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Evaluation of serum ghrelin, nesfatin-1, irisin, and vasoactive intestinal peptide levels in temporal lobe epilepsy patients with and without drug resistance: a cross-sectional study

SUMMARY

OBJECTIVE:

Epilepsy is a common disorder that affects the nervous systems of 1% of worldwide population. In epilepsy, one-third of patients are unresponsive to current drug therapies and develop drug-resistant epilepsy. Alterations in ghrelin, nesfatin-1, and irisin levels with epilepsy were reported in previous studies. Vasoactive intestinal peptide is among the most common neuropeptides in the hippocampus, which is the focus of the seizures in temporal lobe epilepsy. However, there is also lack of evidence of whether these four neuropeptide levels are altered with drug resistant temporal lobe epilepsy or not. The aim herein was the evaluation of the serum levels of nesfatin-1, ghrelin, irisin, and Vasoactive intestinal peptide in drug-resistant temporal lobe epilepsy patients and temporal lobe epilepsy (TLE) without drug resistance, and to compare them to healthy controls.

METHODS:

This cross-sectional study group included 58 temporal lobe epilepsy patients (24 with drug resistant temporal lobe epilepsy and 34 with temporal lobe epilepsy who were not drug-resistant) and 28 healthy subjects. Nesfatin-1, ghrelin, irisin, and Vasoactive intestinal peptide serum levels were determined using enzyme-linked immunosorbent assay.

RESULTS:

The serum ghrelin levels of patients with drug resistant temporal lobe epilepsy were seen to have significantly decreased when compared to those of the control group (p<0.05). Serum nesfatin-1, vasoactive intestinal peptide, and irisin levels were seen to have decreased in the drug resistant temporal lobe epilepsy group when compared to those of the control and temporal lobe epilepsy groups; however, the difference was non-significant (p>0.05).

CONCLUSIONS:

The results herein suggested that ghrelin might contribute to the pathophysiology of drug resistant temporal lobe epilepsy. However, further studies are needed to confirm this hypothesis.

KEYWORDS:
Ghrelin; Neuropeptides; Drug resistant epilepsy; Vasoactive intestinal peptide

INTRODUCTION

Epilepsy is a significantly prevalent neurological condition that affects about 50 million people worldwide11. World Health Organization. Epilepsy. Geneva: World Health Organization; 2019. [cited on Feb. 01, 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/epilepsy
https://www.who.int/news-room/fact-sheet...
. Approximately 25% of epileptic patients have drug resistance22. López González FJ, Osorio XR, Gil-Nagel Rein A, Carreño Martínez M, Serratosa Fernández J, Villanueva Haba V, et al. Drug-resistant epilepsy: definition and treatment alternatives. Neurologia. 2015;30(7):439-46. https://doi.org/10.1016/j.nrl.2014.04.012
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. Human temporal lobe epilepsy (TLE) is both the most prevalent seizure condition in adults33. Waxman S. Molecular neurology. Connecticut: Elsevier; 2010. p. 600 and the most frequent reason for drug-resistant (pharmacoresistant) seizures44. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-30. https://doi.org/10.1001/jama.2012.220
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. Pharmacoresistant epilepsy is associated with poor quality of life, injuries, psychosocial problems, premature mortality55. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical ımpact, potential mechanisms, and new ınnovative treatment options. Pharmacol Rev. 2020;72(3):606-38. https://doi.org/10.1124/pr.120.019539
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, and psychiatric problems66. Weaver DF, Pohlmann-Eden B. Pharmacoresistant epilepsy: unmet needs in solving the puzzle(s). Epilepsia. 2013;54(Suppl 2):80-5. https://doi.org/10.1111/epi.12191
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. Thus, finding new treatments is an urgent necessity77. Portelli J, Massie A, Coppens J, Smolders I, editors. Ghrelin receptors and epilepsy. New York: Springer; 2014. p. 177-89., and there is an unmet need for finding new antiepileptic drugs with novel targets and different mechanisms88. Kambli L, Bhatt LK, Oza M, Prabhavalkar K. Novel therapeutic targets for epilepsy intervention. Seizure. 2017;51:27-34. https://doi.org/10.1016/j.seizure.2017.07.014
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. Furthermore, drug-resistant epilepsy is the cause of 80% of the expenditure of epilepsy44. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-30. https://doi.org/10.1001/jama.2012.220
https://doi.org/10.1001/jama.2012.220...
and the mechanisms underlying pharmocoresistant epilepsy are not completely understood55. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical ımpact, potential mechanisms, and new ınnovative treatment options. Pharmacol Rev. 2020;72(3):606-38. https://doi.org/10.1124/pr.120.019539
https://doi.org/10.1124/pr.120.019539...
.Therefore, major attention has been directed towards elucidating the mechanisms underlying drug resistance.

There are numerous hypotheses explaining the mechanisms related with refractory epilepsy, including methylation, impaired mitochondrial function, neural network, intrinsic severity, transporter, and target hypothesis99. Rosillo-de la Torre A, Luna-Bárcenas G, Orozco-Suárez S, Salgado-Ceballos H, García P, Lazarowski A, et al. Pharmacoresistant epilepsy and nanotechnology. Front Biosci (Elite Ed). 2014;6:329-40. https://doi.org/10.2741/709
https://doi.org/10.2741/709...
. The intrinsic severity hypothesis assumes that drug resistance is the result of high excitatory neurotransmission, which leads to elevated intensity and frequency of seizures99. Rosillo-de la Torre A, Luna-Bárcenas G, Orozco-Suárez S, Salgado-Ceballos H, García P, Lazarowski A, et al. Pharmacoresistant epilepsy and nanotechnology. Front Biosci (Elite Ed). 2014;6:329-40. https://doi.org/10.2741/709
https://doi.org/10.2741/709...
. A deterioration in the balance of inhibitory and excitatory systems in the brain leads to seizures, which have been defined as aberrant, extreme, and synchronous neural activity1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
. Neuropeptides are significant in the field of epilepsy due to their modifying roles1111. Kovac S, Walker MC. Neuropeptides in epilepsy. Neuropeptides. 2013;47(6):467-75. https://doi.org/10.1016/j.npep.2013.10.015
https://doi.org/10.1016/j.npep.2013.10.0...
on inhibitory or excitatory neurotransmitters1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
. Therefore, neuropeptides draw attention as drug or biomarker candidates in the field of epilepsy research1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
.

Ghrelin is described as a new anticonvulsant1212. Portelli J, Michotte Y, Smolders I. Ghrelin: an emerging new anticonvulsant neuropeptide. Epilepsia. 2012;53(4):585-95. https://doi.org/10.1111/j.1528-1167.2012.03423.x
https://doi.org/10.1111/j.1528-1167.2012...
, pleiotropic1313. Portelli J, Thielemans L, Ver Donck L, Loyens E, Coppens J, Aourz N, et al. Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents. Neurotherapeutics. 2012;9(3):658-72. https://doi.org/10.1007/s13311-012-0125-x
https://doi.org/10.1007/s13311-012-0125-...
, and orexigenic peptide, known to be expressed in the brain1414. Ferrini F, Salio C, Lossi L, Merighi A. Ghrelin in central neurons. Curr Neuropharmacol. 2009;7(1):37-49. https://doi.org/10.2174/157015909787602779
https://doi.org/10.2174/1570159097876027...
. Alterations in ghrelin levels have been reported both in clinical1515. Berilgen MS, Mungen B, Ustundag B, Demir C. Serum ghrelin levels are enhanced in patients with epilepsy. Seizure. 2006;15(2):106-11. https://doi.org/10.1016/j.seizure.2005.11.008
https://doi.org/10.1016/j.seizure.2005.1...
1717. Aydin S, Dag E, Ozkan Y, Arslan O, Koc G, Bek S, et al. Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides. 2011;32(6):1276-80. https://doi.org/10.1016/j.peptides.2011.04.021
https://doi.org/10.1016/j.peptides.2011....
and animal studies1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. Irisin is defined as a myokine, which is produced in skeletal muscle with exercise1919. Colaianni G, Grano M. Role of Irisin on the bone-muscle functional unit. Bonekey Rep. 2015;4:765. https://doi.org/10.1038/bonekey.2015.134
https://doi.org/10.1038/bonekey.2015.134...
. In addition, FNDC5, the precursor of irisin, is present in the brain1919. Colaianni G, Grano M. Role of Irisin on the bone-muscle functional unit. Bonekey Rep. 2015;4:765. https://doi.org/10.1038/bonekey.2015.134
https://doi.org/10.1038/bonekey.2015.134...
. Significant alterations in serum levels of irisin2020. Elhady M, Youness ER, Gafar HS, Aziz A, Mostafa RSI. Circulating irisin and chemerin levels as predictors of seizure control in children with idiopathic epilepsy. Neurol Sci. 2018;39(8):1453-1458. https://doi.org/10.1007/s10072-018-3448-5
https://doi.org/10.1007/s10072-018-3448-...
and FNDC5/irisin1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
have been reported. Nesfatin-1 is a recently identified neuropeptide, produced in different areas of the brain2121. Pałasz A, Krzystanek M, Worthington J, Czajkowska B, Kostro K, Wiaderkiewicz R, et al. Nesfatin-1, a unique regulatory neuropeptide of the brain. Neuropeptides. 2012;46(3):105-12. https://doi.org/10.1016/j.npep.2011.12.002
https://doi.org/10.1016/j.npep.2011.12.0...
. Increased nesfatin-1 levels have been reported in clinical1616. Aydin S, Dag E, Ozkan Y, Erman F, Dagli AF, Kilic N, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem. 2009;328(1-2):49-56. https://doi.org/10.1007/s11010-009-0073-x
https://doi.org/10.1007/s11010-009-0073-...
and animal studies1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. Vasoactive intestinal peptide (VIP), a neuropeptide that contains 28 amino acids, is expressed in different areas of the brain2222. Dobolyi A, Kékesi KA, Juhász G, Székely AD, Lovas G, Kovács Z. Receptors of peptides as therapeutic targets in epilepsy research. Curr Med Chem. 2014;21(6):764-87. https://doi.org/10.2174/0929867320666131119154018
https://doi.org/10.2174/0929867320666131...
. VIP is among the neuropeptides in the hippocampus, which is the most common focus of seizures in TLE2222. Dobolyi A, Kékesi KA, Juhász G, Székely AD, Lovas G, Kovács Z. Receptors of peptides as therapeutic targets in epilepsy research. Curr Med Chem. 2014;21(6):764-87. https://doi.org/10.2174/0929867320666131119154018
https://doi.org/10.2174/0929867320666131...
. Although VIP can increase the electrical activity in various areas of the brain and may have a function in seizure pathology, VIP has not often been investigated in the field of epilepsy1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
.

In summary, in previous studies, significant alterations were reported in ghrelin1515. Berilgen MS, Mungen B, Ustundag B, Demir C. Serum ghrelin levels are enhanced in patients with epilepsy. Seizure. 2006;15(2):106-11. https://doi.org/10.1016/j.seizure.2005.11.008
https://doi.org/10.1016/j.seizure.2005.1...
1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
, irisin2020. Elhady M, Youness ER, Gafar HS, Aziz A, Mostafa RSI. Circulating irisin and chemerin levels as predictors of seizure control in children with idiopathic epilepsy. Neurol Sci. 2018;39(8):1453-1458. https://doi.org/10.1007/s10072-018-3448-5
https://doi.org/10.1007/s10072-018-3448-...
, FNDC5/irisin1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
, and nesfatin-11616. Aydin S, Dag E, Ozkan Y, Erman F, Dagli AF, Kilic N, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem. 2009;328(1-2):49-56. https://doi.org/10.1007/s11010-009-0073-x
https://doi.org/10.1007/s11010-009-0073-...
,1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
levels. Despite this, there is also lack of evidence of whether these four neuropeptide levels are altered with drug resistant temporal lobe epilepsy (DRTLE) or not. Therefore, the aim herein was the investigation of possible alterations of these peptides in TLE patients with or without drug resistance.

METHODS

Study design

This cross-sectional study was conducted during the period comprehending November 2018 to March 2020. All of the study protocols received approval from the local Medical Ethics Committee of Van Yuzuncu Yil University. A written informed consent was given to the subjects before participating in the study. Of the 116 eligible subjects, nine were excluded due to refusal to give blood and nine, due to non-fasting status at the time of sampling. Moreover, 13 other subjects were excluded due to a body mass index (BMI) over 30.0 kg/m2, one was excluded with a newly diagnosis of ankylosing spondylitis. Some subjects have two excluded criteria. Finally, 86 subjects remained for this study. The cross-sectional study was carried out on 58 TLE patients (24 with DRTLE and 34 with TLE that was not drug- resistant) (who attended epilepsy outpatient clinic at Van Yuzuncu Yil University, Neurology department) and 28 healthy subjects. All of the patients had a body mass index (BMI) of less than 30.0 kg/m2. The control group included age- and BMI-matched subjects who did not have any chronic illness and a BMI of less than 30.0 kg/m2. The exclusion criteria are BMI greater than 30.0 kg/m2, chronic illness except epilepsy. “TLE is diagnosed by a history of characteristic partial seizure symptoms. The diagnosis is confirmed by the capture of a typical episode during an electroencephalogram (EEG) or video-EEG, with epileptiform activity over one or both temporal regions2323. Devinsky O. Diagnosis and treatment of temporal lobe epilepsy. Rev Neurol Dis. 2004;1(1):2-9. PMID: 16397445. Despite significant advances involving both antiepileptic drugs and surgery in TLE treatment over recent decades, approximately one third of patients with this disease are only poorly controlled, or their seizures are resistant to drugs. “Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”2424. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-77. https://doi.org/10.1111/j.1528-1167.2009.02397.x
https://doi.org/10.1111/j.1528-1167.2009...
by ILAE. This study has been reported in line with the STROBE criteria2525. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495-9. https://doi.org/10.1016/j.ijsu.2014.07.013
https://doi.org/10.1016/j.ijsu.2014.07.0...
.

Ghrelin, nesfatin-1, irisin, and VIP assays

Blood was collected from the subjects at 08:00 and 12:00 h following one night of fasting. Centrifugation of the blood was performed for 5 min at 4,000 rpm. Storage of the serum was at -80°C until the testing. Serum ghrelin, nesfatin-1, irisin, and VIP levels were measured using ELISA. Serum levels of the ghrelin (Cat No: YLA1024HU), VIP (Cat No: YLA0803HU), irisin (Cat No: YLA1361HU), and nesfatin-1 (Cat No: YLA0715HU) (all available commercially from YLbiont, Shanghai, China) were determined using ELISA kits.

Statistical analysis

In the study, ghrelin is considered for sample size calculation. From the previous studies2626. Kefeli A, Yeniova AO, Basyigit S, Uzman M, Asilturk Z, Tanrikulu Y, et al. Effects of helicobacter pylori infections on ghrelin and leptin levels. Arch Sicil Med Chir 4 Acta Med Mediterr. 2016;32(5). https://doi.org/10.19193/0393-6384_2016_5_139
https://doi.org/10.19193/0393-6384_2016_...
, the standard deviation for ghrelin varies between 0.1 and 0.9. Thus, standard deviation was considered as 0.5. For the 95% of confidence coefficient and approximately 80% power value, Type I error is 0.05 (Z value is 1.96 for the 5% type I error), the effect size was defined by the researcher as 0.2. Based on this information, the necessary sample size was calculated by the equation “n=Z2 × σ2/d2

According to this equation, minimum sample size in each group was found as 24 [n=(1.962 × 0.52/0.22 @ 24].

For continuous variables, descriptive statistics were presented as the mean and standard error of the mean (SEM), whereas the categorical variables were presented as counts and percentages. One-way ANOVA was used for comparison of the means of groups. The Duncan multiple comparison test was used for identification of the different means of the groups, followed by ANOVA. To determine linear relations among the variables, the Pearson correlation analysis was performed. Additionally, the chi square test was used for determining relations between categorical variables. Statistical significance was defined as p<0.05, and SPSS v.13 (Chicago, IL, USA) was used for the statistical computations.

RESULTS

Table 1 presents the demographic characteristics of subjects. There were no statistically significant differences in terms of age and BMI between the groups.

Table 1
Demographic characteristics of subjects.

Serum ghrelin levels in the DRTLE group decreased significantly when compared to the control group (p<0.05). The difference between the TLE and DRTLE groups in terms of ghrelin was non-significant (Figure 1A). Serum nesfatin-1 levels had increased in the TLE group, whereas they had decreased in the DRTLE group when compared to the control; however, both were non-significant (Figure 1B).

Figure 1
Serum neuropeptide levels of the control, TLE, and DRTLE groups.

No statistically significant difference was observed between the TLE, DRTLE, and control groups with regards to the serum VIP levels (Figure 1C). Serum irisin levels had decreased in the TLE and DRTLE groups when compared to the control, and they had decreased in DRTLE compared to TLE group; however, both were non-significant (Figure 1D).

DISCUSSION

Increased1515. Berilgen MS, Mungen B, Ustundag B, Demir C. Serum ghrelin levels are enhanced in patients with epilepsy. Seizure. 2006;15(2):106-11. https://doi.org/10.1016/j.seizure.2005.11.008
https://doi.org/10.1016/j.seizure.2005.1...
or decreased1616. Aydin S, Dag E, Ozkan Y, Erman F, Dagli AF, Kilic N, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem. 2009;328(1-2):49-56. https://doi.org/10.1007/s11010-009-0073-x
https://doi.org/10.1007/s11010-009-0073-...
,1717. Aydin S, Dag E, Ozkan Y, Arslan O, Koc G, Bek S, et al. Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides. 2011;32(6):1276-80. https://doi.org/10.1016/j.peptides.2011.04.021
https://doi.org/10.1016/j.peptides.2011....
ghrelin levels have been reported in studies on epilepsy patients. In a previous study, significantly decreased ghrelin levels in the brain and serum were found in acute PTZ-induced seizures; and PTZ kindling models, in rats1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. It was suggested that ghrelin has antiepileptic2727. Obay BD, Tasdemir E, Tümer C, Bilgin HM, Sermet A. Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides. 2007;28(6):1214-9. https://doi.org/10.1016/j.peptides.2007.04.003
https://doi.org/10.1016/j.peptides.2007....
and neuroprotective2828. Morgan AH, Rees DJ, Andrews ZB, Davies JS. Ghrelin mediated neuroprotection – A possible therapy for Parkinson’s disease? Neuropharmacology. 2018;136(Pt B):317-26. https://doi.org/10.1016/j.neuropharm.2017.12.027
https://doi.org/10.1016/j.neuropharm.201...
properties. In the present study, serum ghrelin levels had decreased in the TLE and DRTLE groups when compared to the control. This decrease was non-significant in TLE group, whereas it was significant in the DRTLE group. Aydin et al.1717. Aydin S, Dag E, Ozkan Y, Arslan O, Koc G, Bek S, et al. Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides. 2011;32(6):1276-80. https://doi.org/10.1016/j.peptides.2011.04.021
https://doi.org/10.1016/j.peptides.2011....
suggested that the reason for the reduction of the ghrelin level may have been due to the high uptake of the neuropeptide by CNS for modulating epileptic discharges. Frago et al.2929. Frago LM, Baquedano E, Argente J, Chowen JA. Neuroprotective actions of ghrelin and growth hormone secretagogues. Front Mol Neurosci. 2011;4:23. https://doi.org/10.3389/fnmol.2011.00023
https://doi.org/10.3389/fnmol.2011.00023...
suggested that the anticonvulsant effects of ghrelin may be due to its actions on neuropeptide Y and gamma-aminobutyric acid (GABA). Therefore, in the present study, this decrease may be evaluated as a result of seizures; repetitive seizures may lead a decrease in the body’s storage of ghrelin, which may have been responsible for the significant decrease in the serum levels of the DRTLE group.

Ghrelin has a role in a variety of neurophysiological process, including anti-inflammatory, neuroprotective, neurogenesis3030. Portelli J. Neuropeptide receptors as potential antiepileptic drug targets: focus on the ghrelin axis. 2014;2(1):3-6. [cited on Aug. 15, 2020]. Available from: https://www.um.edu.mt/library/oar//handle/123456789/1961
https://www.um.edu.mt/library/oar//handl...
,3131. Ge T, Yang W, Fan J, Li B. Preclinical evidence of ghrelin as a therapeutic target in epilepsy. 2017;8(35):59929-39. https://doi.org/10.18632/oncotarget.18349
https://doi.org/10.18632/oncotarget.1834...
, anti-convulsant effects3030. Portelli J. Neuropeptide receptors as potential antiepileptic drug targets: focus on the ghrelin axis. 2014;2(1):3-6. [cited on Aug. 15, 2020]. Available from: https://www.um.edu.mt/library/oar//handle/123456789/1961
https://www.um.edu.mt/library/oar//handl...
, learning and memory3131. Ge T, Yang W, Fan J, Li B. Preclinical evidence of ghrelin as a therapeutic target in epilepsy. 2017;8(35):59929-39. https://doi.org/10.18632/oncotarget.18349
https://doi.org/10.18632/oncotarget.1834...
, and can cross blood brain barrier3030. Portelli J. Neuropeptide receptors as potential antiepileptic drug targets: focus on the ghrelin axis. 2014;2(1):3-6. [cited on Aug. 15, 2020]. Available from: https://www.um.edu.mt/library/oar//handle/123456789/1961
https://www.um.edu.mt/library/oar//handl...
. Ghrelin receptor GHSR1a is widely expressed in the body, involving prone areas in seizures, such as the hippocampus3030. Portelli J. Neuropeptide receptors as potential antiepileptic drug targets: focus on the ghrelin axis. 2014;2(1):3-6. [cited on Aug. 15, 2020]. Available from: https://www.um.edu.mt/library/oar//handle/123456789/1961
https://www.um.edu.mt/library/oar//handl...
. The mechanism underlying its anticonvulsant properties remains unknown3030. Portelli J. Neuropeptide receptors as potential antiepileptic drug targets: focus on the ghrelin axis. 2014;2(1):3-6. [cited on Aug. 15, 2020]. Available from: https://www.um.edu.mt/library/oar//handle/123456789/1961
https://www.um.edu.mt/library/oar//handl...
.

In the present study, significant reduction was found in serum ghrelin levels of the DRTLE group compared to the control. The interactivity between ghrelin-NPY/GABA in hypothalamic circuitry was reported1212. Portelli J, Michotte Y, Smolders I. Ghrelin: an emerging new anticonvulsant neuropeptide. Epilepsia. 2012;53(4):585-95. https://doi.org/10.1111/j.1528-1167.2012.03423.x
https://doi.org/10.1111/j.1528-1167.2012...
,3131. Ge T, Yang W, Fan J, Li B. Preclinical evidence of ghrelin as a therapeutic target in epilepsy. 2017;8(35):59929-39. https://doi.org/10.18632/oncotarget.18349
https://doi.org/10.18632/oncotarget.1834...
. It was reported that the blockade of NPY receptors obstruct the anticonvulsant effects of ghrelin in rats’ hippocampus3232. Ghahramanian Golzar M, Babri S, Ataie Z, Ebrahimi H, Mirzaie F, Mohaddes G. NPY receptors blockade prevents anticonvulsant action of ghrelin in the hippocampus of rat. Adv Pharm Bull. 2013;3(2):265-71. https://doi.org/10.5681/apb.2013.043
https://doi.org/10.5681/apb.2013.043...
. Ghrelin supports the releasing of NPY presynaptically and, therefore, the releasing of GABA in the arcuate nucleus of hypotalamus1212. Portelli J, Michotte Y, Smolders I. Ghrelin: an emerging new anticonvulsant neuropeptide. Epilepsia. 2012;53(4):585-95. https://doi.org/10.1111/j.1528-1167.2012.03423.x
https://doi.org/10.1111/j.1528-1167.2012...
. Chronic seizures lead a change in expression of NPY receptors resulting an increase in Y2 and a decrease in Y1 receptors1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
. These changes in response to seizures may be a mechanism for dealing with hyper-excitability1010. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol. 2014;50(2):626-46. https://doi.org/10.1007/s12035-014-8669-x
https://doi.org/10.1007/s12035-014-8669-...
. In the present study, the reduction of serum ghrelin levels might be due to the increased consumption of ghrelin to cope with chronic recurrent seizures which occurred in DRTLE.

Nesfatin-1, a neuropeptide, is expressed in many areas of the brain2121. Pałasz A, Krzystanek M, Worthington J, Czajkowska B, Kostro K, Wiaderkiewicz R, et al. Nesfatin-1, a unique regulatory neuropeptide of the brain. Neuropeptides. 2012;46(3):105-12. https://doi.org/10.1016/j.npep.2011.12.002
https://doi.org/10.1016/j.npep.2011.12.0...
. It induces satiety and is known for being a strong anorexigenic agent2121. Pałasz A, Krzystanek M, Worthington J, Czajkowska B, Kostro K, Wiaderkiewicz R, et al. Nesfatin-1, a unique regulatory neuropeptide of the brain. Neuropeptides. 2012;46(3):105-12. https://doi.org/10.1016/j.npep.2011.12.002
https://doi.org/10.1016/j.npep.2011.12.0...
. Its antiapoptotic and anti-inflammatory effects in the brain tissue of rats has been reported3333. Tang CH, Fu XJ, Xu XL, Wei XJ, Pan HS. The anti-inflammatory and anti-apoptotic effects of nesfatin-1 in the traumatic rat brain. Peptides. 2012;36(1):39-45. https://doi.org/10.1016/j.peptides.2012.04.014
https://doi.org/10.1016/j.peptides.2012....
. In a previous study, serum levels of nesfatin-1 increased significantly in acute PTZ and PTZ-kindling in rats1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. However, the serum nesfatin-1 levels of rats that received valproate treatment were ameliorated and non-significant when compared to the control1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. Herein, serum nesfatin- 1 levels had increased in the TLE group and decreased in the DRTLE group, but the differences were non-significant when compared to the control group. Antiepileptic drug treatment may ameliorate the increased nesfatin-1 levels of the serum. In a previous study, serum nesfatin-1 levels were reported to have increased, in newly diagnosed primary generalized epilepsy patients, approximately 160-fold higher than that of the control; however, this increase was decreased via treatment with antiepileptic drugs, but remained approximately 10-fold higher than that of the control1616. Aydin S, Dag E, Ozkan Y, Erman F, Dagli AF, Kilic N, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem. 2009;328(1-2):49-56. https://doi.org/10.1007/s11010-009-0073-x
https://doi.org/10.1007/s11010-009-0073-...
. In the present study, this decrease may have been due to the long duration of antiepileptic drug treatment.

In the present study, the serum VIP level was also evaluated. VIP is defined as a neuroprotective3434. Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J. 2003;17(8):944-6. https://doi.org/10.1096/fj.02-0799fje
https://doi.org/10.1096/fj.02-0799fje...
neuropeptide. In the present study, serum VIP levels in the TLE and DRTLE groups were similar to that of the control. These results were in accordance with previous studies, in which no significant changes were reported in the VIP levels in the hippocampus of TLE patients3535. Robbins RJ, Brines ML, Kim JH, Adrian T, Delanerolle N, Welsh S, et al. A selective loss of somatostatin in the hippocampus of patients with temporal-lobe epilepsy. Ann Neurol. 1991;29(3):325-32. https://doi.org/10.1002/ana.410290316
https://doi.org/10.1002/ana.410290316...
and brain tissue of PTZ-kindled rats3636. Marksteiner J, Lassmann H, Saria A, Humpel C, Meyer DK, Sperk G. Neuropeptide Levels after Pentylenetetrazol Kindling in the Rat. Eur J Neurosci. 1990;2(1):98-103. https://doi.org/10.1111/j.1460-9568.1990.tb00385.x
https://doi.org/10.1111/j.1460-9568.1990...
. Contrary to our results, increased serum and cerebrospinal fluid VIP levels were reported in children with seizure disorders3737. Ko FJ, Chiang CH, Liu WJ, Chiang W. Somatostatin, substance P, prolactin and vasoactive intestinal peptide levels in serum and cerebrospinal fluid of children with seizure disorders. Gaoxiong Yi Xue Ke Xue Za Zhi. 1991;7(8):391-7. PMID: 1714968. These contrary results may have been due to the age of the subject population.

Irisin is secreted from skeletal muscle with exercise3838. Askari H, Rajani SF, Poorebrahim M, Haghi-Aminjan H, Raeis-Abdollahi E, Abdollahi M. A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review. Pharmacol Res. 2018;129:44-55. https://doi.org/10.1016/j.phrs.2018.01.012
https://doi.org/10.1016/j.phrs.2018.01.0...
. In recent years, its anti-inflammatory and antioxidative effects have drawn much attention from researchers3838. Askari H, Rajani SF, Poorebrahim M, Haghi-Aminjan H, Raeis-Abdollahi E, Abdollahi M. A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review. Pharmacol Res. 2018;129:44-55. https://doi.org/10.1016/j.phrs.2018.01.012
https://doi.org/10.1016/j.phrs.2018.01.0...
. However, its role in the central nervous system is not well known. There are limited studies present on irisin in the field of epilepsy. In a previous study, serum and brain FNDC5/irisin levels were significantly increased in PTZ-kindling, and acute PTZ-induced seizure groups in rats without antiepileptic drug treatment1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. Herein, differences between the serum irisin levels of the control, TLE, and DRTLE groups were non-significant. In a previous study, it was found that chronic antiepileptic drug treatment (valproate) decreased the PTZ-induced increase in serum and brain irisin levels in PTZ- kindling in rats1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. Significantly increased serum levels of irisin were reported in children with idiopathic epilepsy2020. Elhady M, Youness ER, Gafar HS, Aziz A, Mostafa RSI. Circulating irisin and chemerin levels as predictors of seizure control in children with idiopathic epilepsy. Neurol Sci. 2018;39(8):1453-1458. https://doi.org/10.1007/s10072-018-3448-5
https://doi.org/10.1007/s10072-018-3448-...
. These controversial results may have been associated with different factors; the present study conducted on adults and the subjects had therefore received longer antiepileptic drug therapy.

The strength of this study was that for the first time, to the best of our knowledge, the serum nesfatin-1, ghrelin, irisin, and VIP peptide levels in TLE and DRTLE patients were compared to healthy controls.

The limitations of our study are all patients being under antiepileptic drug therapy. Antiepileptic drug treatment and the age of epilepsy patients can influence the serum levels of ghrelin3131. Ge T, Yang W, Fan J, Li B. Preclinical evidence of ghrelin as a therapeutic target in epilepsy. 2017;8(35):59929-39. https://doi.org/10.18632/oncotarget.18349
https://doi.org/10.18632/oncotarget.1834...
. Second, the relation between these four peptide levels and the type of antiepileptic drug used did not investigate. In a previous study, it was reported that antiepileptic drug treatment could alter the serum levels of the ghrelin, FNDC5/irisin, and nesfatin-1 compared to the group who were not under drug treatment in PTZ treated rats1818. Erkec OE, Algul S, Kara M. Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res. 2018;40(11):923-9. https://doi.org/10.1080/01616412.2018.1503992
https://doi.org/10.1080/01616412.2018.15...
. In further studies, these peptides should be tested in the same way, but should be done with a larger sample group with subgroups (age groups, type of antiepileptic drug treatment groups).

CONCLUSIONS

In conclusion, the results herein demonstrated decreased serum ghrelin levels in DRTLE patients when compared to the control. Therefore, the results herein suggested that ghrelin might contribute to the pathophysiology of DRTLE. However, future studies are necessary to confirm this hypothesis.

  • Funding: This study was financially supported by the [Research Fund of the Van Yuzuncu Yil University] under Grant [number TSA-2018-6948].

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    » https://doi.org/10.1016/j.phrs.2018.01.012

Publication Dates

  • Publication in this collection
    16 Aug 2021
  • Date of issue
    Feb 2021

History

  • Received
    02 July 2020
  • Accepted
    04 Oct 2020
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