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Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.

Mizuno A, Cherepanov SM, Kikuchi Y, Fakhrul AA, Akther S, Deguchi K, Yoshihara T, Ishihara K, Shuto S, Higashida H - Brain Sci (2015)

Bottom Line: To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug.To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease.The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. nrh23255@gmail.com.

ABSTRACT
Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Anxiety and social preference tests 30 min after injection of OT or LOT-1. (A) Representative traces show movement tracks of the CD157+/+ and CD157−/− mice over a 20-min period in the social-interaction test in the open field with the social target in the center. Adult male mice were treated with or without intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight) 30 min prior the behavioral experiments. A male mouse as a social target was placed in the center immediately after a 10-min habituation period; (B) Time spent in the inside zone measured over 20 min in CD157+/+ and CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice is in each experimental group is shown in parentheses. One-way ANOVA in one genotype: for CD157+/+ mice (2B, left), F3,14 = 1.01, P < 0.4188; for CD157−/− mice (2B, right), respectively. Two-way ANOVA for genotypes (CD157+/+ and CD157−/−) and drugs (PBS/OT/LOT-1): F3,37 = 9.22, P < 0.0002.
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brainsci-05-00003-f002: Anxiety and social preference tests 30 min after injection of OT or LOT-1. (A) Representative traces show movement tracks of the CD157+/+ and CD157−/− mice over a 20-min period in the social-interaction test in the open field with the social target in the center. Adult male mice were treated with or without intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight) 30 min prior the behavioral experiments. A male mouse as a social target was placed in the center immediately after a 10-min habituation period; (B) Time spent in the inside zone measured over 20 min in CD157+/+ and CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice is in each experimental group is shown in parentheses. One-way ANOVA in one genotype: for CD157+/+ mice (2B, left), F3,14 = 1.01, P < 0.4188; for CD157−/− mice (2B, right), respectively. Two-way ANOVA for genotypes (CD157+/+ and CD157−/−) and drugs (PBS/OT/LOT-1): F3,37 = 9.22, P < 0.0002.

Mentions: When mice were exposed to the novel environment in the open-field apparatus with a social target (a male mouse) in the center, judging from the observed tracks traveled, CD157−/− male mice engaged in less exploratory behavior, particularly in the inside zone, than CD157+/+ males, as shown in representative traces (Figure 2A, top). This suggests that CD157−/− mice displayed anxiety-like behavior and social avoidance behavior, while CD157+/+ mice showed intensive interaction with the target mouse. This behavioral feature was unchanged 30 min after intraperitoneal injection of saline (PBS) in both genotypes (Figure 2A, second row). A marked change was elicited by intraperitoneal OT injection (100 ng/kg body weight) in CD157−/− mice, but no change was observed in CD157+/+ mice (Figure 2A, third row). Injection of LOT-1 (100 ng/kg body weight) resulted in essentially similar recovery from social impairment, while no additional or specific effect was induced by LOT-1 in CD157+/+ mice (Figure 2A, bottom). One-way ANOVA revealed no significant difference in CD157+/+ mice (n = 4–5, F3,14 = 1.01, P = 0.4188) but a significant difference in CD157−/− mice (n = 4–6, F3,15 = 54.14, P = 0.0000) (Figure 2B). Bonferroni’s post hoc tests in CD157−/− mice indicated P = 0.0000 between both non- or saline-treated controls and OT; P = 0.0000 between both controls and LOT-1; and P = 0.019 between OT- and LOT-1-treated mice. Two-way ANOVA analysis for genotypes and drugs resulted in F37,128 = 9.22, P = 0.0002. The results indicated that the synthetic analog, LOT-1, had a significant effect on recovery of social behavior, but the effect seems to be lower than that of native OT at the 30-min time point after treatment.


Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.

Mizuno A, Cherepanov SM, Kikuchi Y, Fakhrul AA, Akther S, Deguchi K, Yoshihara T, Ishihara K, Shuto S, Higashida H - Brain Sci (2015)

Anxiety and social preference tests 30 min after injection of OT or LOT-1. (A) Representative traces show movement tracks of the CD157+/+ and CD157−/− mice over a 20-min period in the social-interaction test in the open field with the social target in the center. Adult male mice were treated with or without intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight) 30 min prior the behavioral experiments. A male mouse as a social target was placed in the center immediately after a 10-min habituation period; (B) Time spent in the inside zone measured over 20 min in CD157+/+ and CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice is in each experimental group is shown in parentheses. One-way ANOVA in one genotype: for CD157+/+ mice (2B, left), F3,14 = 1.01, P < 0.4188; for CD157−/− mice (2B, right), respectively. Two-way ANOVA for genotypes (CD157+/+ and CD157−/−) and drugs (PBS/OT/LOT-1): F3,37 = 9.22, P < 0.0002.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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brainsci-05-00003-f002: Anxiety and social preference tests 30 min after injection of OT or LOT-1. (A) Representative traces show movement tracks of the CD157+/+ and CD157−/− mice over a 20-min period in the social-interaction test in the open field with the social target in the center. Adult male mice were treated with or without intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight) 30 min prior the behavioral experiments. A male mouse as a social target was placed in the center immediately after a 10-min habituation period; (B) Time spent in the inside zone measured over 20 min in CD157+/+ and CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice is in each experimental group is shown in parentheses. One-way ANOVA in one genotype: for CD157+/+ mice (2B, left), F3,14 = 1.01, P < 0.4188; for CD157−/− mice (2B, right), respectively. Two-way ANOVA for genotypes (CD157+/+ and CD157−/−) and drugs (PBS/OT/LOT-1): F3,37 = 9.22, P < 0.0002.
Mentions: When mice were exposed to the novel environment in the open-field apparatus with a social target (a male mouse) in the center, judging from the observed tracks traveled, CD157−/− male mice engaged in less exploratory behavior, particularly in the inside zone, than CD157+/+ males, as shown in representative traces (Figure 2A, top). This suggests that CD157−/− mice displayed anxiety-like behavior and social avoidance behavior, while CD157+/+ mice showed intensive interaction with the target mouse. This behavioral feature was unchanged 30 min after intraperitoneal injection of saline (PBS) in both genotypes (Figure 2A, second row). A marked change was elicited by intraperitoneal OT injection (100 ng/kg body weight) in CD157−/− mice, but no change was observed in CD157+/+ mice (Figure 2A, third row). Injection of LOT-1 (100 ng/kg body weight) resulted in essentially similar recovery from social impairment, while no additional or specific effect was induced by LOT-1 in CD157+/+ mice (Figure 2A, bottom). One-way ANOVA revealed no significant difference in CD157+/+ mice (n = 4–5, F3,14 = 1.01, P = 0.4188) but a significant difference in CD157−/− mice (n = 4–6, F3,15 = 54.14, P = 0.0000) (Figure 2B). Bonferroni’s post hoc tests in CD157−/− mice indicated P = 0.0000 between both non- or saline-treated controls and OT; P = 0.0000 between both controls and LOT-1; and P = 0.019 between OT- and LOT-1-treated mice. Two-way ANOVA analysis for genotypes and drugs resulted in F37,128 = 9.22, P = 0.0002. The results indicated that the synthetic analog, LOT-1, had a significant effect on recovery of social behavior, but the effect seems to be lower than that of native OT at the 30-min time point after treatment.

Bottom Line: To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug.To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease.The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. nrh23255@gmail.com.

ABSTRACT
Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

No MeSH data available.


Related in: MedlinePlus