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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 24 h after injection of OT or LOT-1. (A) Representative traces show movement tracks of the 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 intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight), one day (24 h) prior to the behavioral experiments; (B) Time spent in the inside zone measured over 20 min in CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice in each experimental group is shown in parentheses. One-way ANOVA for drugs: F2,12 = 27.05, P < 0.0001. Bonferroni’s post hoc test indicated between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), and OT and LOT-1 (P = 0.018).
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brainsci-05-00003-f003: Anxiety and social preference tests 24 h after injection of OT or LOT-1. (A) Representative traces show movement tracks of the 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 intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight), one day (24 h) prior to the behavioral experiments; (B) Time spent in the inside zone measured over 20 min in CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice in each experimental group is shown in parentheses. One-way ANOVA for drugs: F2,12 = 27.05, P < 0.0001. Bonferroni’s post hoc test indicated between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), and OT and LOT-1 (P = 0.018).

Mentions: To determine whether this anti-anxiety effect of OT and/or LOT-1 in CD157−/− mice has long-lasting effects (Figure 3A), we tested the time-dependency of the effects on both parameters in the inside zone 24 h after treatment (Figure 3). Interestingly, LOT-1 treatment retained the rescue effect to a greater extent than OT (one-way ANOVA, F2,12 = 27.05, P = 0.0000). As shown in Figure 3B, Bonferroni’s post hoc test indicated significant differences between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), or OT and LOT-1 (P = 0.018) (n = 5 per group).


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 24 h after injection of OT or LOT-1. (A) Representative traces show movement tracks of the 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 intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight), one day (24 h) prior to the behavioral experiments; (B) Time spent in the inside zone measured over 20 min in CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice in each experimental group is shown in parentheses. One-way ANOVA for drugs: F2,12 = 27.05, P < 0.0001. Bonferroni’s post hoc test indicated between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), and OT and LOT-1 (P = 0.018).
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Related In: Results  -  Collection

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brainsci-05-00003-f003: Anxiety and social preference tests 24 h after injection of OT or LOT-1. (A) Representative traces show movement tracks of the 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 intraperitoneal injection of phosphate buffered saline (PBS), OT (100 ng/kg of body weight), or LOT-1 (100 ng/kg of body weight), one day (24 h) prior to the behavioral experiments; (B) Time spent in the inside zone measured over 20 min in CD157−/− mice with different treatments. The data are expressed as the means ± s.e.m. The number of mice in each experimental group is shown in parentheses. One-way ANOVA for drugs: F2,12 = 27.05, P < 0.0001. Bonferroni’s post hoc test indicated between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), and OT and LOT-1 (P = 0.018).
Mentions: To determine whether this anti-anxiety effect of OT and/or LOT-1 in CD157−/− mice has long-lasting effects (Figure 3A), we tested the time-dependency of the effects on both parameters in the inside zone 24 h after treatment (Figure 3). Interestingly, LOT-1 treatment retained the rescue effect to a greater extent than OT (one-way ANOVA, F2,12 = 27.05, P = 0.0000). As shown in Figure 3B, Bonferroni’s post hoc test indicated significant differences between PBS and OT (P = 0.0000), PBS and LOT-1 (P = 0.005), or OT and LOT-1 (P = 0.018) (n = 5 per group).

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