Circadian System Functionality, Hippocampal Oxidative Stress, and Spatial Memory in the APPswe/PS1dE9 Transgenic Model of Alzheimer Disease: Effects of Melatonin or Ramelteon

被引:40
作者
Bano Otalora, Beatriz [1 ]
Popovic, Natalija [2 ]
Gambini, Juan [3 ]
Popovic, Miroljub [2 ]
Vina, Jose [3 ]
Bonet-Costa, Vicent [3 ]
Reiter, Russel J. [4 ]
Javier Camello, Pedro [5 ]
Angeles Rol, Maria [1 ]
Antonio Madrid, Juan [1 ]
机构
[1] Univ Murcia, Fac Biol, Dept Physiol, E-30100 Murcia, Spain
[2] Univ Murcia, Fac Med, Dept Human Anat & Psychobiol, Murcia, Spain
[3] Univ Valencia, Fac Med, Dept Philosophy, Valencia, Spain
[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA
[5] Univ Extremadura, Sch Nursing, Dept Physiol, Caceres, Spain
关键词
Alzheimer disease; Body temperature rhythm; Circadian system; Hippocampus; Melatonin; Oxidative stress; Ramelteon; Spatial memory; AMYLOID PRECURSOR PROTEIN; MT1/MT2 RECEPTOR AGONIST; MOUSE MODEL; LOCOMOTOR-ACTIVITY; EXOGENOUS MELATONIN; RHYTHM DISTURBANCES; OBJECT RECOGNITION; MICE; DEFICITS; TAK-375;
D O I
10.3109/07420528.2012.699119
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes beta-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (tau) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24 h. Whereas melatonin maintained t at 24 h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswe/PS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD. (Author correspondence: jamadrid@um.es)
引用
收藏
页码:822 / 834
页数:13
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