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Increased orexin expression promotes sleep/wake disturbances in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

Liu R, Sheng ZF, Cai B, Zhang YH, Fan DS - Chin. Med. J. (2015)

Bottom Line: Correlation analysis confirmed moderate to high correlations between sleep/wake time (total sleep time, wakefulness time, rapid eye movement [REM] sleep time, non-REM sleep time, and deep sleep time) and increase in orexins (prepro-orexin, orexin A and B).Increased orexins may promote wakefulness and result in these disturbances before and after disease onset, thus making them potential therapeutic targets for amelioration of sleep disturbances in ALS.Further studies are required to elucidate the underlying mechanisms in the future.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Peking University Third Hospital, Beijing 100191, China.

ABSTRACT

Background: Sleep/wake disturbances in patients with amyotrophic lateral sclerosis (ALS) are well-documented, however, no animal or mechanistic studies on these disturbances exist. Orexin is a crucial neurotransmitter in promoting wakefulness in sleep/wake regulation, and may play an important role in sleep disturbances in ALS. In this study, we used SOD1-G93A transgenic mice as an ALS mouse model to investigate the sleep/wake disturbances and their possible mechanisms in ALS.

Methods: Electroencephalogram/electromyogram recordings were performed in SOD1-G93A transgenic mice and their littermate control mice at the ages of 90 and 120 days, and the samples obtained from these groups were subjected to quantitative reverse transcriptase-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay.

Results: For the first time in SOD1-G93A transgenic mice, we observed significantly increased wakefulness, reduced sleep time, and up-regulated orexins (prepro-orexin, orexin A and B) at both 90 and 120 days. Correlation analysis confirmed moderate to high correlations between sleep/wake time (total sleep time, wakefulness time, rapid eye movement [REM] sleep time, non-REM sleep time, and deep sleep time) and increase in orexins (prepro-orexin, orexin A and B).

Conclusion: Sleep/wake disturbances occur before disease onset in this ALS mouse model. Increased orexins may promote wakefulness and result in these disturbances before and after disease onset, thus making them potential therapeutic targets for amelioration of sleep disturbances in ALS. Further studies are required to elucidate the underlying mechanisms in the future.

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Prepro-orexin increases in SOD1-G93A transgenic mice. (a) Q-PCR was performed in the hypothalamic tissues from the SOD1-G93A transgenic mice and control groups. Prepro-orexin mRNA is significantly elevated in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice, compared to control. (b) Western blotting was performed with antibody anti-orexin-prepro in the SOD1-G93A transgenic mice and control groups. Prepro-orexin expression is increased in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice as compared to control. Data are expressed as mean ± standard error of mean (n = 4–6/group). *P < 0.05 and †P < 0.01. HT: hypothalamus; PCR: Polymerase chain reaction.
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Figure 2: Prepro-orexin increases in SOD1-G93A transgenic mice. (a) Q-PCR was performed in the hypothalamic tissues from the SOD1-G93A transgenic mice and control groups. Prepro-orexin mRNA is significantly elevated in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice, compared to control. (b) Western blotting was performed with antibody anti-orexin-prepro in the SOD1-G93A transgenic mice and control groups. Prepro-orexin expression is increased in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice as compared to control. Data are expressed as mean ± standard error of mean (n = 4–6/group). *P < 0.05 and †P < 0.01. HT: hypothalamus; PCR: Polymerase chain reaction.

Mentions: Next, we evaluated the changes in the orexin system in the SOD1-G93A transgenic mice. First, we tested the level of mRNA and protein expression of prepro-orexin. Q-PCR showed increased levels of prepro-orexin mRNA in the hypothalamus of the 90-day (1.84 ± 0.24 vs. 1.00 ± 0.20, P < 0.05) and 120-day (2.06 ± 0.25 vs. 1.00 ± 0.14, P < 0.01) SOD1-G93A transgenic mice, compared to controls [Figure 2a]. The western blotting analysis also showed increased levels of prepro-orexin protein in the hypothalamus of both 90-day (2.33 ± 0.24 vs. 1.00 ± 0.18, P < 0.01) and 120-day (2.30 ± 0.14 vs. 1.00 ± 0.19, P < 0.01) SOD1-G93A transgenic mice as compared to littermate controls [Figure 2b].


Increased orexin expression promotes sleep/wake disturbances in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

Liu R, Sheng ZF, Cai B, Zhang YH, Fan DS - Chin. Med. J. (2015)

Prepro-orexin increases in SOD1-G93A transgenic mice. (a) Q-PCR was performed in the hypothalamic tissues from the SOD1-G93A transgenic mice and control groups. Prepro-orexin mRNA is significantly elevated in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice, compared to control. (b) Western blotting was performed with antibody anti-orexin-prepro in the SOD1-G93A transgenic mice and control groups. Prepro-orexin expression is increased in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice as compared to control. Data are expressed as mean ± standard error of mean (n = 4–6/group). *P < 0.05 and †P < 0.01. HT: hypothalamus; PCR: Polymerase chain reaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Prepro-orexin increases in SOD1-G93A transgenic mice. (a) Q-PCR was performed in the hypothalamic tissues from the SOD1-G93A transgenic mice and control groups. Prepro-orexin mRNA is significantly elevated in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice, compared to control. (b) Western blotting was performed with antibody anti-orexin-prepro in the SOD1-G93A transgenic mice and control groups. Prepro-orexin expression is increased in the hypothalamus of the 90 and 120 days SOD1-G93A transgenic mice as compared to control. Data are expressed as mean ± standard error of mean (n = 4–6/group). *P < 0.05 and †P < 0.01. HT: hypothalamus; PCR: Polymerase chain reaction.
Mentions: Next, we evaluated the changes in the orexin system in the SOD1-G93A transgenic mice. First, we tested the level of mRNA and protein expression of prepro-orexin. Q-PCR showed increased levels of prepro-orexin mRNA in the hypothalamus of the 90-day (1.84 ± 0.24 vs. 1.00 ± 0.20, P < 0.05) and 120-day (2.06 ± 0.25 vs. 1.00 ± 0.14, P < 0.01) SOD1-G93A transgenic mice, compared to controls [Figure 2a]. The western blotting analysis also showed increased levels of prepro-orexin protein in the hypothalamus of both 90-day (2.33 ± 0.24 vs. 1.00 ± 0.18, P < 0.01) and 120-day (2.30 ± 0.14 vs. 1.00 ± 0.19, P < 0.01) SOD1-G93A transgenic mice as compared to littermate controls [Figure 2b].

Bottom Line: Correlation analysis confirmed moderate to high correlations between sleep/wake time (total sleep time, wakefulness time, rapid eye movement [REM] sleep time, non-REM sleep time, and deep sleep time) and increase in orexins (prepro-orexin, orexin A and B).Increased orexins may promote wakefulness and result in these disturbances before and after disease onset, thus making them potential therapeutic targets for amelioration of sleep disturbances in ALS.Further studies are required to elucidate the underlying mechanisms in the future.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Peking University Third Hospital, Beijing 100191, China.

ABSTRACT

Background: Sleep/wake disturbances in patients with amyotrophic lateral sclerosis (ALS) are well-documented, however, no animal or mechanistic studies on these disturbances exist. Orexin is a crucial neurotransmitter in promoting wakefulness in sleep/wake regulation, and may play an important role in sleep disturbances in ALS. In this study, we used SOD1-G93A transgenic mice as an ALS mouse model to investigate the sleep/wake disturbances and their possible mechanisms in ALS.

Methods: Electroencephalogram/electromyogram recordings were performed in SOD1-G93A transgenic mice and their littermate control mice at the ages of 90 and 120 days, and the samples obtained from these groups were subjected to quantitative reverse transcriptase-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay.

Results: For the first time in SOD1-G93A transgenic mice, we observed significantly increased wakefulness, reduced sleep time, and up-regulated orexins (prepro-orexin, orexin A and B) at both 90 and 120 days. Correlation analysis confirmed moderate to high correlations between sleep/wake time (total sleep time, wakefulness time, rapid eye movement [REM] sleep time, non-REM sleep time, and deep sleep time) and increase in orexins (prepro-orexin, orexin A and B).

Conclusion: Sleep/wake disturbances occur before disease onset in this ALS mouse model. Increased orexins may promote wakefulness and result in these disturbances before and after disease onset, thus making them potential therapeutic targets for amelioration of sleep disturbances in ALS. Further studies are required to elucidate the underlying mechanisms in the future.

Show MeSH
Related in: MedlinePlus