Escitalopram or novel herbal mixture treatments during or following exposure to stress reduce anxiety-like behavior through corticosterone and BDNF modifications

Ravid Doron, Dafna Lotan, Ziv Versano, Layla Benatav, Motty Franko, Shir Armoza, Nadav Kately, Moshe Rehavi, Ravid Doron, Dafna Lotan, Ziv Versano, Layla Benatav, Motty Franko, Shir Armoza, Nadav Kately, Moshe Rehavi

Abstract

Anxiety disorders are a major public health concern worldwide. Studies indicate that repeated exposure to adverse experiences early in life can lead to anxiety disorders in adulthood. Current treatments for anxiety disorders are characterized by a low success rate and are associated with a wide variety of side effects. The aim of the present study was to evaluate the anxiolytic effects of a novel herbal treatment, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram. We recently demonstrated the anxiolytic effects of these treatments in BALB mice previously exposed to one week of stress. In the present study, ICR mice were exposed to post natal maternal separation and to 4 weeks of unpredictable chronic mild stress in adolescence, and treated during or following exposure to stress with the novel herbal treatment or with escitalopram. Anxiety-like behavior was evaluated in the elevated plus maze. Blood corticosterone levels were evaluated using radioimmunoassay. Brain derived neurotrophic factor levels in the hippocampus were evaluated using enzyme-linked immunosorbent assay. We found that (1) exposure to stress in childhood and adolescence increased anxiety-like behavior in adulthood; (2) the herbal treatment reduced anxiety-like behavior, both when treated during or following exposure to stress; (3) blood corticosterone levels were reduced following treatment with the herbal treatment or escitalopram, when treated during or following exposure to stress; (4) brain derived neurotrophic factor levels in the hippocampus of mice treated with the herbal treatment or escitalopram were increased, when treated either during or following exposure to stress. This study expands our previous findings and further points to the proposed herbal compound's potential to be highly efficacious in treating anxiety disorders in humans.

Conflict of interest statement

Competing Interests: Dr. Ravid Doron and Mr. Nadav Kately have an approved patent relating to the herbal treatment for anxiety disorders (PCT 61-311,537, USA). All authors assert that none have any commercial, financial, or nonfinancial involvements or competing interests that might present an appearance of a conflict of interest in connection with the submitted manuscript.

Figures

Figure 1. Experiment 2 outline.
Figure 1. Experiment 2 outline.
Figure 2. Experiment 3 outline.
Figure 2. Experiment 3 outline.
Figure 3. Effect of stress manipulation on…
Figure 3. Effect of stress manipulation on anxiety-like-behavior in the Elevated Plus Maze.
The time spent in open arms of the EPM was significantly higher in control mice (n = 17), compared to stressed mice (n = 51). Significantly different from the control group: *p

Figure 4. Behavioral and biological effects of…

Figure 4. Behavioral and biological effects of NHT and escitalopram treatments following exposure to stress.

Figure 4. Behavioral and biological effects of NHT and escitalopram treatments following exposure to stress.
Figure 4A: Treatment effect on time spent in the open arms of the EPM (saline: n = 40; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Figure 4B: Treatment effect on number of EPM closed arms entries (saline: n = 40; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Figure 4C: Treatment effect on blood corticosterone levels (saline: n = 17; NHT 15 mg/kg: n = 18; NHT 30 mg/kg: n = 18; escitalopram: n = 16). Figure 4D: Treatment effect on hippocampus BDNF levels (saline: n = 26; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Significantly different from the control group: *p

Figure 5. Behavioral and biological effects of…

Figure 5. Behavioral and biological effects of the NHT and escitalopram treatment during exposure to…

Figure 5. Behavioral and biological effects of the NHT and escitalopram treatment during exposure to stress.
Figure 5A: Treatment effect on time spent in the open arms of the EPM (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5B: Treatment effect on number of EPM closed arms entries (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5C: Treatment effect on blood corticosterone levels (saline: n = 24; NHT 15 mg/kg: n = 17; NHT 30 mg/kg: n = 17; escitalopram: n = 17). Figure 5D: Treatment effect on hippocampus BDNF levels (saline: n = 20; NHT 15 mg/kg: n = 15; NHT 30 mg/kg: n = 12; escitalopram: n = 10). Significantly different from the control group: *p
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References
    1. Thase ME (2006) Managing depressive and anxiety disorders with escitalopram. Expert Opin Pharmacother 7: 429–440. - PubMed
    1. Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4: 775–790. - PubMed
    1. De Bellis MD, Van Dillen T (2005) Childhood post-traumatic stress disorder: an overview. Child Adolesc Psychiatr Clin N Am 14: : 745–772, ix. - PubMed
    1. Reinhold JA, Mandos LA, Rickels K, Lohoff FW (2011) Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother 12: 2457–2467. - PubMed
    1. Barbui C, Cipriani A (2009) Review: maintenance antidepressants reduce risk of relapse but effect is not as great in recurrent depression. Evid Based Ment Health 12: 79. - PubMed
Show all 56 references
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This work was funded by the Israel Science Foundation (http://www.isf.org.il/english/ [ISF 738/11]), by the National Institute for Psychobiology in Israel (http://www.psychobiology.org.il/ [NIPI-7-2011-12]), and by the Open University foundation. No individuals employed or contracted by the funders (other than the named authors) played any role in: study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure 4. Behavioral and biological effects of…
Figure 4. Behavioral and biological effects of NHT and escitalopram treatments following exposure to stress.
Figure 4A: Treatment effect on time spent in the open arms of the EPM (saline: n = 40; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Figure 4B: Treatment effect on number of EPM closed arms entries (saline: n = 40; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Figure 4C: Treatment effect on blood corticosterone levels (saline: n = 17; NHT 15 mg/kg: n = 18; NHT 30 mg/kg: n = 18; escitalopram: n = 16). Figure 4D: Treatment effect on hippocampus BDNF levels (saline: n = 26; NHT 15 mg/kg: n = 24; NHT 30 mg/kg: n = 22; escitalopram: n = 23). Significantly different from the control group: *p

Figure 5. Behavioral and biological effects of…

Figure 5. Behavioral and biological effects of the NHT and escitalopram treatment during exposure to…

Figure 5. Behavioral and biological effects of the NHT and escitalopram treatment during exposure to stress.
Figure 5A: Treatment effect on time spent in the open arms of the EPM (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5B: Treatment effect on number of EPM closed arms entries (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5C: Treatment effect on blood corticosterone levels (saline: n = 24; NHT 15 mg/kg: n = 17; NHT 30 mg/kg: n = 17; escitalopram: n = 17). Figure 5D: Treatment effect on hippocampus BDNF levels (saline: n = 20; NHT 15 mg/kg: n = 15; NHT 30 mg/kg: n = 12; escitalopram: n = 10). Significantly different from the control group: *p
Similar articles
References
    1. Thase ME (2006) Managing depressive and anxiety disorders with escitalopram. Expert Opin Pharmacother 7: 429–440. - PubMed
    1. Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4: 775–790. - PubMed
    1. De Bellis MD, Van Dillen T (2005) Childhood post-traumatic stress disorder: an overview. Child Adolesc Psychiatr Clin N Am 14: : 745–772, ix. - PubMed
    1. Reinhold JA, Mandos LA, Rickels K, Lohoff FW (2011) Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother 12: 2457–2467. - PubMed
    1. Barbui C, Cipriani A (2009) Review: maintenance antidepressants reduce risk of relapse but effect is not as great in recurrent depression. Evid Based Ment Health 12: 79. - PubMed
Show all 56 references
Publication types
MeSH terms
Grant support
This work was funded by the Israel Science Foundation (http://www.isf.org.il/english/ [ISF 738/11]), by the National Institute for Psychobiology in Israel (http://www.psychobiology.org.il/ [NIPI-7-2011-12]), and by the Open University foundation. No individuals employed or contracted by the funders (other than the named authors) played any role in: study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5. Behavioral and biological effects of…
Figure 5. Behavioral and biological effects of the NHT and escitalopram treatment during exposure to stress.
Figure 5A: Treatment effect on time spent in the open arms of the EPM (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5B: Treatment effect on number of EPM closed arms entries (saline: n = 25; NHT 15 mg/kg: n = 20; NHT 30 mg/kg: n = 19; escitalopram: n = 20). Figure 5C: Treatment effect on blood corticosterone levels (saline: n = 24; NHT 15 mg/kg: n = 17; NHT 30 mg/kg: n = 17; escitalopram: n = 17). Figure 5D: Treatment effect on hippocampus BDNF levels (saline: n = 20; NHT 15 mg/kg: n = 15; NHT 30 mg/kg: n = 12; escitalopram: n = 10). Significantly different from the control group: *p

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