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Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate-induced seizures
被引:7
|作者:
Park, Jung Hoon
[1
]
Hwang, Yeonggwang
[1
]
Nguyen, Yen Nhi Doan
[1
]
Kim, Hyoung-Chun
[1
,2
]
Shin, Eun-Joo
[1
,2
]
机构:
[1] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon, South Korea
[2] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 24341, South Korea
基金:
新加坡国家研究基金会;
关键词:
astroglial phenotype;
kainate;
melatonin receptors;
neuroinflammation;
ramelteon;
TEMPORAL-LOBE EPILEPSY;
KAINIC ACID;
OXIDATIVE STRESS;
MELATONIN RECEPTORS;
STATUS EPILEPTICUS;
IN-VIVO;
INFLAMMATORY RESPONSE;
ALZHEIMERS-DISEASE;
LIPID-PEROXIDATION;
RAT HIPPOCAMPUS;
D O I:
10.1111/jpi.12921
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Evidence suggests that the neuroprotective effects of melatonin involve both receptor-dependent and -independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post-KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression-like behaviors following KA-induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 mu g/mu L) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA-induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA-induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor kappa B (NF kappa B) induced by KA. Consequently, ramelteon attenuated the KA-induced hippocampal neuronal loss, memory impairment, and depression-like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon-mediated activation of melatonin receptors provides neuroprotection against KA-induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NF kappa B signaling to attenuate neuroinflammatory changes.
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页数:25
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