Abstract
Background: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. Methods: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Results: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatoninmediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Conclusions: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.
| Original language | English |
|---|---|
| Pages (from-to) | 1-14 |
| Number of pages | 14 |
| Journal | International Journal of Neuropsychopharmacology |
| Volume | 18 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 01-01-2015 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Psychiatry and Mental health
- Pharmacology (medical)
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Melatonin attenuates memory impairment induced by klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential. / Shin, Eun Joo; Chung, Yoon Hee; Le, Hoang Lan Thi; Jeong, Ji Hoon; Dang, Duy Khanh; Nam, Yunsung; Wie, Myung Bok; Nah, Seung Yeol; Nabeshima, Yo Ichi; Nabeshima, Toshitaka; Kim, Hyoung Chun.
In: International Journal of Neuropsychopharmacology, Vol. 18, No. 6, 01.01.2015, p. 1-14.Research output: Contribution to journal › Article
TY - JOUR
T1 - Melatonin attenuates memory impairment induced by klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential
AU - Shin, Eun Joo
AU - Chung, Yoon Hee
AU - Le, Hoang Lan Thi
AU - Jeong, Ji Hoon
AU - Dang, Duy Khanh
AU - Nam, Yunsung
AU - Wie, Myung Bok
AU - Nah, Seung Yeol
AU - Nabeshima, Yo Ichi
AU - Nabeshima, Toshitaka
AU - Kim, Hyoung Chun
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Background: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. Methods: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Results: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatoninmediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Conclusions: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.
AB - Background: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. Methods: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Results: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatoninmediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Conclusions: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.
UR - http://www.scopus.com/inward/record.url?scp=84939211434&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939211434&partnerID=8YFLogxK
U2 - 10.1093/ijnp/pyu105
DO - 10.1093/ijnp/pyu105
M3 - Article
C2 - 25550330
AN - SCOPUS:84939211434
VL - 18
SP - 1
EP - 14
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
SN - 1461-1457
IS - 6
ER -