Investigating Accumulative Effect of Fluoxetine and Fagonia indica as an Anti-Stress Therapy

Abstract

Introduction: Chronic stress causes structural modifications in brain, ultimately impacting behavior, emotions and cognition. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), acts as the first line of defense against stress, but unfortunately is associated with a long list of side effects. Fagonia indica has been found to have antioxidant, anti-inflammatory and anti-cancerous properties. Objective: To study the cumulative effects of Fluoxetine and Fagonia indica on social behavior in restrained stress mice model. Methods: The study was conducted on 48 female BALB/c mice, randomly divided into groups. Restrained stress was induced for 4 hours for a duration of 30 days. Treatment with Fluoxetine (18 mg/kg/day) and/or Fagonia indica plant extract (400 mg/kg/day) was administered orally. Behavior tests were conducted to assess anxiety, sociability, social novelty, intrinsic inquisitiveness, recognition memory and motor coordination. Biochemical tests were performed to check the effects of stress and drug treatments on critical organs, such as liver, kidneys and heart. Results: Marble burying test revealed increased anxiety levels of stress mice (12.25 ± 3.4) compared to the control group (4.5 ± 1.6). Both of the monotherapies showed significant improvement, with Fluoxetine monotherapy (4.8 ± 1.1), Fagonia indica monotherapy (4.5 ± 0.6) and the combination therapy (2.75 ± 0.25), respectively. Insignificantly decreased social propensity was seen in stressed mice (0.58 ± 0.05) compared to the control (0.61 ± 0.03). Improved sociability was seen following treatments, with significant difference observed only in the combination therapy (0.66 ± 0.08). Interestingly, percentage exit circle test and recognition memory index results, revealed no drastic changes among the groups. Beam balance tests revealed impaired motor coordination in stressed mice (2.25 ± 0.75) compared to the control group (0.75 ± 0.25). Significant improvement was seen the Fagonia indica monotherapy group (0.75 ± 0.25) and the combination therapy group (0.5 ± 0.3). Regarding cortisol levels, no significant changes were observed among the groups. Stressed group showed increased ALT (43.3 ± 4.3) and ALP levels (129.3 ± 22.2), compared to the control group, ALT (14.0 ± 6.7) and ALP (64.3 ± 17.1). All three treatments managed to bring ALT levels within Abstract xix the normal reference range (22-32 U/L). Fluoxetine monotherapy group resulted in high ALP (189.3 ± 22.1) and urea levels (4.6 ± 0.3) which were counteracted by Fagonia indica in the combination therapy; ALP (133.0 ± 4.7) and urea (1.6 ± 0.5) respectively. Lipid profile revealed normal total cholesterol (81-208 mg/dl) and LDL: HDL among the groups except for Fagonia indica group where high levels were seen. Interestingly Fluoxetine group was found to counteract this in the combination therapy. Conclusion: Restrained stress exhibited declined social behavior. Following Fluoxetine administration either alone or in combination with Fagonia indica, an improvement in anxiety, sociability, intrinsic inquisitiveness and motor coordination was seen. Regarding biochemical tests, overall Fagonia indica was able to counteract the adverse effects of Fluoxetine in the combination therapy. Although an improvement was seen in the combination therapy compared to the monotherapies, unfortunately it was not significant. Furthermore, high serum cholesterol and LDL: HDL levels in response to Fagonia indica treatment suggest that it might not be advisable for cardiac dysfunction patients. A detailed GCMS analysis of Fagonia indica plant extract and further studies with focus on the molecular aspects are needed.