Effects of Citicoline Administration on Synaptic Proteins in Rapid Eye Movement Sleep-deprived Rats

Overview

Journal Iran J Basic Med Sci

Publisher Mashhad University of Medical Sciences

Specialty General Medicine

Date 2022 Aug 1

PMID 35911643

Authors

Aysen Cakir

Busra Ocalan

Cansu Cansu

Guldal Gulec Suyen

Mehmet Cansev

Nevzat Kahveci

Affiliations

Soon will be listed here.

Abstract

Objectives: Sleep has a pivotal role in learning-memory and sleep deprivation (SD) negatively affects synaptic functioning. Cytidine-5-diphosphocholine (Citicoline) has been known to improve learning and memory functions. Our objective was to explore the effects of Citicoline on hippocampal and cortical synaptic proteins in rapid eye movement (REM) sleep-deprived rats.

Materials And Methods: Rats (n=36) were randomly divided into 6 groups. Environmental control or sleep deprivation was done by placing the rat on a 13 cm diameter platform (Large Platform [LP] group) or on a 6.5 cm diameter platform (REMSD group), respectively, for 96 hours. Rats randomized for controls (Home Cage [HC] group) were followed up in home cages. Rats in each of the REMSD, LP or HC group were randomized to receive either saline (0,9%NaCl) or Citicoline (600 μmol/kg) intraperitoneally twice a day for four days. After the experiments, rats were sacrificed; their cerebral cortices and hippocampi were dissected for analyzing the levels of pre-synaptic proteins synaptophysin and synapsin I, and the post-synaptic density protein-95 (PSD-95) by Western-blotting.

Results: Hippocampal levels of PSD-95, but not the pre-synaptic proteins, were reduced by REM sleep deprivation. Citicoline treatment ameliorated the reduction in PSD-95 levels in REM sleep-deprived rats. On the other hand, REM sleep deprivation was not found to be significantly effective on pre- or post-synaptic proteins in cerebral cortex.

Conclusion: REM sleep deprivation reduces hippocampal PSD-95 levels which are enhanced by Citicoline treatment. These data propose that Citicoline may ameliorate the adverse effects of SD on hippocampal synaptic functioning.

References

Lopez-Coviella I, Agut J, Savci V, Ortiz J, Wurtman R . Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels. J Neurochem. 1995; 65(2):889-94. DOI: 10.1046/j.1471-4159.1995.65020889.x. View

Secades J . Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol. 2017; 63(S03):S1-S73. View

Dumoulin Bridi M, Aton S, Seibt J, Renouard L, Coleman T, Frank M . Rapid eye movement sleep promotes cortical plasticity in the developing brain. Sci Adv. 2015; 1(6):e1500105. PMC: 4646776. DOI: 10.1126/sciadv.1500105. View

Ilcol Y, Cansev M, Yilmaz M, Hamurtekin E, Ulus I . Intraperitoneal administration of CDP-choline and its cholinergic and pyrimidinergic metabolites induce hyperglycemia in rats: involvement of the sympathoadrenal system. Arch Physiol Biochem. 2007; 113(4-5):186-201. DOI: 10.1080/13813450701531243. View

Prince T, Abel T . The impact of sleep loss on hippocampal function. Learn Mem. 2013; 20(10):558-69. PMC: 3768199. DOI: 10.1101/lm.031674.113. View

Cansev M, Marzloff G, Sakamoto T, Ulus I, Wurtman R . Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009; 31(3):181-92. DOI: 10.1159/000193394. View

Sheng M, Kim E . The postsynaptic organization of synapses. Cold Spring Harb Perspect Biol. 2011; 3(12). PMC: 3225953. DOI: 10.1101/cshperspect.a005678. View

Wurtman R, Ulus I, Cansev M, Watkins C, Wang L, Marzloff G . Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006; 1088(1):83-92. DOI: 10.1016/j.brainres.2006.03.019. View

Gundogdu E, Bekar A, Turkyilmaz M, Gumus A, Kafa I, Cansev M . CDP-choline modulates matrix metalloproteinases in rat sciatic injury. J Surg Res. 2015; 200(2):655-63. DOI: 10.1016/j.jss.2015.10.003. View

10.

Chi P, Greengard P, Ryan T . Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Neuron. 2003; 38(1):69-78. DOI: 10.1016/s0896-6273(03)00151-x. View

11.

Kennedy E, Weiss S . The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem. 1956; 222(1):193-214. View

12.

Cansev M, Ozarda Ilcol Y, Yilmaz M, Hamurtekin E, Ulus I . Choline, CDP-choline or phosphocholine increases plasma glucagon in rats: involvement of the peripheral autonomic nervous system. Eur J Pharmacol. 2008; 589(1-3):315-22. DOI: 10.1016/j.ejphar.2008.05.017. View

13.

Johnson O, Ouimet C . A regulatory role for actin in dendritic spine proliferation. Brain Res. 2006; 1113(1):1-9. DOI: 10.1016/j.brainres.2006.06.116. View

14.

Sultan F, Day J . Epigenetic mechanisms in memory and synaptic function. Epigenomics. 2011; 3(2):157-81. PMC: 3350307. DOI: 10.2217/epi.11.6. View

15.

Sakamoto T, Cansev M, Wurtman R . Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007; 1182:50-9. PMC: 2140951. DOI: 10.1016/j.brainres.2007.08.089. View

16.

Park H, Kang W, Paik J, Kim J . Effect of valproic acid through regulation of NMDA receptor-ERK signaling in sleep deprivation rats. J Mol Neurosci. 2011; 47(3):554-8. DOI: 10.1007/s12031-011-9673-5. View

17.

Youngblood B, Zhou J, Smagin G, Ryan D, Harris R . Sleep deprivation by the "flower pot" technique and spatial reference memory. Physiol Behav. 1997; 61(2):249-56. DOI: 10.1016/s0031-9384(96)00363-0. View

18.

Tarsa L, Goda Y . Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A. 2002; 99(2):1012-6. PMC: 117422. DOI: 10.1073/pnas.022575999. View

19.

Evans G, Cousin M . Tyrosine phosphorylation of synaptophysin in synaptic vesicle recycling. Biochem Soc Trans. 2005; 33(Pt 6):1350-3. PMC: 2077014. DOI: 10.1042/BST0331350. View

20.

Guzman-Marin R, Ying Z, Suntsova N, Methippara M, Bashir T, Szymusiak R . Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats. J Physiol. 2006; 575(Pt 3):807-19. PMC: 1995680. DOI: 10.1113/jphysiol.2006.115287. View