Browsing by Author "Onat, Filiz"

Now showing 1 - 8 of 8

Astrocytes as a target for therapeutic strategies in epilepsy: current insights
(Frontiers, 2023-07-31) Çarçak, Nihan; Onat, Filiz; Sitnikova, Evgenia
Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1- BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosinemetabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.
Climate change and epilepsy: Insights from clinical and basic science studies
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-01-01) Gulcebi I, Medine; Bartolini, Emanuele; Lee, Omay; Lisgaras, Christos Panagiotis; Onat, Filiz; Mifsud, Janet; Striano, Pasquale; Vezzani, Annamaria; Hildebrand, Michael S.; Jimenez-Jimenez, Diego; Junck, Larry; Lewis-Smith, David; Scheffer, Ingrid E.; Thijs, Roland D.; Zuberi, Sameer M.; Blenkinsop, Stephen; Fowler, Hayley J.; Foley, Aideen; Sisodiya, Sanjay M.; Balestrini, Simona; Berkovic, Samuel; Cavalleri, Gianpiero; Correa, Daniel Jose; Custodio, Helena Martins; Galovic, Marian; Guerrini, Renzo; Henshall, David; Howard, Olga; Hughes, Kelvin; Katsarou, Anna; Koeleman, Bobby P. C.; Krause, Roland; Lowenstein, Daniel; Mandelenaki, Despoina; Marini, Carla; O'Brien, Terence J.; Pace, Adrian; De Palma, Luca; Perucca, Piero; Pitkanen, Asla; Quinn, Finola; Selmer, Kaja Kristine; Steward, Charles A.; Swanborough, Nicola; Thijs, Roland; Tittensor, Phil; Trivisano, Marina; Weckhuysen, Sarah; Zara, Federico; Consortium, Epilepsy Climate Change
Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change. (C) 2021 Elsevier Inc. All rights reserved.
Dexmedetomidine, an alpha 2A receptor agonist, triggers seizures unilaterally in GAERS during the pre-epileptic phase: does the onset of spike-and-wave discharges occur in a focal manner?
(Frontiers, 2023-12-11) Yavuz, Melis; İyiköşker, Pelin; Mutlu, Nursima; Kılıçparlar, Serra; Şalcı, Öykü Hazal; Dolu, Gökçen; Kaymakçılar, Elif Nur; Akkol, Serdar; Onat, Filiz
Introduction: The genetic absence epilepsy rat from Strasbourg (GAERS) is a rat model for infantile absence epilepsy with spike-and-wave discharges (SWDs). This study aimed to investigate the potential of alpha 2A agonism to induce seizures during the pre-epileptic period in GAERS rats. Methods: Stereotaxic surgery was performed on male pups and adult GAERS rats to implant recording electrodes in the frontoparietal cortices (right/left) under anesthesia (PN23–26). Following the recovery period, pup GAERS rats were subjected to electroencephalography (EEG) recordings for 2 h. Before the injections, pup epileptiform activity was examined using baseline EEG data. Dexmedetomidine was acutely administered at 0.6 mg/kg to pup GAERS rats 2–3 days after the surgery and once during the post-natal (PN) days 25–29. Epileptiform activities before injections triggered unilateral SWDs and induced sleep durations, and power spectral density was evaluated based on EEG traces. Results: The most prominent finding of this study is that unilateral SWD-like activities were induced in 47% of the animals with the intraperitoneal dexmedetomidine injection. The baseline EEGs of pup GAERS rats had no SWDs as expected since they are in the pre-epileptic period but showed low-amplitude non-rhythmic epileptiform activity. There was no di􀀀erence in the duration of epileptiform activities between the basal EEG groups and DEX-injected unilateral SWD-like-exhibiting and non-SWD-like activities groups; however, the sleep duration of the unilateral SWD-like-exhibiting group was shorter. Power spectrum density (PSD) results revealed that the 1.75-Hz power in the left hemisphere peaks significantly higher than in the right. Discussion: As anticipated, pup GAERS rats in the pre-epileptic stage showed no SWDs. Nevertheless, they exhibited sporadic epileptiform activities. Specifically, dexmedetomidine induced SWD-like activities solely within the left hemisphere. These observations imply that absence seizures might originate unilaterally in the left cortex due to a2AAR agonism. Additional research is necessary to explore the precise cortical focal point of this activity.
Investigation of Neurogenesis in Kindled Wistar and Genetic Absence Epilepsy Rats
(MARMARA UNIV, INST HEALTH SCIENCES, 2022-01-01) Kandemir, Cansu; Yavuz, Melis; Karakaya, Fatma Bedia; Kaya, Ozlem Tugce Cilingir; Onat, Filiz; Sirvanci, Serap
Objective: The most common type of epilepsy affecting about 50 million people worldwide is temporal lobe epilepsy (TLE). Chemical and electrical kindling methods in animals can be used to form TLE model. In the present study, it was aimed to investigate neurogenesis in the hippocampus of adult kindled Wistar rats and genetic absence epilepsy rats from Strasbourg (GAERS) rats by immunofluorescence methods.Methods: Adult Wistar and GAERS albino rats weighing 250-300 gr were injected pentylenetetrazole (PTZ) (35 mg/kg, s.c.) every other day to produce chemical kindling. Animals having 5 times grade 5 seizures were considered to be kindled. Intracardiac perfusion was performed under deep anesthesia on the 7th and 14th days after the last grade 5 seizure. Immunofluorescence methods were used to demonstrate newly formed neurons, astroglial cells, and mature neurons, by using anti-doublecortin (DCX), anti-glial fibrillary acidic protein (GFAP), and antineuronal nuclear antigen (NeuN) primary antibodies, respectively. Sections were then examined under a fluorescence microscope.Results: DCX (+) cells were found to be increased in GAERS control groups compared to the Wistar control groups
Involvement of orexin type-2 receptors in genetic absence epilepsy rats
(Frontiers, 2023-11-30) Toplu, Aylin; Mutlu, Nursima; Erdeve, Elif Tuğçe; Sarıyıldız, Özge; Çelik, Musa; Arslan, Devrim Öz; Akman, Özlem; Molnar, Zoltar; Çarçak, Nihan; Onat, Filiz
Introduction: Orexin is a neuropeptide neurotransmitter that regulates the sleep/ wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. The pharmacological effect of a selective OX2R agonist, YNT-185 on spike-andwave- discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated. Methods: The effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slowwave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats. Results: We showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p < 0.05). However, intrathalamic and intracortical microinjections of YNT-185 did not show a significant effect on SWDs. ICV microinjections of YNT-185 affect sleep states by increasing the percentage of SWS and showed a significant treatment effect on the 1–4 Hz delta frequency band power during the 1–2 h post-injection period where YNT-185 significantly decreased the SWDs. OXR2 protein levels were significantly reduced in the cortex and thalamus of GAERS when compared to Wistar rats. Conclusion: This study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS and revealed a suppressive effect of OX2R agonist on SWDs as evidenced by the significantly reduced expression of OX2R in the cortex and thalamus. YNT-185 effect on SWDs could be attributed to its regulation of wake/sleep states. The results constitute a step toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy.
Pharmacokinetic characterization of favipiravir in patients with COVID-19
(WILEY, 2022-01-01) Gulhan, Rezzan; Eryuksel, Emel; Oglu, Medine Gulcebi Idriz; Culpan, Yekta; Toplu, Aylin; Kocakaya, Derya; Tigen, Elif; Sengel, Buket Erturk; Sili, Uluhan; Yildizeli, Sehnaz Olgun; Balcan, Mehmet Baran; Elci, Abdullah; Bulut, Cenk; Karaalp, Atila; Yananli, Hasan Raci; Guner, Abdullah Emre; Hatipoglu, Mustafa; Karakurt, Sait; Korten, Volkan; Ratnaraj, Neville; Patsalos, Philip; Ay, Pinar; Onat, Filiz
This prospective observational study describes the pharmacokinetic characteristics of favipiravir in adult patients hospitalized for mild to moderate COVID-19 with a positive RT-PCR test. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a maintenance dose of 1200 mg/day. Serial blood samples were collected on Day 2 and Day 4 of the therapy. Laboratory findings of the patients (n = 21) and in-hospital mortality were recorded. Favipiravir concentrations exhibited substantial variability and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough) on Day 2 was 21.26 (interquartile range {[}IQR], 8.37-30.78) mu g/mL, whereas it decreased significantly to 1.61 (IQR, 0.00-6.41) mu g/mL on Day 4, the area under the concentration-time curve decreased by 68.5\%. Day 2 C0-trough of female patients was higher than male patients. Our findings indicate that favipiravir concentrations show significant variability during the treatment of COVID-19 and therapeutic drug monitoring may be necessary to maintain targeted concentrations.
Pharmacologically induced absence seizures versus kindling in Wistar rats
(KARE PUBL, 2020-01-01) Carcak, Nihan; Sahiner, Melike; Akman, Ozlem; Idrizoglu, Medine Gulcebi; Cortez, Miguel A.; Snead, O. Carter; Eskazan, Esat; Onat, Filiz
OBJECTIVE: This study aimed to investigate the effects of gamma-butyrolactone (GBL), a prodrug of gamma-Hydroxybutyric acid-induced absence seizures on the development of kindling in Wistar rats. METHODS: Three groups of adult male Wistar rats under anesthesia were implanted with bilateral cortical recording elec- trodes for the GBL group (GBL) and/or bipolar stimulation electrodes into the right basolateral amygdala for the Kindling group (KI) alone and Kindling plus GBL group (GBL+KI). Rats in the KI and GBL+KI groups were stimulated twice daily at the afterdischarge threshold until they reached Racine's stage 5 seizure state. The animals in the GBL + group had an i.p injection of GBL 20 minutes before each electrical stimulation, and the effects of GBL-induced seizures on the development of kindling were investigated. The animals in the GBL group were injected GBL twice daily i.p. for 15 days without receiving any electrical stimulation. RESULTS: The KI animals reached stage 5 seizure stage at 12th stimulations, whereas the GBL+KI rats reached at 27th stimulations. The mean numbers of stimulations needed for the development of the first stage 3, 4, or 5 generalized seizures were significantly higher in the GBL+KI group than the KI group. CONCLUSION: The resistance to amygdala kindling in the GBL model can be modulated by the absence seizure mechanism alone, without the intervention of an abnormal genetic background.
The Acute and Delayed Effects of Vagal Nerve Stimulation on an Absence Epilepsy Model in WAG/Rij
(TURKISH NEUROSURGICAL SOC, 2016-01-01) Uyar, Ramazan; Turk, Cezmi Cagri; Isik, Nejat; Kalelioglu, Mufit; Onat, Filiz; Ozek, Memet
AIM: Vagal nerve stimulation (VNS) is an effective method of treatment for epilepsy patients either unresponsive to medical therapy or not suitable for resective surgeries. We designed an experimental study on Wistar Albino Glaxo rats from Rijswijk (WAG\textbackslash{}Rij) to investigate the effects of VNS on a non-convulsive epilepsy model. MATERIAL and METHODS: The experiment was performed on six WAG/Rij rats, a validated strain for genetic absence seizures. The animals were underwent VNS and the effects were investigated on electroencephalography (EEG) recordings at 22, 24, 26 hours of stimulation and 15 days after the cessation, for duration of spike and wave complexes (SWC), the numbers, mean duration of SWC and frequencies in an hour. RESULTS: EEG recordings demonstrated that the mean duration of SWC was 353.1 seconds and the number of activity per hour was 62 at the baseline. There were statistically significant decreases in the total duration of SWC and the number of activities (61.8\% and 78\% decrease, respectively). There were no significant decreases in the mean duration of SWC and the frequencies. CONCLUSION: The acute stimulation of the vagal nerve caused a statistically significant decrease both in overall duration of SWC and the number of complexes in an hour. Moreover, the positive effects seemed to last even 15 days after the cessation of the stimulation. Further studies focusing on different stimulation parameters and delayed effects of the VNS on human absence seizures are warranted.