Antidepressant activity of Zembrin alone and combined with desipramine in flinders sensitive line rats

Abstract

Introduction: People with major depressive disorder and comorbid anxiety disorders tend to have poor response to treatment compared to patient with major depressive disorder alone. The standardized extract of Sceletium tortuosum (Zembrin®) is a multi-model serotonin reuptake transporter (SERT) and phosphodiesterase (PDE) 4B inhibitor that may be a promising novel therapy for patients with depression, either as monotherapy or as an augmentation strategy in poor responders. Therefore, investigation into its therapeutic potential alone following sub-chronic treatment and in combination with a known standard antidepressant is required. Aim of the study: To assess the dose-related antidepressant- and anxiolytic-like effects of Zembrin® (ZEM) in the Flinders Sensitive Line (FSL) rats, a genetic model of depression, alone and as an adjunctive treatment with low-dose desipramine (DMI), and correlation with altered regional brain monoamines and phosphodiesterase 4B expression. Material and methods: For confirmation of the model, 12 male Flinders Resistant Line (FRL) rats and 12 male FSL rats (control group) were treated with saline for 14 days via oral gavage. Seven groups (n =12) of male FSL rats were treated with a 3-tier dose of ZEM (10, 25 & 30 mg/kg/day), and a 2-tier dose of DMI (15 & 30 mg/kg/day) for 14 days via oral gavage to establish predictive validity. To assess augmentation potential, ZEM (10 & 30 mg/kg/day), was combined with a low dose of DMI (15 mg/kg/day) over 14 days. Following treatment, depressive- like behaviour was assessed in the Forced Swim Test (FST), and anxiety-like behaviour was assessed in the Open Field Test (OFT) and Elevated Plus Maze (EPM). The behavioural assessment was followed by analyses of cortical and hippocampal monoamines and PDE4B levels. Results: Depressive-like behaviour was significantly increased in FSL rats versus Flinders Resistant Line (FRL) control rats. DMI (15 & 30 mg/kg/day) significantly decreased immobility and increased struggling behaviour in the FST. ZEM (10, 25 & 30 mg/kg/day) showed no antidepressant-like properties in the FST versus SAL (saline) treated FSL rats. Similarly, combinations of ZEM+DMI showed no antidepressant-like properties in FST versus FSL saline treated rats. ZEM-10+DMI-15 and ZEM-30+DMI-15 showed no antidepressant-like effects in FSL rats versus DMI-15 treated rats. ZEM- ABSTRACT ABSTRACT ii 10+DMI-15 and ZEM-30+DMI-15 significantly reduced immobility in the FST in FSL rats versus ZEM- (10 & 30 mg/kg/day) monotherapies. FSL rats did not demonstrate anxiety in either the OFT or EPM versus FRL rats. There was significantly increased cortical norepinephrine (NE) levels in FRL rats versus FSL saline control, nevertheless, the hippocampal serotonin (5-HT) levels were reduced in the FRL rats versus FSL saline control. In the DMI-30 treated rats, hippocampal and cortical NE levels were reduced versus FSL saline rats, whereas the hippocampal NE levels were reduced in DMI-15 versus FSL saline rats. ZEM-30 significantly increased frontal cortical NE and 5-HT levels versus the FSL saline control group. Neither DMI (15 mg/kg/day) nor ZEM (10 & 30 mg/kg/day) monotherapies reduced cortical and hippocampal PDE4B levels in FSL rats versus SAL FSL control group. However, ZEM-10+DMI-15 and ZEM-30+DMI-15 combination therapies significantly reduced hippocampal PDE4B levels versus FSL SAL treated rats. ZEM-30+DMI-15 significantly increased cortical PDE4B levels versus FSL SAL treated rats. Conclusions: FSL rats showed distinct depressive- like characteristics versus FRL controls. DMI alone reverse depressive-like behavioural characteristics in FSL rats. We were unable to confirm the antidepressant-like effects of ZEM in this study, either alone or in combination with DMI. These results may be model-related. Nevertheless, studies on hippocampal PDE4 levels do lend some support for the augmentation potential of ZEM as an add-on therapy for patients responding poorly to standard antidepressants, especially where specific actions on the hippocampal PDE4B are required. Combination of ZEM with antidepressants i.e., NRIs may be depressogenic displaying increased cortical PDE4B levels. However, further work is needed.