|Year : 2017 | Volume
| Issue : 4 | Page : 163-167
Interictal ceramide kinase in migraine
Manal H Maabady1, Ghada S Abdelazim1, Asmaa El Madbouly2
1 Department of Neurology, Al-Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Al-Azhar University, Cairo, Egypt
|Date of Submission||23-May-2017|
|Date of Acceptance||27-Feb-2018|
|Date of Web Publication||19-Jul-2018|
Ghada S Abdelazim
Neurology, Lecturer, Department of Neurology, Al-Azhar University, Cairo
Source of Support: None, Conflict of Interest: None
Introduction Migraine is a common neurologic disorder. It is still controversial whether migraine is a primarily vascular disorder or caused by neuronal dysfunction, but it is likely that both have a significant role to play.
Objective The objective of this study was to evaluate serum levels of interictal ceramide kinase in patients with migraine.
Patients and methods A total of 35 patients with migraine, including 12 patients with migraine with aura and 23 patients with migraine without aura, and 16 apparently healthy, age-matched and sex-matched individuals were included in this study. Patients underwent full history taking, including type of headache, frequency of headache attacks per month, and assessment of migraine-related disability by the Migraine Disability Assessment Scale. Serum ceramide kinase level was evaluated for both patients (during pain-free period) and control participants using quantitative sandwich enzyme-linked immunosorbent assay.
Results The patients with migraine had significantly higher serum levels of ceramide kinase than the control group, and these levels were significantly correlated with the frequency of the attacks and with scores of Migraine Disability Assessment Scale.
Conclusion The results suggested that migraine is associated with alteration in sphingolipid metabolism and that might be because of increased levels of ceramide kinase.
Keywords: ceramide kinase, migraine, sphingolipids
|How to cite this article:|
Maabady MH, Abdelazim GS, El Madbouly A. Interictal ceramide kinase in migraine. Al-Azhar Assiut Med J 2017;15:163-7
| Introduction|| |
Although the full pathophysiology of migraine is not known, current theories suggest that migraine is largely an inherited brain disorder associated with a sterile, neurogenic inflammation and alterations in neuronal excitability and the cerebrovasculature ,. Several lines of evidence also indicate that migraineurs have a greater risk of stroke and disorders related to lipid metabolism, including hypercholesterolemia, impaired insulin sensitivity, and obesity ,,,.
Sphingolipids (e.g. sphingomyelins and ceramides) are a group of bioactive lipids that are critical components of membrane microdomains ,. In addition to important structural roles, these lipids function as second messengers in a multitude of cellular processes regulating energy homeostasis, apoptosis, and inflammation ,,.
Recent human research suggests that even subtle changes of sphingolipid balance may be involved in neurologic disorders (e.g. dementia and multiple sclerosis) and obesity ,,,. Furthermore, emerging basic science evidence suggests that sphingolipids may participate in neuronal functions and signaling pathways associated with pain ,.
Ceramides are important lipid mediators that serve as signaling molecules capable of regulating multiple cellular functions, including apoptosis, atherosclerosis, insulin resistance, and inflammation ,. Ceramides are phosphorylated by the enzyme ceramide kinase (CERK) to form ceramide-1-phosphate (C1P). CERK was first observed in brain synaptic vesicles and found to be highly expressed in brain, heart, skeletal muscles, and liver .
Maintenance of equilibrium between ceramide and C1P seems to be crucial for cell and tissue homeostasis and accumulation of one or the other results in metabolic dysfunction and disease .
In a recent study, total ceramide and dihydroceramide (DHC) levels were decreased in those with episodic migraine as compared with controls. Low total ceramide and DHC might be because of an increase in CERK activity in those with migraine .
In this study, we tried to test the hypothesis of increased CERK levels in patients with migraines.
| Patients and methods|| |
A total of 51 patients participated in this study. There were 35 patients with migraine, aged from 20 to 50 years, who were divided into two subgroups: those with migraine with aura (12 patients), and those with migraine without aura (23 patients). They were recruited from the neurology outpatient clinic of Al Zahraa University Hospital. Moreover, 16 apparently healthy individuals were included who served as a control group; they were age-matched and sex-matched with the patient group the study was approved from the ethical committee of faculty of medicine, Al Azhar University.
This is a case–control (comparative) study.
Patients were diagnosed according to the Headache Classification Committee of the International Headache Society diagnostic criteria .
Participants with diabetes; chronic immune or inflammatory disorders; thyroid, renal, or cerebrovascular diseases; and chronic pain other than migraine were excluded.
Patients underwent full history taking including type of headache, frequency of headache attacks per month, and assessment of migraine-related disability by the Migraine Disability Assessment Scale (MiDAS) .
Migraine Disability Assessment Scale
It consisted of seven questions referring to the effect of migraine in three activity domains: work/school, housework, and social and leisure activities, all these are evaluated for the preceding 3 months. To assess the severity and degree of disability caused by migraine, the Migraine Disability Assessment Scale was applied:
- 0–5: little or no disability.
- 6–10: mild disability.
- 11–20: moderate disability.
- ≥21: severe disability.
Complete blood picture (Sysmex Kx21N; Sysmex, Kobe, Japan), blood glucose level, liver and kidney functions, and lipid profile, including total cholesterol, low-density lipoproteins, high-density lipoproteins and triglycerides were performed for all participants using Cobas C-311 Autoanalyser (Roche, Mannheim, Germany).
Measurement of serum levels of ceramide kinase enzyme
During the pain-free period for patients, venous blood samples were collected in a serum separator tube. The sample was allowed to clot for two hours at room temperature, and the serum was separated by centrifugation at 1000g for 15 min and stored in aliquot at −20°C until analysis.
Serum levels of CERK were measured by quantitative sandwich enzyme-linked immunosorbent assay using Human Ceramide Kinase ELISA kit (catalog number: CSB-EL005256HU; Cusabio, Hubei, China) according to the manufacturer’s instructions. The detection range of the kit is 18.75–1200 pg/ml. Each sample was run in duplicate and compared with a standard curve. The mean concentration was determined for each sample.
Data entry and statistical analysis were performed using the statistical package for social sciences, version 20 (SPSS Inc., Chicago, Illinois, USA). Independent-samples t-test of significance was used when comparing between two means. χ2-test of significance was used to compare proportions between two qualitative parameters. Pearson’s correlation coefficient (r) test was used for correlating data.
- Probability (P value) considerations were as follows:
- P-value less than 0.05 was considered significant.
- P-value less than 0.001 was considered as highly significant.
- P-value more than 0.05 was considered insignificant.
| Results|| |
Characteristics of the study population
This study included 35 patients with migraine, with 20 (57.1%) females and 15 (42.9%) males, and 16 control participants, with eight (50%) females and eight (50%) males. The mean age in the patients group was 37.49±7.85 years, and the mean age of the control group was 36.17±11.40 years.
There were no statistically significant differences between the two groups regarding demographic data ([Table 1]).
|Table 1 Comparison between patients and control according to demographic data|
Click here to view
The patients group was divided into two groups: 12 patients with migraine with aura and 23 patients with migraine without aura. There were no statistically significant differences between the two groups regarding age, sex, duration of headache, and frequency of headache attacks per month (P>0.05) ([Table 2]).
|Table 2 Comparison between patients with migraine with and without aura according to duration of headache and frequency of headache|
Click here to view
Results of serum ceramide kinase levels
As shown in [Table 3], mean serum levels of CERK were statistically significantly higher in patient group (255.42±44.57) than in the control group (53.61±11.23) (P<0.05; [Figure 1]).
|Table 3 Comparison between patients and control groups regarding serum levels of ceramide kinase|
Click here to view
|Figure 1 Comparison between patients and control according to ceramide kinase. (pg/ml).|
Click here to view
Regarding both types of migraine, there were no statistically significant differences between CERK serum levels in patients with migraine with aura (237.48±36.91) and those without aura (264.77±46.06) (P>0.05), and the increase was in favor of those without aura ([Table 4] and [Figure 2]).
|Table 4 Comparison between patients with migraine with and without aura regarding ceramide kinase serum levels (pg/ml)|
Click here to view
|Figure 2 Comparison between patients with migraine with and without aura according to ceramide kinase serum levels (pg/ml).|
Click here to view
Correlation between serum ceramide kinase levels and clinical variables
There was a positive significant correlation between CERK levels and frequency of attacks per month and MiDAS score ([Table 5] and [Figure 3] and [Figure 4]).
|Table 5 Correlation between ceramide kinase serum levels (pg/ml) and frequency of headache attacks and Migraine Disability Assessment Scale score using Pearson’s correlation coefficient in the patient group|
Click here to view
|Figure 3 Positive significant correlation between serum ceramide kinase level (pg/ml) and frequency of headache/month.|
Click here to view
|Figure 4 Positive significant correlation between serum ceramide kinase levels and Migraine Disability Assessment Scale (MiDAS) score in the patient group.|
Click here to view
| Discussion|| |
This is a case–control study that analyzed the serum levels of CERK, one of the enzymes that catalyzes the phosphorylation of ceramide, interictally in patients with migraine. We found that the serum levels of interictal CERK were significantly higher in patients with migraine than in age-matched and sex-matched controls. Although the data from experimental systems support a role for ceramides in nociceptive processing ,,,, few studies had evaluated the relationship between circulating total or individual species of ceramides and its metabolites in human participants with any headache disorder, including migraine ,.
One of the most important studies was that of Peterlin et al. , who conducted a study on 52 women with episodic migraine and concluded that serum levels of total ceramide and its precursor, DHC, were decreased in women with episodic migraines compared with controls. These findings suggest that migraineurs have decreased de-novo synthesis of ceramides as well as an independent downstream increase in the conversion of ceramide metabolic products (e.g., sphingomyelin).
Our study was consistent with that as we found increase in the levels of CERK in migraineurs than in controls, which serves the hypothesis of increased ceramide catabolism in migraineurs.
Regarding substrate specificity, it was reported that phosphorylation of ceramide by CERK is stereospecific, and it was also reported that a minimum of a 12-carbon acyl chain was required for normal CERK activity, whereas the short-chain ceramide analogs were poor substrates for CERK. It was also concluded that CERK phosphorylates only the naturally occurring d-erythroceramides, and also sphingosine has been shown not to be a substrate for CERK .
Interestingly, in the previous study, the authors explained that the changes in ceramide levels in migraineurs were largely driven by reductions in the very long-chain ceramides (ceramide C24:0, DHC C24:0, and monohexosylceramide C26:0). These results could be consistent with our results, which support the increase of ceramide catabolism via the increase in CERK levels. Moreover, they also concluded that there were no differences in total dihydrosphingomyelin, sphingomyelin, lactosylceramide, or sphingosine-1-phosphate (ceramide metabolites) in migraineurs as compared with controls.
In our study, we found no statistically significant difference in serum CERK levels between both types of migraine (with and without aura).
This may be consistent in part with the study conducted by Peterlin and colleagues, who demonstrated that none of the sphingolipid concentrations differed with headache frequency or across migraine subgroups of those with versus without aura.
However, in our study, we found a positive significant correlation between serum CERK levels and frequency of headache attacks. This may reflect chronic activation of a compensatory system in the face of repetitive and chronically increased neurogenic inflammation.
Moreover, the serum CERK levels were significantly correlated with the degree of disability assessed by MiDAS in the patient group.
There were some limitations in this study. The first was the small sample size. Second, we hypothesized that the increase in the serum levels of the enzyme is an evidence of increased activity, whereas there might be several factors that affect the enzymatic activity. Moreover, further study of the levels of C1P levels in migraineurs is important. Finally, this work suggests that sphingolipid dysmetabolism could be involved in the pathophysiology of migraine as a neurologic disorder.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol 2013; 75:365–391.
Goadsby PJ. Pathophysiology of migraine. Neurol Clin 2009; 27:335–360.
Peterlin BL, Rosso AL, Williams MA, Rosenberg JR, Haythornthwaite JA, Merikangas KR et al.
Episodic migraine and obesity and the influence of age, race, and sex. Neurology 2013; 81:1314–1321.
Rainero I, Limone P, Ferrero M, Valfre W, Pelissetto C, Robino E et al.
Insulin sensitivity is impaired in patients with migraine. Cephalalgia 2005; 25:593–597.
Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a complex association with clinical implications. Lancet Neurol 2012; 11:92–100.
Peterlin BL, Tietjen GE, Gower BA, Ward TN, Tepper SJ, White LW et al.
Ictaladiponectin levels in episodic migraineurs: a randomized pilot trial. Headache 2013; 53:474–490.
Bikman BT, Summers SA. Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 2011; 121:4222–4230.
Hirabayashi Y. A world of sphingolipids and glycolipids in the brain: novel functions of simple lipids modified with glucose. Proc Jpn Acad Ser B Phys Biol Sci 2012; 88:129–143.
Joseph EK, Levine JD. Caspasesignalling in neuropathic and inflammatory pain in the rat. Eur J Neurosci 2004; 20:2896–2902.
Mielke MM, Bandaru VV, Haughey NJ, Xia J, Fried LP, Yasar S et al.
Serum ceramides increase the risk of Alzheimer disease: the Women’s Health and Aging Study II. Neurology 2012; 79:633–641.
Haughey NJ, Cutler RG, Tamara A, McArther JC, Varagas DL, Pardo CA et al.
Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 2004; 55:257–267.
Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ. A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain 2008; 131:3092–3102.
Blachnio-Zabielska AU, Pulka M, Baranowski M et al.
Ceramide metabolism is affected by obesity and diabetes in human adipose tissue. J Cell Physiol 2012; 227:550–557.
Park KA, Vasko MR. Lipid mediators of sensitivity in sensory neurons. Trends Pharmacol Sci 2005; 26:571–577.
Arana L, Gangoiti P, Ouro A, Trueba M, Gomez-Munoz A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis 2010; 9:15.
Claus RA, Dorer MJ, Bunck AC, Deigner HP. Inhibition of sphingomyelin hydrolysis: targeting the lipid mediator ceramide as a key regulator of cellular fate. Curr Med Chem 2009; 16:1978–2000.
Hinkovska-Galcheva V, Shyman JA. Ceramide-1-phosphate in phagocytosis and calcium homeostasis. Adv Exp Med Biol 2010; 688:131–140.
Mencarelli C, Martinez-Martinez P. Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 2013; 70:181–203.
Peterlin BL, Mielke MM, Dickens AM, Chattrejee S, Dash P et al.
Interictal, circulating sphingolipids in women with episodic migraine. Neurology 2015; 85:1214–1223.
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33:629.
Vladetic M, Janculjak D, Soldo SB, Kralik K, Buljan K. Health related quality of life and ways of coping with stress in patients with migraine. Neurol Sci 2017; 38:295–301.
Gnanasekaran A, Sundukova M, van den Maagdenberg AM, Fabbretti E, Nistri A. Lipid rafts control P2 × 3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol Pain 2011; 7:77.
Salvemini D, Doyle T, Kress M, Nicol G. Therapeutic targeting of the ceramide-to-sphingosine 1-phosphate pathway in pain. Trends Pharmacol Sci 2013; 34:110–118.
Vecino AM, Alvarez-Cermeno JC, Jimenez-Huete A, Navarro JL, Cesar JM. Lipid composition of platelets in patients suffering from migraine without aura. Headache 1996; 36: 440–441.
Gomez-Munoz A. Ceramide-1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta 2006; 1758:2049–2056.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]