Medicine (RMH) - Research Publications
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ItemCognitive deficits in a rat model of temporal lobe epilepsy using touchscreen-based translational tools(WILEY, 2019-08)OBJECTIVE: Cognitive deficits are commonly observed in people with epilepsy, but the biologic causation of these is challenging to identify. Animal models of epilepsy can be used to explore pathophysiologic mechanisms leading to cognitive problems, as well as to test novel therapeutics. We utilized a well-validated animal model of epilepsy to explore cognitive deficits using novel translational assessment tools/automated rodent touchscreen assays. METHODS: To induce epilepsy, adult Wistar rats were subjected to kainic acid-induced status epilepticus or sham control (n = 12/group). Two months following induction, animals underwent the Pairwise Discrimination and Reversal learning touchscreen tasks, novel object recognition, and the Y maze test of spatial memory. RESULTS: In the Pairwise Discrimination paradigm, only 40% of epilepsy animals acquired the discrimination learning criterion, compared to 100% of sham animals (P = 0.003). Epilepsy and sham animals that successfully acquired the discrimination progressed onto the reversal phase, which measures cognitive flexibility. Of interest, there were no differences in the rate of reversal learning; however, on the first reversal session, epilepsy rats committed more perseverative errors than shams (mean ± SEM: 6.3 ± 0.9 vs 1.8 ± 0.5, P < 0.0001). Additional behavioral analysis revealed that epilepsy rats were significantly impaired in novel object recognition and short-term spatial learning and memory. SIGNIFICANCE: Using translationally relevant behavioral tools in combination with traditional assays to measure cognition in animal models, here we identify impairments in learning and memory, and enhanced perseverative behaviors in rats with epilepsy. These tools can be used in future research to explore biologic mechanisms and treatments for cognitive deficits associated with epilepsy.
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ItemChronic fluoxetine treatment accelerates kindling epileptogenesis in mice independently of 5-HT2A receptors(WILEY, 2018-07)Patients with epilepsy often have mood disorders, and these are commonly treated with antidepressant drugs. Although these drugs are often successful in mitigating depressive symptoms, how they affect the epileptogenic processes has been little studied. Recent evidence has demonstrated that treatment with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs adversely promotes epileptogenesis, which may be of great concern considering the number of patients exposed to these drugs. This study investigated 5-HT2A receptor signaling as a potential mechanism driving the pro-epileptogenic effects of the prototypical SSRI fluoxetine. Male homozygous 5-HT2A receptor knockout mice or wild-type littermates (n = 9-14/group) were treated with continuous fluoxetine (10 mg kg-1 d-1 , sc) or vehicle and subjected to electrical kindling of the amygdala. Compared to vehicle, fluoxetine treatment accelerated kindling epileptogenesis (P < .001), but there was no effect of genotype (P = .75), or any treatment x genotype interaction observed (P = .90). Of interest, fluoxetine treatment increased afterdischarge thresholds in both genotypes (P = .007). We conclude that treatment with fluoxetine promotes epileptogenesis in mice, but this effect is not mediated by 5-HT2A receptors. This suggests that antidepressants may accelerate the onset of acquired epilepsy in patients who have experienced epileptogenic cerebral insults.
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ItemDisease-Modifying Effects of Neural Regeneration Peptide 2945 in the GAERS Model of Absence Epilepsy(SPRINGER/PLENUM PUBLISHERS, 2017-07)Epilepsy is a common neurological condition characterised by spontaneous recurrent seizures. Current anti-epileptic drugs are only effective and tolerated in ~70% of patients, leaving a substantial proportion of patients untreated. As such, there is a pressing need to develop new therapies. We assessed the anti-seizure activity of Neural Regeneration Peptide 2945 (NRP 2945) in the GAERS model of absence epilepsy. Drug effects on seizures were assessed using two study designs. Male adult GAERS were implanted with EEG electrodes to measure seizure frequency. The first study compared the effects of acute sc injection of vehicle, NRP 10 µg/kg, NRP 20 µg/kg, and controlled against the active comparator Valproaic acid (200 mg/kg). In the second study, animals received one of four treatments for 4 weeks: vehicle, NRP 60 µg/kg/day, NRP 120 µg/kg/day (delivered by continuous infusion) or NRP 20 µg/kg sc injected every second day (e.s.d). In the acute study, we found significant (p < 0.01) anti-seizure effects in animals treated with NRP2945 (20 µg/kg) and VPA, with NRP2945 slightly more efficacious, despite the 70,000 times lower molar dosage. In the chronic study, animals receiving 120 µg/kg/day and NRP 20 µg/kg e.s.d had significantly fewer seizures (p < 0.001), compared with vehicle. These effects were sustained for at least 10 days after drug treatment had ceased, indicative of disease-modifying activity. We demonstrate sustained anti-seizure effects of NRP2945, a potent small molecule peptide which enters the brain and is devoid of adverse effects. Early stage first-in-man trials have been initiated for subcutaneously delivered NRP2945 which is a promising step to providing therapeutic benefits for refractory epilepsy patients.
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ItemDNA Methylation Mediates Persistent Epileptiform Activity In Vitro and In Vivo(PUBLIC LIBRARY SCIENCE, 2013-10-02)Epilepsy is a chronic brain disorder involving recurring seizures often precipitated by an earlier neuronal insult. The mechanisms that link the transient neuronal insult to the lasting state of epilepsy are unknown. Here we tested the possible role of DNA methylation in mediating long-term induction of epileptiform activity by transient kainic acid exposure using in vitro and in vivo rodent models. We analyzed changes in the gria2 gene, which encodes for the GluA2 subunit of the ionotropic glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor and is well documented to play a role in epilepsy. We show that kainic acid exposure for two hours to mouse hippocampal slices triggers methylation of a 5' regulatory region of the gria2 gene. Increase in methylation persists one week after removal of the drug, with concurrent suppression of gria2 mRNA expression levels. The degree of kainic acid-induced hypermethylation of gria2 5' region varies between individual slices and correlates with the changes in excitability induced by kainic acid. In a rat in vivo model of post kainic acid-induced epilepsy, we show similar hypermethylation of the 5' region of gria2. Inter-individual variations in gria2 methylation, correlate with the frequency and intensity of seizures among epileptic rats. Luciferase reporter assays support a regulatory role for methylation of gria2 5' region. Inhibition of DNA methylation by RG108 blocked kainic acid-induced hypermethylation of gria2 5' region in hippocampal slice cultures and bursting activity. Our results suggest that DNA methylation of such genes as gria2 mediates persistent epileptiform activity and inter-individual differences in the epileptic response to neuronal insult and that pharmacological agents that block DNA methylation inhibit epileptiform activity raising the prospect of DNA methylation inhibitors in epilepsy therapeutics.
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ItemEthosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy(WILEY, 2013-04)PURPOSE: Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying antiepileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (1) possesses antiepileptogenic effects in the genetic absence epilepsy rats from Strasbourg (GAERS) model of GGE, (2) is associated with a mitigation of behavioral comorbidities, and (3) influences gene expression in the somatosensory cortex region where seizures are thought to originate. METHODS: GAERS and nonepileptic control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22 weeks of age. Subsequently, all animals received tap water only for another 12 weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviors were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using quantitative polymerase chain reaction (qPCR). KEY FINDINGS: ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12-week posttreatment phase (p < 0.05). Furthermore, the anxiety-like behaviors present in GAERS were reduced by ESX treatment (p < 0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme messenger RNA (mRNA) in cortex. SIGNIFICANCE: Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with antiepileptogenic effects against absence seizures and mitigation of behavioral comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.