routine life is affected due to excessive anxiety. Lifestyle modifications like yoga, meditation and dietary alterations can be helpful in the early part of anxiety disorder. However, most of the anxiety patients are benefited by pharmacotherapy. Benzodiazepines even though established efficacy for many anxiety disorders, associated with many adverse effects. 8,9 Oxidative stress mechanisms underlying anxiety disorder have been in existence since long time. It was claimed that nitric oxide and peroxynitrite might play a major role in setting up a vicious etiological cycle involving free radicals and inflammatory cytokines in post-traumatic stress disorder. 19,20 Association of vitamin E depletion, increased oxidative stress markers and anxiety behaviors in phospholipid transfer protein knock-out mice has further suggested an oxidative role in the pathogenesis of anxiety. 21 Even clinical studies have reported elevated lipid peroxidation byproducts in obsessive -compulsive disorder, panic disorder and social phobia. [22][23][24][25] Thus, anti-oxidants could have anxiolytic potential by preventing oxidative pathway. Green tea, polyphenol (-) epigallocatechin gallate and chlorogenic acid, a dietary polyphenol have shown anxiolytic effects in experimental models due to their potent antioxidant property. 10,26 Around 50-65% of anxiety patients are benefited by herbal medications with conventional medications. 27,28   In this study, BS has shown significant anxiolytic activity in preclinical models. BS in a dose of 50 mg/kg significantly increased the time spent in light box and decrease in the time spent in dark box (p<0.05) when compared to control group in LDA model (Table 1). Whereas, in EPM model 200 mg/kg of BS has shown significant anxiolytic action (p<0.001) when compared to control group (Table 2). Although, EPM and LDA models are used to assess the anxiolytic activity of drugs, the results are not always consistent between them. This difference in the dose-response in EPM and LDA models is due to different aspects of anxiety behavior, such as bright light anxiety behavior in LDA model and open-space-anxiety like behavior in EPM model. 29 Exact mechanism of BS as an anxiolytic is yet to be elucidated in further studies. BS may protect the cellular components against oxidative stress and increase GABA levels in the brain. 16 Thus, BS can be an alternative anti-anxiety drug in near future. However, further studies are required to elucidate its exact mechanism of action, efficacy and adverse effects in humans.