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Seizures are a symptom of epilepsy, characterized by spontaneous firing due to an imbalance of excitatory and inhibitory features. While mammalian seizure models receive the most attention, the simplicity and tractability of invertebrate model systems, specifically C. elegans and D. melanogaster, have many advantages in understanding the molecular and cellular mechanisms of seizure behavior. This research explores C. elegans and D. melanogaster as electroconvulsive seizure models to investigate methods to both modulate and better understand seizure susceptibility. A common underlying feature of seizures in mammals, worms, and flies involves regulating excitation and inhibition. The C. elegans locomotor circuit is regulated via well characterized GABAergic and cholingeric motoneurons that innervate two rows of dorsal and ventral body wall muscles. In this research, we developed an electroconvulsive seizure assay which utilizes the locomotor circuit as a behavioral read out of neuronal function. When inhibition is decreased in the circuit, for example by decreasing GABAergic input, we find a general increase in the time to recovery from a seizure. After establishing the contribution of excitation and inhibition to seizure recovery, we explored a ubiquitin ligase, associated with comorbidity of an X-linked Intellectual Disorder and epilepsy in humans, and established that the worm homolog, eel-1, contributes to seizure susceptibility similarly to the human gene. Next, we investigated a cGMP-dependent protein kinase (PKG) that functions in the nervous system of both worms and flies and determined that increasing PKG activity, decreases the time to recovery from an electroconvulsive seizure. These experiments suggest a potential novel role for a major protein, PKG, in seizure susceptibility and that the C. elegans and D. melanogaster electroconvulsive seizure assays can be used to investigate possible genes involved in seizure susceptibility and future therapeutic to treat epilepsy. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Studies have shown that some canines have the ability to predict seizures in people with epilepsy, and that canines can be trained to recognize changes in humans before an epileptic seizure and make these predictions. It is not known with any certainty to what the canines are alerting. However, canines’ exceptional sense of smell and their ability to discriminate human scent is well established. Therefore, it is possible that the canines could be responding to an olfactory cue, such as the release of some volatile organic compounds (VOCs) prior to the onset of a seizure. Individuals release a wide array of VOCs, both odorous and non-odorous, from their bodies. The odorous VOCs collectively make up human scent and a number of these VOCs have been identified as biomarkers of different diseases. Evidence suggests that canines can perceive these biomarkers, leading to early detection of underlying physical ailments before individuals are aware of their own symptoms. The main purpose of this study was to use headspace solid phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) to analyze hand odor, saliva and breath samples from epileptic with and without seizure activity to determine if the human scent profiles resulting from a seizure event differs from the scent profiles in the absence of seizure activity. the HS-SPME-GC-MS method was also used to analyze and compare hand odor, saliva and breath samples of healthy individuals and epilepsy patients to determine if the profiles can be differentiated. Comparison of the VOCs in each specimen from healthy individuals and epileptic patients revealed compounds that could be used as potential biomarkers to differentiate between healthy and epileptic individuals. Comparison of the VOCs in each specimen from epileptic patients with and without seizure activity revealed compounds that could be used as potential biomarkers for epileptic seizures. Finally, canine trials were used to verify that these compounds are indeed biomarkers.

The purpose of this study was to determine how early seizure blockade with ethosuximide (ESX) would influence ion channel expression and long-term spike-wave discharge (SWD) activity in epileptic WAG/Rij rats. The goal was to elucidate the question Do seizures beget seizures? in a genetically prone model and if so, to attempt to interrupt this cycle by early intervention. In our first experiment, we used immunocytochemistry to determine the effect of ESX on cortical expression of ion channels in treated and untreated WAG/Rij rats and age-matched Wistar controls. This experiment revealed that treatment with ESX blocked the upregulation of Nav1.1 and Nav1.6 as well as the downregulation of HCN1 that is associated with epileptic activity in rats (p < .05). In a second experiment, WAG/Rij rats were divided into 3 groups: untreated (H2O), temporary early treatment (ESX 4 month), and continuous early treatment (ESX continuous), and SWD activity was measured by electroencephalogram (EEG) at various timepoints. This second experiment revealed that animals in the ESX 4 month group spent less percent time in SWD (0.242 ± .068 SEM) than animals in the H2O group (0.769 ± .060 SEM, p < .001), although they spent slightly more percent time in SWD than animals in the ESX continuous group (0.020 ± .065 SEM, p = .003). This effect was predominantly due to seizure number, and average seizure duration did not vary among the three groups. Additionally, power spectrum analysis revealed a significant correlation when the difference between power spectra for H2O and ESX 4 month rats was compared to the power spectrum of a seizure (Pearson correlation equals 0.955, 2-tailed significance < .000000001), suggesting quantitatively that seizures were reduced by temporary early treatment. This suggests that early prevention of SWD may reduce the burden of seizures later in life, and that possibilities for prevention of genetic absence epilepsy should be further investigated.

Introduction: One potential new therapy for epilepsy involves the omega-3 polyunsaturated fatty acids (PUFAs), and more specifically docosahexaenoic acid (DHA).   Methods: The anticonvulsant properties of the n-3 PUFAs were assessed in a series of different experiments. Subjects received chronic dietary supplementation, sub-chronic and acute injections of either fish oil (chronic) or DHA (sub-chronic, acute). Animals were tested in the electrical afterdischarge thresholds (ADTs) model in the amygdale and the maximal pentylenetetrazol (PTZ) model.   Results: Chronic, sub-chronic, and acute administrations of n-3 PUFAs were anticonvulsant in both the electrical stimulation and maximal PTZ models. In chronic experiments, amygala ADTs increased following 3 months of fish oil administration. Fourteen days of DHA i.p. injections increased latencies to maximal PTZ seizures. Acute injection of DHA s.c. and i.v. increased unesterified serum DHA and seizure latency. Conclusions: The present research suggests that n-3 PUFAs, and more specifically DHA, have anticonvulsant effects in vivo.

Introduction: One potential new therapy for epilepsy involves the omega-3 polyunsaturated fatty acids (PUFAs), and more specifically docosahexaenoic acid (DHA).   Methods: The anticonvulsant properties of the n-3 PUFAs were assessed in a series of different experiments. Subjects received chronic dietary supplementation, sub-chronic and acute injections of either fish oil (chronic) or DHA (sub-chronic, acute). Animals were tested in the electrical afterdischarge thresholds (ADTs) model in the amygdale and the maximal pentylenetetrazol (PTZ) model.   Results: Chronic, sub-chronic, and acute administrations of n-3 PUFAs were anticonvulsant in both the electrical stimulation and maximal PTZ models. In chronic experiments, amygala ADTs increased following 3 months of fish oil administration. Fourteen days of DHA i.p. injections increased latencies to maximal PTZ seizures. Acute injection of DHA s.c. and i.v. increased unesterified serum DHA and seizure latency. Conclusions: The present research suggests that n-3 PUFAs, and more specifically DHA, have anticonvulsant effects in vivo.

Thesis (M.Eng.). / Written for the Dept. of Biomedical Engienering and Montreal Neurological Institute. Title from title page of PDF (viewed 2009/06/17). Includes bibliographical references.

Thesis (Ph.D. in Pharmacology) -- University of Colorado, 2006. / Typescript. Includes bibliographical references (leaves 125-149). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Behavioral and neurochemical studies were carried out with 21 days-old rats pretreated or not with nimodipine (10 or 30mg/Kg, i.p.) on pilocarpine-induced seizures (400mg/Kg, s.c.) to investigate the mechanism involved in the acute phase of seizures and the effects of nimodipine on seizures. The behavioral studies showed peripheral cholinergic signs, stereotyped movements, convulsions, status epilepticus in all animals and death in less degree after administration of P400, and the pretreatment with nimodipine reduced convulsions, the latency of first convulsion and death. Neurochemical studies in striatum showed levels increased of lipid peroxidation, nitrite and catalase activity, and nimodipine reverted this effect. Biochemical studies showed that striatum cholinergic and dopaminergic receptors in young rats were decreased after observation period, while the Kd values decreased only in D2 dopaminergics receptors. P400 decreased dopamine and serotonin levels and their metabolites DOPAC and 5-HIAA, respectively; otherwise, the dopaminergic HVA metabolite was increased. In this time, the pretreatment with nimodipine decreased dopaminergic metabolite and increased serotonergic, HVA and 5-HIAA, respectively. Our results showed that young animals are sensitive to epileptogenic stimuli, but they are relatively resistant to death, and nimodipine exhibited a protective effect on the pilocarpine-induced seizures. However, the knowledge of seizures physiopathology and effects of nimodipine on seizures should be better investigated. / Estudos comportamentais e neuroquÃmicos foram realizados em ratos com 21 dias de idade, atravÃs do prÃ-tratamento ou nÃo com nimodipina (10 ou 30mg/Kg, i.p.) e administraÃÃo de pilocarpina (400mg/Kg, s.c., P400), a fim de investigar o mecanismo da fase aguda do processo convulsivo e os efeitos da nimodipina nas convulsÃes. Os animais foram observados durante 1h e logo depois sacrificados. Os estudos comportamentais mostraram que P400, produziu sinais colinÃrgicos perifÃricos (SCP), movimentos estereotipados (ME), convulsÃes e estado epilÃptico em todos os animais, todavia o Ãndice de morte foi em torno de 30%. O prÃ-tratamento com nimodipina nÃo alterou os SCP e ME, mas diminuiu o Ãndice de convulsÃes e aumentou as latÃncias da primeira convulsÃo e morte. Os estudos neuroquÃmicos em corpo estriado, apÃs 1h da administraÃÃo de P400, revelaram um aumento nos nÃveis de peroxidaÃÃo lipÃdica, produÃÃo de nitrito e atividade da catalase, e esses efeitos foram revertidos pelo prÃ-tratamento com nimodipina. A densidade dos receptores colinÃrgicos (M1+M2) e dopaminÃrgicos (D1 e D2) apresentou-se diminuÃda, enquanto a constante de dissociaÃÃo (Kd) foi diminuÃda apenas nos receptores D2. P400 reduziu a concentraÃÃo das monoaminas dopamina (DA) e serotonina (5-HT), e de seus respectivos metabÃlitos, 3,4 Ãcido dihidroxifenilacÃtico (DOPAC) e Ãcido 5-hidroxiindolacÃtico (5-HIAA), enquanto nos nÃveis do metabÃlito dopaminÃrgico, Ãcido homovanÃlico (HVA), foi observado um aumento. Por sua vez, o prÃ-tratamento com nimodipina nas convulsÃes com P400 resultou em uma reduÃÃo do metabÃlito dopaminÃrgico e aumento do metabÃlito serotonÃrgico, HVA e 5-HIAA, respectivamente. Nossos estudos mostram que os animais imaturos sÃo susceptÃveis Ãs convulsÃes, mas apresentam uma certa resistÃncia à morte durante o processo convulsivo, e que a nimodipina exerce uma atividade protetora minimizando as convulsÃes induzidas por P400. Contudo, o conhecimento da fisiopatologia da convulsÃo e a identificaÃÃo dos efeitos da nimodipina nas convulsÃes devem ser melhor investigados para facilitar o conhecimento dos fatores inerentes à epilepsia e aÃÃes da nimodipina no processo convulsivo.

Class of 2013 Abstract / Specific Aims: Guidelines developed by the Brain Trauma Foundation recommend the use of prophylactic anticonvulsants, particularly phenytoin, for the prevention of early posttraumatic seizures for patients with severe traumatic brain injuries. The purpose of this study is to evaluate the effectiveness of levetiracetam, a newer anticonvulsant, for posttraumatic seizure prevention in patients with severe traumatic brain injury. Methods: This study was approved by the University of Arizona Medical Center Institutional Review Board. The project consists of a retrospective cohort analysis from January 1, 2010 to September 30, 2011. We have abstracted data from all patients with traumatic brain injuries over this time period from the University of Arizona Medical Center Trauma Registry, and have matched these patients with their records in the pharmacy database to determine who received levetiracetam versus no prophylaxis. Patients younger than 18 years of age, pregnant women, patients who were deemed to be nonsalvageable, and patients who had a seizure prior to initiation of levetiracetam were excluded from the study. The following data was collected: age, gender, ethnicity, mechanism of injury, injury severity score, ED GCS, ED SBP, ED pulse, ED RR, blood alcohol level, ICU length of stay, number of ventilator days, hospital length of stay, FIM score at discharge (totals, and by component), diagnosis, surgery and complication type, anticonvulsant given, type of beta-blocker given, maximum and minimum dose used, cumulative doses given, and whether there exists a known prior history of anticonvulsant use. All data were recorded without patient identifiers and have been kept confidential. A multivariate logistic regression analysis was used to evaluate a relationship between other data collected from the patients’ medical records and seizure occurrence. Chi Square or Fisher's Exact test will be used in the final analysis to compare the effectiveness of levetiracetam versus no prophylaxis to prevent posttraumatic brain injury seizures. Significance is defined as p<0.05 for all analyses. Main Results: The results are pending the final data analysis. Conclusion: To be determined.