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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

Effects of cysteamine in chronic corticosterone-treated mice on TrkB protein levels in the frontal cortex and hippocampus.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. TrkB protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-Actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle and #p<0.05 versus CORT.
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pone-0026153-g005: Effects of cysteamine in chronic corticosterone-treated mice on TrkB protein levels in the frontal cortex and hippocampus.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. TrkB protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-Actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle and #p<0.05 versus CORT.

Mentions: Subsequently, we determined if cysteamine could reverse corticosterone-induced decreases in TrkB protein levels. CD-1 mice were treated for 7 weeks with vehicle or corticosterone in the presence or absence of cysteamine during the last three weeks of corticosterone treatment. In the frontal cortex, two-way ANOVA with corticosterone/vehicle pretreatment and cysteamine/vehicle as main effects indicated significant main effect of pretreatment [(F(1,18) = 34.69; p<0.0001] and treatment [F(1,18) = 26.81; p<0.0001], but without a significant pretreatment x treatment interaction [F(1,18) = 0.3669; p = 0.552]. Post hoc analysis with Bonferroni's multiple comparison test showed that treatment with cysteamine significantly increased TrkB protein levels in frontal cortex (Fig 5A). The increase in TrkB protein levels was observed in both corticosterone (p<0.001) and non-corticosterone treated animals (p<0.05). Similar to frontal cortex, data from hippocampus showed significant main effect of pretreatment [F(1,18) = 40.84; P<0.0001] and treatment [F(1,18) = 88.46; p<0.0001]. No significant effect was found in pretreatment x treatment interaction in hippocampus [F(1,18) = 2.729; p = 0.118]. The reduction in TrkB protein levels in the hippocampus induced by chronic corticosterone was reversed by cysteamine (Fig 5B; p<0.05). We did not find any significant change in truncated TrkB levels following cysteamine treatment in the vehicle or corticosterone treated groups (data not shown). Taken together, these results suggest that chronic cysteamine treatment is effective in reversing the reductions in TrkB protein levels induced by excess glucocorticoids.


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)

Effects of cysteamine in chronic corticosterone-treated mice on TrkB protein levels in the frontal cortex and hippocampus.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. TrkB protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-Actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle and #p<0.05 versus CORT.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198436&req=5

pone-0026153-g005: Effects of cysteamine in chronic corticosterone-treated mice on TrkB protein levels in the frontal cortex and hippocampus.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. TrkB protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-Actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle and #p<0.05 versus CORT.
Mentions: Subsequently, we determined if cysteamine could reverse corticosterone-induced decreases in TrkB protein levels. CD-1 mice were treated for 7 weeks with vehicle or corticosterone in the presence or absence of cysteamine during the last three weeks of corticosterone treatment. In the frontal cortex, two-way ANOVA with corticosterone/vehicle pretreatment and cysteamine/vehicle as main effects indicated significant main effect of pretreatment [(F(1,18) = 34.69; p<0.0001] and treatment [F(1,18) = 26.81; p<0.0001], but without a significant pretreatment x treatment interaction [F(1,18) = 0.3669; p = 0.552]. Post hoc analysis with Bonferroni's multiple comparison test showed that treatment with cysteamine significantly increased TrkB protein levels in frontal cortex (Fig 5A). The increase in TrkB protein levels was observed in both corticosterone (p<0.001) and non-corticosterone treated animals (p<0.05). Similar to frontal cortex, data from hippocampus showed significant main effect of pretreatment [F(1,18) = 40.84; P<0.0001] and treatment [F(1,18) = 88.46; p<0.0001]. No significant effect was found in pretreatment x treatment interaction in hippocampus [F(1,18) = 2.729; p = 0.118]. The reduction in TrkB protein levels in the hippocampus induced by chronic corticosterone was reversed by cysteamine (Fig 5B; p<0.05). We did not find any significant change in truncated TrkB levels following cysteamine treatment in the vehicle or corticosterone treated groups (data not shown). Taken together, these results suggest that chronic cysteamine treatment is effective in reversing the reductions in TrkB protein levels induced by excess glucocorticoids.

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