Evaluation of differential effects of CDP-choline and choline on parasympathetic activity and changes in choline levels with heart rate variability
Year 2024,
Volume: 37 Issue: 1, 80 - 85, 28.01.2024
Hasan Kazdağlı
,
Şüheda Alpay
,
Hasan Fehmi Özel
,
Elif Barış
Abstract
Objective: Heart rate variability (HRV) is used to evaluate the autonomic activity of heartbeat. This study aimed to investigate the
effects of cholinomimetic drugs cytidine diphosphate-choline (CDP-choline) and choline, on short-term HRV parameters.
Materials and Methods: Animals were randomized into three groups; control (0.9% NaCl), choline (100 mg/kg), CDP-choline (400
mg/kg). Electrocardiography recordings were obtained for 45-minutes after treatments with 15-minutes intervals. HRV analyses and
total choline level measurements in serum and heart tissues were performed.
Results: High frequency power and total power increased in treatment groups, while heart rates were decreased. Low frequency was
decreased with choline while very low frequency power decreased with CDP-choline. Choline affected most of the HRV parameters
in the first 15 minutes, while the effect of CDP-choline started within 30 minutes. Total choline levels were higher in both treatment
groups than in the control while the levels were also higher in the choline group compared to CDP-choline group.
Conclusion: This study showed that CDP-choline and choline treatments produced a rapid response to short-term HRV parameters,
while increasing tissue choline levels. Moreover, the differences in effects and onset time between the drugs on HRV might be related
to tissue choline concentration.
References
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of homeostasis. Mol Cell 2014; 54: 281-88. doi: 10.1016/j.
molcel.2014.03.030.
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interpretation, and clinical use. Task Force of the European
Society of Cardiology and the North American Society of
Pacing and Electrophysiology. Circulation 1996; 93: 1043-65.
doi: 10.1161/01.CIR.93.5.1043.
- Brodal P. The central nervous system : structure and function.
New York: Oxford University Press, 2004; 224-33.
- Parrish W R, Rosas-Ballina M, Gallowitsch-Puerta M, et al.
Modulation of TNF release by choline requires alpha7 subunit
nicotinic acetylcholine receptor-mediated signaling. Mol
Med Camb Mass 2008; 14: 567-74. doi: 10.2119/2008-00079.
Parrish.
- Papke R, Bencherif M, Lippiello P. An evaluation of neuronal
nicotinic acetylcholine receptor activation by quaternary
nitrogen compounds indicates that choline is selective
for the α7 subtype. Neurosci Lett 1996; 213: 201-04. doi:
10.1016/0304-3940(96)12889-5.
- Ulus I H, Millington W R, Buyukuysal R L, Kiran B K. Choline
as an agonist: Determination of its agonistic potency on
cholinergic receptors. Biochem Pharmacol 1988; 37: 2747-55.
doi: 10.1016/0006-2952(88)90037-8.
- Cornell R B, Ridgway N D. CTP: phosphocholine
cytidylyltransferase: Function, Regulation, and Structure of an
amphitropic enzyme required for membrane biogenesis. Prog
Lipid Res 2015; 59: 147-71. doi: 10.1016/j.plipres.2015.07.001.
- Köppen A, Klein J, Holler T, Löffelholz K. Synergistic effect
of nicotinamide and choline administration on extracellular
choline levels in the brain. J Pharmacol Exp Ther 1993; 266:
720-25.
- Savci V, Goktalay G, Cansev M, Cavun S, Yilmaz M S, Ulus I H.
Intravenously injected CDP-choline increases blood pressure
and reverses hypotension in haemorrhagic shock: Effect is
mediated by central cholinergic activation. Eur J Pharmacol
2003; 468: 129-39. doi: 10.1016/S0014-2999(03)01602-9.
- Synoradzki K, Grieb P. Citicoline: A superior form of choline?
Nutrients 2019; 11: 1569. doi: 10.3390/nu11071569.
- Cheng M, Bhujwalla Z M, Glunde K. Targeting phospholipid
metabolism in cancer. Front Oncol 2016; 6: 266. doi: 10.3389/
fonc.2016.00266.
- Grieb P. Neuroprotective properties of citicoline: facts, doubts
and unresolved issues. CNS Drugs 2014; 28: 185-93. doi:
10.1007/s40263.014.0144-8.
- Ottobelli L, Manni G L, Centofanti M, Iester M, Allevena F,
Rossetti L. Citicoline oral solution in glaucoma: is there a role
in slowing disease progression? Ophthalmologica 2013; 229:
219-26. doi: 10.1159/000350496.
- Skripuletz T, Manzel A, Gropengiesser K, et al. Pivotal role of
choline metabolites in remyelination. Brain 2015; 138: 398-13
doi: 10.1093/brain/awu358.
- Bagdas D, Sonat F A, Hamurtekin E, Sonal S, Gurun M S. The
antihyperalgesic effect of cytidine-5′-diphosphate-choline in
neuropathic and inflammatory pain models. Behav Pharmacol
2011; 22: 589-98. doi: 10.1097/FBP.0b013e32834a1efb.
- Sato N, Miyake S, Akatsu J, Kumashiro M. Power spectral
analysis of heart rate variability in healthy young women
during the normal menstrual cycle. Psychosom Med 1995; 57:
331-35. doi: 10.1097/00006.842.199507000-00004.
- Halliwill J R, Billman G E. Effect of general anesthesia on
cardiac vagal tone. Am J Physiol 1992; 262: H1719-24. doi:
10.1152/ajpheart.1992.262.6.H1719.
- Baris E, Simsek O, Efe H, et al. Effects of CDP-Choline and
Choline on COX pathway in LPS-Induced Inflammatory
Response in Rats. Int J Pharmacol 2021; 17: 84-96. doi:
10.3923/ijp.2021.84.96.
- Dempsey R J, Raghavendra Rao V L. Cytidinediphosphocholine
treatment to decrease traumatic brain injury—induced
hippocampal neuronal death, cortical contusion volume, and
neurological dysfunction in rats. J Neurosurg 2003; 98: 867-
73. doi: 10.3171/jns.2003.98.4.0867.
- Ha T H, Oh B, Kang J-O. Electrocardiogram recordings
in anesthetized mice using lead II. J Vis Exp 2020; 20. doi:
10.3791/61583.
- Shaffer F, Ginsberg J P. An Overview of heart rate variability
metrics and norms. Front Public Health 2017; 5: 1-17. doi:
10.3389/fpubh.2017.00258.
- Lin T-T, Sung Y-L, Wu C-E, Zhang H, Liu Y-B, Lin
S-H. Proarrhythmic risk and determinants of cardiac
autonomic dysfunction in collagen-induced arthritis rats.
BMC Musculoskelet Disord 2016; 17: 1-8. doi: 10.1186/
s12891.016.1347-6.
- Kamen P W, Krum H, Tonkin A M. Poincaré plot of heart
rate variability allows quantitative display of parasympathetic
nervous activity in humans. Clin Sci Lond Engl 1996; 91: 201-
8. doi: 10.1042/cs0910201.
- Lippman N, Stein K M, Lerman B B. Comparison of
methods for removal of ectopy in measurement of heart rate
variability. Am J Physiol 1994; 267: H411-8. doi: 10.1152/
ajpheart.1994.267.1.H411.
- Kazdağlı H, Özel H F, Özbek M, Alpay Ş, Alenbey M. Classical
heart rate variability and nonlinear heart rate analysis in mice
under napentobarbital and ketamine/xylazine anesthesia. Turk
J Med Sci 2022; 52: 858-69. doi: 10.55730/1300-0144.5383.
- Kocaturk M, Yilmaz Z, Cansev M, et al. Choline or CDPcholine
restores hypotension and improves myocardial and
respiratory functions in dogs with experimentally – Induced
endotoxic shock. Res Vet Sci 2021; 141: 116-28. doi: 10.1016/j.
rvsc.2021.10.010.
- Adibhatla R M, Hatcher J F. Cytidine 5’-diphosphocholine
(CDP-choline) in stroke and other CNS disorders. Neurochem
Res 2005; 30: 15-23. doi: 10.1007/s11064.004.9681-8.
[28] Scremin O U, Li M G, Roch M, Booth R, Jenden D J.
Acetylcholine and choline dynamics provide early and late
markers of traumatic brain injury. Brain Res 2006; 1124: 155-
66. doi: 10.1016/j.brainres.2006.09.062.
- Başkaya M K, Dogan A, Rao A M, Dempsey R J. Neuroprotective
effects of citicoline on brain edema and blood-brain barrier
breakdown after traumatic brain injury. J Neurosurg 2000; 92:
448-52. doi: 10.3171/jns.2000.92.3.0448.
- Javaid S, Farooq T, Rehman Z, et al. Dynamics of cholinecontaining
phospholipids in traumatic brain injury and
associated comorbidities. Int J Mol Sci 2021; 22: 11313. doi:
10.3390/ijms222111313.
- Cansev M, Yilmaz M S, Ilcol Y O, Hamurtekin E, Ulus I H.
Cardiovascular effects of CDP-choline and its metabolites:
Involvement of peripheral autonomic nervous system. Eur J
Pharmacol 2007; 577: 129-42. doi: https://doi.org/10.1016/j.
ejphar.2007.08.029.
- Ilcol Y O, Gurun M S, Taga Y, Ulus I H. Choline increases
serum insulin in rat when injected intraperitoneally and
augments basal and stimulated aceylcholine release from the
rat minced pancreas in vitro. Eur J Biochem 2003; 270: 991-99.
doi: 10.1046/j.1432-1033.2003.03472.x.
Year 2024,
Volume: 37 Issue: 1, 80 - 85, 28.01.2024
Hasan Kazdağlı
,
Şüheda Alpay
,
Hasan Fehmi Özel
,
Elif Barış
References
- Chovatiya R, Medzhitov R. Stress, inflammation, and defense
of homeostasis. Mol Cell 2014; 54: 281-88. doi: 10.1016/j.
molcel.2014.03.030.
- Heart rate variability: Standards of measurement, physiological
interpretation, and clinical use. Task Force of the European
Society of Cardiology and the North American Society of
Pacing and Electrophysiology. Circulation 1996; 93: 1043-65.
doi: 10.1161/01.CIR.93.5.1043.
- Brodal P. The central nervous system : structure and function.
New York: Oxford University Press, 2004; 224-33.
- Parrish W R, Rosas-Ballina M, Gallowitsch-Puerta M, et al.
Modulation of TNF release by choline requires alpha7 subunit
nicotinic acetylcholine receptor-mediated signaling. Mol
Med Camb Mass 2008; 14: 567-74. doi: 10.2119/2008-00079.
Parrish.
- Papke R, Bencherif M, Lippiello P. An evaluation of neuronal
nicotinic acetylcholine receptor activation by quaternary
nitrogen compounds indicates that choline is selective
for the α7 subtype. Neurosci Lett 1996; 213: 201-04. doi:
10.1016/0304-3940(96)12889-5.
- Ulus I H, Millington W R, Buyukuysal R L, Kiran B K. Choline
as an agonist: Determination of its agonistic potency on
cholinergic receptors. Biochem Pharmacol 1988; 37: 2747-55.
doi: 10.1016/0006-2952(88)90037-8.
- Cornell R B, Ridgway N D. CTP: phosphocholine
cytidylyltransferase: Function, Regulation, and Structure of an
amphitropic enzyme required for membrane biogenesis. Prog
Lipid Res 2015; 59: 147-71. doi: 10.1016/j.plipres.2015.07.001.
- Köppen A, Klein J, Holler T, Löffelholz K. Synergistic effect
of nicotinamide and choline administration on extracellular
choline levels in the brain. J Pharmacol Exp Ther 1993; 266:
720-25.
- Savci V, Goktalay G, Cansev M, Cavun S, Yilmaz M S, Ulus I H.
Intravenously injected CDP-choline increases blood pressure
and reverses hypotension in haemorrhagic shock: Effect is
mediated by central cholinergic activation. Eur J Pharmacol
2003; 468: 129-39. doi: 10.1016/S0014-2999(03)01602-9.
- Synoradzki K, Grieb P. Citicoline: A superior form of choline?
Nutrients 2019; 11: 1569. doi: 10.3390/nu11071569.
- Cheng M, Bhujwalla Z M, Glunde K. Targeting phospholipid
metabolism in cancer. Front Oncol 2016; 6: 266. doi: 10.3389/
fonc.2016.00266.
- Grieb P. Neuroprotective properties of citicoline: facts, doubts
and unresolved issues. CNS Drugs 2014; 28: 185-93. doi:
10.1007/s40263.014.0144-8.
- Ottobelli L, Manni G L, Centofanti M, Iester M, Allevena F,
Rossetti L. Citicoline oral solution in glaucoma: is there a role
in slowing disease progression? Ophthalmologica 2013; 229:
219-26. doi: 10.1159/000350496.
- Skripuletz T, Manzel A, Gropengiesser K, et al. Pivotal role of
choline metabolites in remyelination. Brain 2015; 138: 398-13
doi: 10.1093/brain/awu358.
- Bagdas D, Sonat F A, Hamurtekin E, Sonal S, Gurun M S. The
antihyperalgesic effect of cytidine-5′-diphosphate-choline in
neuropathic and inflammatory pain models. Behav Pharmacol
2011; 22: 589-98. doi: 10.1097/FBP.0b013e32834a1efb.
- Sato N, Miyake S, Akatsu J, Kumashiro M. Power spectral
analysis of heart rate variability in healthy young women
during the normal menstrual cycle. Psychosom Med 1995; 57:
331-35. doi: 10.1097/00006.842.199507000-00004.
- Halliwill J R, Billman G E. Effect of general anesthesia on
cardiac vagal tone. Am J Physiol 1992; 262: H1719-24. doi:
10.1152/ajpheart.1992.262.6.H1719.
- Baris E, Simsek O, Efe H, et al. Effects of CDP-Choline and
Choline on COX pathway in LPS-Induced Inflammatory
Response in Rats. Int J Pharmacol 2021; 17: 84-96. doi:
10.3923/ijp.2021.84.96.
- Dempsey R J, Raghavendra Rao V L. Cytidinediphosphocholine
treatment to decrease traumatic brain injury—induced
hippocampal neuronal death, cortical contusion volume, and
neurological dysfunction in rats. J Neurosurg 2003; 98: 867-
73. doi: 10.3171/jns.2003.98.4.0867.
- Ha T H, Oh B, Kang J-O. Electrocardiogram recordings
in anesthetized mice using lead II. J Vis Exp 2020; 20. doi:
10.3791/61583.
- Shaffer F, Ginsberg J P. An Overview of heart rate variability
metrics and norms. Front Public Health 2017; 5: 1-17. doi:
10.3389/fpubh.2017.00258.
- Lin T-T, Sung Y-L, Wu C-E, Zhang H, Liu Y-B, Lin
S-H. Proarrhythmic risk and determinants of cardiac
autonomic dysfunction in collagen-induced arthritis rats.
BMC Musculoskelet Disord 2016; 17: 1-8. doi: 10.1186/
s12891.016.1347-6.
- Kamen P W, Krum H, Tonkin A M. Poincaré plot of heart
rate variability allows quantitative display of parasympathetic
nervous activity in humans. Clin Sci Lond Engl 1996; 91: 201-
8. doi: 10.1042/cs0910201.
- Lippman N, Stein K M, Lerman B B. Comparison of
methods for removal of ectopy in measurement of heart rate
variability. Am J Physiol 1994; 267: H411-8. doi: 10.1152/
ajpheart.1994.267.1.H411.
- Kazdağlı H, Özel H F, Özbek M, Alpay Ş, Alenbey M. Classical
heart rate variability and nonlinear heart rate analysis in mice
under napentobarbital and ketamine/xylazine anesthesia. Turk
J Med Sci 2022; 52: 858-69. doi: 10.55730/1300-0144.5383.
- Kocaturk M, Yilmaz Z, Cansev M, et al. Choline or CDPcholine
restores hypotension and improves myocardial and
respiratory functions in dogs with experimentally – Induced
endotoxic shock. Res Vet Sci 2021; 141: 116-28. doi: 10.1016/j.
rvsc.2021.10.010.
- Adibhatla R M, Hatcher J F. Cytidine 5’-diphosphocholine
(CDP-choline) in stroke and other CNS disorders. Neurochem
Res 2005; 30: 15-23. doi: 10.1007/s11064.004.9681-8.
[28] Scremin O U, Li M G, Roch M, Booth R, Jenden D J.
Acetylcholine and choline dynamics provide early and late
markers of traumatic brain injury. Brain Res 2006; 1124: 155-
66. doi: 10.1016/j.brainres.2006.09.062.
- Başkaya M K, Dogan A, Rao A M, Dempsey R J. Neuroprotective
effects of citicoline on brain edema and blood-brain barrier
breakdown after traumatic brain injury. J Neurosurg 2000; 92:
448-52. doi: 10.3171/jns.2000.92.3.0448.
- Javaid S, Farooq T, Rehman Z, et al. Dynamics of cholinecontaining
phospholipids in traumatic brain injury and
associated comorbidities. Int J Mol Sci 2021; 22: 11313. doi:
10.3390/ijms222111313.
- Cansev M, Yilmaz M S, Ilcol Y O, Hamurtekin E, Ulus I H.
Cardiovascular effects of CDP-choline and its metabolites:
Involvement of peripheral autonomic nervous system. Eur J
Pharmacol 2007; 577: 129-42. doi: https://doi.org/10.1016/j.
ejphar.2007.08.029.
- Ilcol Y O, Gurun M S, Taga Y, Ulus I H. Choline increases
serum insulin in rat when injected intraperitoneally and
augments basal and stimulated aceylcholine release from the
rat minced pancreas in vitro. Eur J Biochem 2003; 270: 991-99.
doi: 10.1046/j.1432-1033.2003.03472.x.