Revista Cienfica, FCV-LUZ / Vol. XXXV Recibido: 03/05/2025 Aceptado:04/07/2025 Publicado: 30/07/2025 hps://doi.org/10.52973/rcfcv-e35650 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 5 Revista Cienfica, FCV-LUZ / Vol. XXXV hps://doi.org/10.52973/rcfcv-e35692 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico The Effects of Topiramate and Flunarizine on serum Glutamine and neuropepde Y levels in adolescent Rats with a Migraine model Efectos del Topiramato y la Flunarizina sobre los niveles séricos de glutamina y neuropépdo en ratas adolescentes con migraña Nesrin Ceylan 1 Yıldıray Başbuğan 2* 1 Ankara Yıldırım Beyazıt University, Faculty of Medicine, Department of Pediatric Neurology, 65080. Ankara, Türkiye 2 Van Yüzüncü Yıl University, Faculty of Veterinary Medicine, Department of Internal Medicine, 65080. Van, Türkiye. *Corresponding author: yildiraybasbugan@yyu.edu.tr ABSTRACT This study aimed to invesgate the effects of topiramate and flunarizine on serum glutamine and neuropepde Y (NPY) levels in adolescent (6 weeks) rats with a migraine model induced by trinitroglycerin (NTG). For this purpose, 48 Wistar albino male rats in the adolescent stage were used. The rats were divided into 6 groups, each consisng of 8 animals. Group 1 (n=8): Healthy control group; no agent was applied. Group 2 (n=8): Migraine group; NTG (10 mg/kg, IP) was administered once daily. Group 3 (n=8): Migraine + Topiramate group; NTG (10 mg/ kg, IP) was administered once daily, and topiramate (50 mg) was administered orally twice a day. Group 4 (n=8): Migraine + Flunarizine group; NTG (10 mg/kg, IP) was administered once daily, and flunarizine (5 mg) was administered orally twice a day. Group 5 (n=8): Topiramate group only; topiramate (50 mg) was administered orally twice a day. Group 6 (n=8): Flunarizine group only; flunarizine (5 mg) was administered orally twice a day. All applicaons were performed for 5 days. In the migraine-induced group, a significant increase in glutamine and NPY levels was observed compared to the control group. However, in the topiramate and flunarizine groups (grup 5 and 6), no significant differences were detected in these levels compared to the control group. The NTG applicaon was found to be suitable for creang a migraine model, but to observe beer clinical findings, an increase in both dose and duraon may be necessary. It was concluded that migraine results in brain damage, and as an indicator of damage, both NPY and glutaminase levels may increase. Glutaminase might be slightly more sensive than NPY in detecng brain damage in migraine, but this sensivity should be further compared in more experimental studies. Key words: Migraine; adolescent rats; Topiramate; Flunarizine RESUMEN Este estudio se propuso invesgar los efectos del topiramato y la flunarizina sobre los niveles séricos de glutamina y neuropépdo Y (NPY) en ratas adolescentes con un modelo de migraña inducida por trinitroglicerina (NTG). Para ello, se ulizaron 48 ratas macho albinas Wistar en fase adolescente. Las ratas se dividieron en 6 grupos, cada uno de los cuales constaba de 8 animales. Grupo 1 (n=8): Grupo de control sano; no se aplicó ningún agente. Grupo 2 (n=8): Grupo migrañoso; se administró NTG (10 mg/kg, IP) una vez al día. Grupo 3 (n=8): Grupo migraña + topiramato; se administró NTG (10 mg/kg, IP) una vez al día y topiramato (50 mg) por vía oral dos veces al día. Grupo 4 (n=8): Grupo de migraña + flunarizina; NTG (10 mg/kg, IP) se administró una vez al día, y flunarizina (5 mg) se administró por vía oral dos veces al día. Grupo 5 (n=8): Grupo de topiramato únicamente; se administró topiramato (50 mg) por vía oral dos veces al día. Grupo 6 (n=8): Sólo grupo de flunarizina; se administró flunarizina (5 mg) por vía oral dos veces al día. Todas las aplicaciones se realizaron durante 5 días. En el grupo inducido por migraña, se observó un aumento significavo de los niveles de glutamina y NPY en comparación con el grupo de control. Sin embargo, en los grupos de topiramato y flunarizina (grupos 5 y 6) no se detectaron diferencias significavas en estos niveles en comparación con el grupo de control. Se comprobó que la aplicación de NTG es adecuada para crear un modelo de migraña, pero para observar mejores resultados clínicos puede ser necesario aumentar tanto la dosis como la duración. Se llegó a la conclusión de que la migraña provoca daños cerebrales y, como indicador de los mismos, pueden aumentar tanto los niveles de NPY como de glutaminasa. La glutaminasa podría ser ligeramente más sensible que el NPY a la hora de detectar daños cerebrales en la migraña, pero esta sensibilidad debería seguir comparándose en más estudios experimentales. Palabras clave: Migraña; ratas adolescentes; Topiramato; Flunarizina

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Migraine is an episodic headache disorder accompanied by neurological, gastrointesnal, and autonomic changes and is typically associated with symptoms such as nausea, voming, and light sensivity [1]. Pediatric migraine is common in childhood, with a prevalence of 3-10.6%, and is one of the most common types of chronic episodic headaches [2 , 3 , 4]. It is recommended to avoid unnecessary tests in the diagnosis of migraine and to apply appropriate pharmacological treatments. Flunarizine is frequently preferred as an effecve prophylacc agent in pediatric cases [5]. It is reported that rats are used as animal species for the migraine model and there are different migraine model methods [6 , 7]. In animal models, nitroglycerin (NTG) is commonly used to invesgate migraine aacks. NTG triggers migraine through its vasodilator effect and is administered in rats (Raus norvegicus) at a dose of 10 mg/kg [8 , 9] Adolescent rats are considered a suitable model represenng childhood and adolescence in humans [6 , 7 , 10]. Glutamine and neuropepde Y (NPY) are significant biomarkers in the pathophysiology of migraine. Elevated plasma glutamate levels in migraine paents, which decrease following prophylacc treatment, have been reported [11]. Oxidave agents are reported to acvate Transient Receptor Potenal (TRP) ion channels, triggering migraine aacks [12]. This study invesgates the effects of Topiramate and Flunarizine on serum glutamine and NPY levels in a migraine model created in adolescent rats. The aim of the study was to test the effects of Flunarizine and Topiramate on the symptoms and some pathophysiological processes of NTG-induced migraine in adolescent rats. MATERIALS AND METHODS This study was conducted with ethical approval from the Local Ethics Commiee for Animal Experiments of Van Yüzüncü Yil University (decision date: 01.12.2022, number: 2022/12-16). Experimental procedures were carried out at the Experimental Medicine Applicaon and Research Center of Van Yüzüncü Yil University. Experimental animals and housing condions The study used 48 Wistar albino rats, aged 6 weeks (adolescent period). The animals were housed in a room with a 12-hour light/dark cycle, temperature of 20-24°C, and humidity of 40-60%. They were fed standard rat chow and tap water ad libitum. Groups and treatments Rats were randomly divided into 6 groups, with 8 animals per group: Healthy control group (n=8): No procedure was applied. Migraine group (n=8): NTG (10 mg/kg) was administered intraperitoneally once a day (d) for 5 d. Migraine + Topiramate group (n=8): NTG (10 mg/kg) was administered once a d, and Topiramate (50 mg/kg) was administered orally twice a d, 12 hours (h) apart, for 5 d. Migraine + Flunarizine group (n=8): NTG (10 mg/kg) was administered once a d, and Flunarizine (5 mg/kg) was administered orally twice a d, 12 h apart, for 5 d. Topiramate Only group (n=8): Topiramate (50 mg/kg) was administered orally twice a d, 12 h apart, for 5 d. Flunarizine only group (n=8): Flunarizine (5 mg/kg) was administered orally twice a d, 12 h apart, for 5 d. Euthanasia and sample collecon At the end of the experiment, all animals were euthanized under general anesthesia using 10 mg/kg Xylazine HCl and 75 mg/kg Ketamine, followed by exsanguinaon. Plasma and serum were separated from the blood samples (Nuve®, NF 1200, Türkiye). Serum analyses NPY levels: Measured using the species-specific Rat Neuropepde Y ELISA test (Cat. No: SL0521Ra; Sunlong Biotech Co. Ltd.®). Glutaminase levels: Determined using the Rat Glutaminase ELISA test (Cat. No: NE010201603; Nephenne®). Histopathological analysis Brain ssue samples were fixed in 10% formalin and embedded in paraffin aſter roune histological processing. Secons of 5 μm thickness were stained with hematoxylin-eosin (H&E) and examined under a light microscope (E-400; Nikon, Japan). Images were recorded with a DS-Ri2 video camera (DS- U3; Nikon, Japan). Stascal analysis The results of the study are shown as Mean and Standard Deviaon. One-way Analysis of Variance (ANOVA) was used to compare group means. Following the analysis of variance, the Duncan test was used to determine the different groups. The stascal significance level was taken as 5% and the SPSS (IBM SPSS for Windows, ver.26) stascal package program was used for calculaons. RESULTS AND DISCUSSION A migraine aack is characterized by neuronal and vascular changes involving corcal exitability and the trigeminovascular system. The pathophysiology of migraine has not yet been fully elucidated. Depression, which involves neuronal, glial and 2 of 5

Effects of Topiramate and Flunarizine in Rats with migraine / Ceylan and Başbuğan UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico vascular cells, has been reported to affect the cerebral cortex in migraine symptoms. Glial cells play a key role in the alteraon of corcal exitability in migraine. Glial cells are crical for central nervous system homeostasis under both physiological and pathological condions. These cells may play a role in the development and progression of neurological diseases [14], 15 , 16 , 17]. The general clinical condion of the rats in all groups was good and no significant difference was observed between the groups. It is stated that aſter the applicaon of NTG in the migraine model, they showed signs of head scratching and tail liſting [18]. During the study, increased head scratching and cage climbing behavior, temporary tension and tail liſting behaviors were observed in the migraine-induced groups following the applicaon of NTG (10 mg/kg). This situaon is consistent with the researchers’ statements that it occurs because of the migraine model [7 , 13 , 18]. They state that these behaviors disappeared over me and no significant difference was detected in food and water consumpon compared to the control group. Several studies using magnezaon transfer rao (MTR) imaging in migraine paents have reported focal microstructural damage associated with migraine; (another study reported no significant difference in MTR in the whole brain and normal- appearing white maer in migraine paents compared to control subjects. Ischemic microvascular disorders together with focal hypoperfusion of the cerebral parenchyma are known to cause white maer lesions (WMLs) The pathophysiological mechanism leading to the formaon of WMLs in migraine and the histopathological effect of migraine-related WMLs are not fully understood [19 , 20 , 21 , 22]. Necroc neurons and hyperemia were observed in all groups except the control group (FIG. A), but these findings did not show a significant difference between the groups. In the migraine group, glial nodules, necroc neurons, hyperemic vessels and inflammatory cells were observed in the brain parenchyma (FIGS. 1B-C-D). Glial nodules were not observed in the topiramate group, but hyperemic vessels were evident (FIG. 1G). Glial nodules were not detected in the flunarizine group and histopathological findings were generally normal (FIG. 1H). These findings prove that NTG causes histopathological changes, and the migraine model occurs as stated by the researchers [7 , 18 , 19]. Glial nodules were detected in only one rat in the Migraine + Topiramate Group (FIG. 1E). No pathological changes were observed in the other members of the group. A similar situaon was also present in the Migraine + Flunarizine Group (FIG. 1F). No nodules were detected in the Topiramate Only Group, but intensely hyperemic vessels were noted (FIG. 1G). No structural changes were observed in the Flunarizine Only Group and histopathological findings were normal (FIG. 1H). In the light of these histopathological findings, it is thought that this is due to the effecveness of Topiramate and Flunarizine drugs used in migraine treatment [23], 24 , 25]. FIGURE 1. Photomicrographs of rat brain secons stained by hematoxylin and eosin staining (H&E.). A) Control group; The normal histological structure of the brain ssue is observed. B) Migraine group; Glial nodules are observed in the brain. C) Migraine group; Necroc neurons are observed in the brain. D) Migraine group; Hyperemia in brain ssue, inflammatory cells (arrows), and free erythrocytes in the brain parenchyma (arrowheads). E) Migraine + Topiramate group; Glial nodule structure observed in brain ssue. F) Migraine + Flunarizine group; Presence of glial nodules observed in brain ssue (arrows). G) Topiramate group; Hyperemia observed in brain ssue (arrows). H) Flunarizine group; Histological structure of brain ssue is close to normal. The decrease in glial nodules and the loss of necroc neurons support the effecveness of the treatment protocols used. These findings suggest that both drugs have neuroprotecve effects in reducing migraine-induced brain ssue damage. Hyperemic vascular structure was observed in only one animal in the Topiramate only Group, while there was no structural change in the Flunarizine only Group; It shows that Flunarizine and Topiramate drugs work with different mechanisms as stated by the researchers [24 , 25], and that the use of these drugs in therapeuc doses does not cause serious histopathological damage. Biochemical findings In this study, the effects of Topiramate and Flunarizine on serum Glutaminase and neuropepde Y (NPY) levels were evaluated in rats with a migraine model induced by nitroglycerin (NTG). During the study, transient tension and tail-raising behaviors were observed following NTG (10 mg/ kg) administraon in the migraine groups, which gradually disappeared over me. This observaon is considered an indicator that NTG successfully induces migraine aacks. Similarly, Sua et al. [13] reported increased locomotor acvity in the NTG-treated group, supporng the validity of the migraine model. Neuropepde Y (NPY) is a molecule that acts as a neuromodulator in the nervous system and regulates various funcons such as pain, stress, feeding, and blood pressure [26]. In this study, although numerical differences in NPY levels were observed among the groups, these differences were not stascally significant compared to the control group (P>0.05) (TABLE I). In their experimental migraine model study, Guo et al (2021) found that NPY mRNA expression and plasma NPY levels in rats with migraine were significantly higher than the control group [27]. 3 of 5

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico TABLE I Neuropepde Y and Glutaminase Levels. Groups Neuropepde Y (pg/mL) Glutaminase (ng/mL) Control 40.79 ± 13.13ᵃ 1.41 ± 0.87ᵃ Migraine 57.63 ± 15.84ᵃ 4.10 ± 1.32ᵇ Migraine + Topiramate 43.57 ± 9.40ᵃ 1.74 ± 1.09ᵃ Migraine + Flunarizine 49.85 ± 9.60ᵃ 1.69 ± 1.77ᵃ Topiramate only 48.94 ± 13.73ᵃ 1.93 ± 0.87ᵃ Flunarizine only 47.96 ± 11.72ᵃ 1.93 ± 0.87ᵃ P Value P>0.05 P>0.05 No stascally significant difference was found when the control and treatment groups were compared as a result of NPY analysis (P>0.05). Glutaminase analysis showed a stas- cally significant increase in glutaminase levels in the migraine group (NTG) compared to the control and other groups (P<0.05) These findings suggest that NPY is secreted during migraine aacks and that topiramate and flunarizine, used in migraine treatment, exhibit therapeuc effects. Considering NPY’s role in stress, pain, and neuronal excitability, its role in migraine pathophysiology warrants further detailed invesgaon [28 , 29]. Glutaminase is an enzyme considered a marker of brain ssue damage. Ferrari et al. [11] reported significantly elevated plasma glutamate levels in migraine paents compared to control groups. In this study, Glutaminase levels in the migraine group (4.10 ± 1.32 ng/mL) were significantly higher than in the control group (1.41 ± 0.87 ng/mL) (P<0.05), confirming the successful establishment of the migraine model (TABLE I). The lower Glutaminase levels observed in the Topiramate and Flunarizine groups compared to the migraine group suggest that these drugs suppress Glutaminase levels and demonstrate their therapeuc effects on migraine. These findings suggest that, as researchers [23], 24 , 25] have different mechanisms and that these drugs may have migraine related neuroinflammaon reducing effects. CONCLUSION The nitroglycerin (NTG) administraon at a dose of 10 mg/kg is suitable for establishing a migraine model. However, increasing the dose and duraon could provide more pronounced clinical and histopathological findings. Elevated levels of NPY and glutaminase were observed during migraine inducon. However, As a result of the stascal analysis, it was seen that glutaminase may be more sensive than NPY as a marker of brain damage. This sensivity requires further validaon through more extensive experimental studies. Both Topiramate and Flunarizine showed posive effects on biochemical parameters (NPY and glutaminase) and histopathological findings. This indicates that both drugs may be effecve in migraine treatment. While the results of this study provide important informaon about the pathophysiology of migraine, long-term studies with more comprehensive analyses on the migraine model are needed. ACKNOWLEDGEMENTS This study was supported by Van Yüzüncü Yıl University Scienfic Research Project Coordinaon Unit as project number TSA-2022-9960. We would like to thank the Van Yüzüncü Yıl University Scienfic Research Projects Coordinaon Unit for their support. Conflict of interest The authors declare that they have no compeng financial interests. Project informaon This research was conducted under the project number TSA-2022-9960, supported by the Scienfic Research Projects Coordinaon Unit of Van Yüzüncü Yıl University. BIBLIOGRAPHIC REFERENCES [1] Graves BW. Management of migraine headaches. 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