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Cysteamine attenuates the decreases in TrkB protein levels and the anxiety/depression-like behaviors in mice induced by corticosterone treatment.

Kutiyanawalla A, Terry AV, Pillai A - PLoS ONE (2011)

Bottom Line: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus.Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Health Behavior, Georgia Health Sciences University, Augusta, Georgia, United States of America.

ABSTRACT

Objective: Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of anxiety-like behaviors observed in many neuropsychiatric disorders. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays an important role in stress-mediated changes in structural as well as functional neuroplasticity. Studies designed to elucidate the mechanisms whereby TrkB signaling is regulated in chronic stress might provide valuable information for the development of new therapeutic strategies for several stress-related psychiatric disorders.

Materials and methods: We examined the potential of cysteamine, a neuroprotective compound to attenuate anxiety and depression like behaviors in a mouse model of anxiety/depression induced by chronic corticosterone exposure.

Results: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus. Furthermore, cysteamine treatment reversed the anxiety and depression like behavioral abnormalities induced by chronic corticosterone treatment. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.

Conclusions: The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

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Related in: MedlinePlus

Experimental designs used for testing the behavioral and biochemical responses to cysteamine treatment in CD-1 and TrkB knockout mice.(1) CD-1 male mice were treated for 7 weeks with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) in presence or absence of cysteamine (150 mg/kg) during the last three weeks of corticosterone or vehicle treatment. At the end of the treatment, the same animal was successively tested in the Open Field (OF) paradigm, the Light/dark test, the Elevated Plus Maze test (EPM), the Tail Suspension Test (TST) and then sacrificed for protein or mRNA analysis. (2) Cysteamine (150 mg/kg) or water (vehicle) was administered through drinking water to TrkB knockout and wild type mice for 21 days. At the end of the treatment, mice were killed and brains removed for behavioral and biochemical analyses.
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pone-0026153-g001: Experimental designs used for testing the behavioral and biochemical responses to cysteamine treatment in CD-1 and TrkB knockout mice.(1) CD-1 male mice were treated for 7 weeks with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) in presence or absence of cysteamine (150 mg/kg) during the last three weeks of corticosterone or vehicle treatment. At the end of the treatment, the same animal was successively tested in the Open Field (OF) paradigm, the Light/dark test, the Elevated Plus Maze test (EPM), the Tail Suspension Test (TST) and then sacrificed for protein or mRNA analysis. (2) Cysteamine (150 mg/kg) or water (vehicle) was administered through drinking water to TrkB knockout and wild type mice for 21 days. At the end of the treatment, mice were killed and brains removed for behavioral and biochemical analyses.

Mentions: The expression of the BDNF receptor, TrkB was examined in frontal cortex and hippocampus after 3, 5 and 7 weeks of corticosterone treatment. In the frontal cortex, two-way ANOVA revealed a significant main effect of treatment [F(1,25) = 6.063; p = 0.02] and a significant treatment x time interaction [F(2,25) = 3.304; p = 0.05], without a significant effect of time [F(2,25) = 1.639; p = 0.214]. Post hoc analysis indicated that treatment with corticosterone for 3 (Fig 2A) and 5 (Fig 2B) weeks did not change TrkB protein levels, but 7-week treatment resulted in a significant decrease in TrkB protein levels (Fig 2C; p<0.05). In hippocampus, there was a significant main effect of time [F(2,24) = 16.07; p<0.0001] and treatment [F(1,24) = 34.63; p<0.0001],without a significant treatment x time interaction [F(2,24) = 1.295; p = 0.292]. Interestingly, TrkB protein levels in the hippocampus were significantly decreased in groups treated with corticosterone for 3 (Fig 3A;p<0.01), 5 (Fig 3B; p<0.01) and 7 (Fig 3C; p<0.05) weeks. We also examined the protein levels of truncated TrkB in the above brain areas following corticosterone treatment; however, we did not find any change in truncated TrkB levels in any of the treatment groups (data not shown). To determine whether TrkB downregulation occurred at the mRNA level, we examined TrkB mRNA expression in the frontal cortex and hippocampus from the 7-week corticosterone treated mice. TrkB mRNA levels in corticosterone-treated mice did not differ from vehicle-treated mice (Fig 4).


Cysteamine attenuates the decreases in TrkB protein levels and the anxiety/depression-like behaviors in mice induced by corticosterone treatment.

Kutiyanawalla A, Terry AV, Pillai A - PLoS ONE (2011)

Experimental designs used for testing the behavioral and biochemical responses to cysteamine treatment in CD-1 and TrkB knockout mice.(1) CD-1 male mice were treated for 7 weeks with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) in presence or absence of cysteamine (150 mg/kg) during the last three weeks of corticosterone or vehicle treatment. At the end of the treatment, the same animal was successively tested in the Open Field (OF) paradigm, the Light/dark test, the Elevated Plus Maze test (EPM), the Tail Suspension Test (TST) and then sacrificed for protein or mRNA analysis. (2) Cysteamine (150 mg/kg) or water (vehicle) was administered through drinking water to TrkB knockout and wild type mice for 21 days. At the end of the treatment, mice were killed and brains removed for behavioral and biochemical analyses.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198436&req=5

pone-0026153-g001: Experimental designs used for testing the behavioral and biochemical responses to cysteamine treatment in CD-1 and TrkB knockout mice.(1) CD-1 male mice were treated for 7 weeks with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) in presence or absence of cysteamine (150 mg/kg) during the last three weeks of corticosterone or vehicle treatment. At the end of the treatment, the same animal was successively tested in the Open Field (OF) paradigm, the Light/dark test, the Elevated Plus Maze test (EPM), the Tail Suspension Test (TST) and then sacrificed for protein or mRNA analysis. (2) Cysteamine (150 mg/kg) or water (vehicle) was administered through drinking water to TrkB knockout and wild type mice for 21 days. At the end of the treatment, mice were killed and brains removed for behavioral and biochemical analyses.
Mentions: The expression of the BDNF receptor, TrkB was examined in frontal cortex and hippocampus after 3, 5 and 7 weeks of corticosterone treatment. In the frontal cortex, two-way ANOVA revealed a significant main effect of treatment [F(1,25) = 6.063; p = 0.02] and a significant treatment x time interaction [F(2,25) = 3.304; p = 0.05], without a significant effect of time [F(2,25) = 1.639; p = 0.214]. Post hoc analysis indicated that treatment with corticosterone for 3 (Fig 2A) and 5 (Fig 2B) weeks did not change TrkB protein levels, but 7-week treatment resulted in a significant decrease in TrkB protein levels (Fig 2C; p<0.05). In hippocampus, there was a significant main effect of time [F(2,24) = 16.07; p<0.0001] and treatment [F(1,24) = 34.63; p<0.0001],without a significant treatment x time interaction [F(2,24) = 1.295; p = 0.292]. Interestingly, TrkB protein levels in the hippocampus were significantly decreased in groups treated with corticosterone for 3 (Fig 3A;p<0.01), 5 (Fig 3B; p<0.01) and 7 (Fig 3C; p<0.05) weeks. We also examined the protein levels of truncated TrkB in the above brain areas following corticosterone treatment; however, we did not find any change in truncated TrkB levels in any of the treatment groups (data not shown). To determine whether TrkB downregulation occurred at the mRNA level, we examined TrkB mRNA expression in the frontal cortex and hippocampus from the 7-week corticosterone treated mice. TrkB mRNA levels in corticosterone-treated mice did not differ from vehicle-treated mice (Fig 4).

Bottom Line: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus.Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Health Behavior, Georgia Health Sciences University, Augusta, Georgia, United States of America.

ABSTRACT

Objective: Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of anxiety-like behaviors observed in many neuropsychiatric disorders. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays an important role in stress-mediated changes in structural as well as functional neuroplasticity. Studies designed to elucidate the mechanisms whereby TrkB signaling is regulated in chronic stress might provide valuable information for the development of new therapeutic strategies for several stress-related psychiatric disorders.

Materials and methods: We examined the potential of cysteamine, a neuroprotective compound to attenuate anxiety and depression like behaviors in a mouse model of anxiety/depression induced by chronic corticosterone exposure.

Results: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus. Furthermore, cysteamine treatment reversed the anxiety and depression like behavioral abnormalities induced by chronic corticosterone treatment. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.

Conclusions: The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

Show MeSH
Related in: MedlinePlus