Gender-Specific Effects of Chronic Y-27632 Administration On Spike-and-Wave Discharges in Genetic Absence Epilepsy Rats

Melis Yavuz; İsmail Ata Yüceel; Görkem Gökkaya; Deniz Athena Tekdemir; Gül Batum; Berfe Bengisu Aydın; Filiz Onat

doi:10.31067/acusaglik.1347853

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Gender-Specific Effects of Chronic Y-27632 Administration On Spike-and-Wave Discharges in Genetic Absence Epilepsy Rats

Year 2024, , 121 - 126, 01.04.2024

Melis Yavuz , İsmail Ata Yüceel Görkem Gökkaya Deniz Athena Tekdemir Gül Batum Berfe Bengisu Aydın Filiz Onat

https://doi.org/10.31067/acusaglik.1347853

Abstract

Background/Purpose: The acute intracerebroventricular (i.c.v.) injection of a Rho kinase inhibitor Y-27632 has been demonstrated to reduce the total seizure duration and mean duration of seizures in male GAERS (Genetic Absence Epilepsy Rats from Strasbourg). The purpose of this research is to determine the chronic use of five days will effect the spike-and-wave discharges (SWD) of absence epilepsy in female GAERS as well as to show if there is any difference in the expression of SWDs between female and male GAERS.
Methods: Five female weighing about 150-350 grams, and male GAERS were used in experiments. Stereotaxic surgery was performed to insert EEG recording electrodes over the fronto-parietal cortices under anesthesia. Female GAERS were injected with the substance Y-27632 intraperitoneally over the course of five days rats, and compared to the baseline EEG of the same animals. In addition male and female GAERS baseline SWD characteristics were analyzed using EEG recordings and paired and unpaired t-tests were performed.
Results: Total and mean SWD duration, and the number of SWDs did not significantly differ when applied to female GAERS. Although a trend of reduced total duration was observed in female rats it was not statistically significant. For the comparison of the mean duration and number of SWDs between the female and male GAERS, a significant difference was observed (p< 0.05). While the mean duration for SWDs is shorter in duration in females (t(8) = 3.23, p = 0.01), the number of SWDs were more in females in comparison to male GAERS (t(8) = 2.97, p = 0.02).
Conclusion: This study highlights the intricate relationship between gender, epilepsy, and pharmacological interventions. Although some outcomes did not reach statistical significance, trends suggest potential gender-related differences in SWD response to Y-27632 or SWD expression in general. The administration route may not be as effective in intraperitoneal route as in i.c.v. Further experiments can be performed by changing the route of administration.

Keywords

GAERS, SWDs, ROCK, Y27632, female

References

1. Panayiotopoulos CP, Chroni E, Daskalopoulos C, Baker A, Rowlinson S, Walsh P. Typical absence seizures in adults: clinical, EEG, video-EEG findings and diagnostic/syndromic considerations. J Neurol Neurosurg Psychiatry. 1992;55(11):1002-8.
2. Loscher W. Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochem Res. 2017;42(7):1873-88.
3. Löscher W, Ferland R, Ferraro T. Strain effects on expression of seizures and epilepsy. In: Pitkänen A, Buckmaster P, Galanopoulou AS, Moshé SL, editors. Models of seizures and epilepsy. 2nd edition. San Diego, California: Elsevier; 2017. p. 21-38.
4. Coenen AM, Van Luijtelaar EL. The WAG/Rij rat model for absence epilepsy: age and sex factors. Epilepsy Res. 1987;1(5):297-301.
5. Marescaux C, Vergnes M. Genetic Absence Epilepsy in Rats from Strasbourg (GAERS). The Italian Journal of Neurological Sciences. 1995;16(1):113-8.
6. Reid CA, Phillips AM, Petrou S. HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications. Br J Pharmacol. 2012;165(1):49-56.
7. Cain SM, Tyson JR, Choi HB, Ko R, Lin PJC, LeDue JM, et al. CaV 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. Epilepsia. 2018;59(4):778-91.
8. Gülhan Aker R, Tezcan K, Carçak N, Sakalli E, Akin D, Onat FY. Localized cortical injections of ethosuximide suppress spike-and-wave activity and reduce the resistance to kindling in genetic absence epilepsy rats (GAERS). Epilepsy Res. 2010;89(1):7-16.
9. Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O'Brien TJ, et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia. 2013;54(4):635-43.
10. Yavuz M, Aydin B, Carcak N, Akman O, Raci Yananli H, Onat F. Atipamezole, a specific alpha2A antagonist, suppresses spike-and-wave discharges and alters Ca(2(+)) /calmodulin-dependent protein kinase II in the thalamus of genetic absence epilepsy rats. Epilepsia. 2020.
11. Yavuz M, Akkol S, Onat F. ALPHA-2A ADRENERGIC RECEPTOR (α2AR) ACTIVATION IN GENETIC ABSENCE EPILEPSY: AN ABSENCE STATUS MODEL? Authorea. 2022.
12. Nourbakhsh K, Yadav S. Kinase Signaling in Dendritic Development and Disease. Front Cell Neurosci. 2021;15:624648.
13. Jeon BT, Jeong EA, Park SY, Son H, Shin HJ, Lee DH, et al. The Rho-kinase (ROCK) inhibitor Y-27632 protects against excitotoxicity-induced neuronal death in vivo and in vitro. Neurotoxicity research. 2013;23(3):238-48.
14. Kitaoka Y, Kitaoka Y, Kumai T, Lam TT, Kuribayashi K, Isenoumi K, et al. Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res. 2004;1018(1):111-8.
15. Inan S, Büyükafşar K. Antiepileptic effects of two Rho-kinase inhibitors, Y-27632 and fasudil, in mice. Br J Pharmacol. 2008;155(1):44-51.
16. Çarçak N, Yavuz M, Eryiğit Karamahmutoğlu T, Kurt AH, Urhan Küçük M, Onat FY, et al. Suppressive effect of Rho-kinase inhibitors Y-27632 and fasudil on spike-and-wave discharges in genetic absence epilepsy rats from Strasbourg (GAERS). Naunyn Schmiedebergs Arch Pharmacol. 2018;391(11):1275-83.
17. Becker JB, Koob GF. Sex Differences in Animal Models: Focus on Addiction. Pharmacol Rev. 2016;68(2):242-63.
18. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509(7500):282-3. 19. Prendergast BJ, Onishi KG, Zucker I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev. 2014;40:1-5.
20. Christensen J, Kjeldsen MJ, Andersen H, Friis ML, Sidenius P. Gender differences in epilepsy. Epilepsia. 2005;46(6):956-60.
21. Reddy DS. The neuroendocrine basis of sex differences in epilepsy. Pharmacology Biochemistry and Behavior. 2017;152:97-104.
22. Akman O, Moshé SL, Galanopoulou AS. Sex-specific consequences of early life seizures. Neurobiol Dis. 2014;72 Pt B(Pt B):153-66.
23. van Luijtelaar G, Onat FY, Gallagher MJ. Animal models of absence epilepsies: what do they model and do sex and sex hormones matter? Neurobiol Dis. 2014;72 Pt B:167-79.
24. Budde B, Maksimenko V, Sarink K, Seidenbecher T, van Luijtelaar G, Hahn T, et al. Seizure Prediction in Genetic Rat Models of Absence Epilepsy: Improved Performance through Multiple-Site Cortico-Thalamic Recordings Combined with Machine Learning. eNeuro. 2022;9(1).
25. Islam MR, Abdullah JM. Age-dependent Electroencephalographic Differences in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) Model of Absence Epilepsy. The Malaysian journal of medical sciences : MJMS. 2014;21(Spec Issue):34-40.
26. Yavuz M, Albayrak N, Özgür M, Gülçebi İdriz Oğlu M, Çavdar S, Onat F. The effect of prenatal and postnatal caffeine exposure on pentylentetrazole induced seizures in the non-epileptic and epileptic offsprings. Neurosci Lett. 2019;713:134504.
27. Powell KL, Tang H, Ng C, Guillemain I, Dieuset G, Dezsi G, et al. Seizure expression, behavior, and brain morphology differences in colonies of Genetic Absence Epilepsy Rats from Strasbourg. Epilepsia. 2014;55(12):1959-68.
28. Karakaya FB, Yavuz M, Sirvanci S. Histological analysis of the effects of thymoquinone on testicular damage in pentylenetetrazole-induced temporal lobe epilepsy model. Andrologia. 2021;53(10):e14130.
29. Ozmen B, Ciftci RK, Yavuz M, Carcak N, Gulcebi Idriz Oglu M, Molnar Z, et al., editors. Automatic detection of seizure activity from EEG recordings of genetic rat model of absence epilepsy. SIU 2021 - 29th IEEE Conference on Signal Processing and Communications Applications, Proceedings; 2021.