Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

Rupasinghe, Rayiky; Dezsi, Gabi; Öztürk, Ezgi; Carron, Simone F.; Hudson, Matthew R.; Casillas‐Espinosa, Pablo M.; Jones, Nigel C.

doi:10.1016/j.expneurol.2022.114088

Cited by 4 publications

(4 citation statements)

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“…To test the antiseizure effect of E2730, a separate cohort of male Wistar rats ( n = 27) underwent kainic acid‐induced SE at 11‐week age 33 . Five rats died during the induction of SE, and 10 weeks later, the remaining animals ( n = 22) were randomly assigned to either of the three doses of E2730 (10, 20, or 100 mg/kg/day) or vehicle for continuous infusion via the osmotic pumps.…”

Section: Methodsmentioning

confidence: 99%

“…To test the antiseizure effect of E2730, a separate cohort of male Wistar rats (n = 27) underwent kainic acid-induced SE at 11-week age. 33 Five rats died during the induction of SE, and 10 weeks later, the remaining animals (n = 22) were randomly assigned to either of the three doses of E2730 (10, 20, or 100 mg/kg/day) or vehicle for continuous infusion via the osmotic pumps. The rats were subjected to continuous video-electroencephalographic (EEG) monitoring for 1 week, then the pumps were replaced by a different dose of E2730 or vehicle (in randomized order) until each rat had received 4 x 1-week treatment periods (Figure 1B).…”

Section: Antiseizure Testing In Mtle Modelmentioning

confidence: 99%

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E2730, an uncompetitive γ‐aminobutyric acid transporter‐1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy

et al. 2023

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ObjectiveMore than one‐third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current anti‐seizure medications (ASMs), while half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of GABA transporter‐1 (GAT‐1), and to test its seizure suppression effects in a chronic rat model of MTLE.MethodsWe first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20 or 100 mg/kg/day of E2730 subcutaneously for one week. Blood sampling and behavioural assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for a week in a randomised cross‐over design. Continuous video‐EEG monitoring was acquired during the treatment period to evaluate epileptic seizures.ResultsPlasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well‐tolerated at all doses and any sedation or neuromotor impairment was mild and transient, resolving within 48 hours of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups.SignificanceThis study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Antiseizure Testing In Mtle Modelmentioning

confidence: 99%

E2730, an uncompetitive γ‐aminobutyric acid transporter‐1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy

et al. 2023

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“…GAERS underwent surgical implantation of cortical recording electrodes to facilitate visualization of electroencephalogram (EEG), as previously described. 29,33 Briefly, rats were anesthetized with isoflurane, placed in a stereotaxic frame, and the scalp shaven and skull exposed. Six burr holes were drilled through the skull, taking care not to breach the dura.…”

Section: Electrode Implantation Surgerymentioning

confidence: 99%

Metyrapone abolishes spike–wave discharge seizures in genetic absence epilepsy rats from Strasbourg by reducing stress hormones

et al. 2023

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Objective: Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures.Methods: Adult male GAERS (n = 38) and nonepileptic control (NEC) rats (n = 4) were used. First, rats were subjected to 30-min restraint stress to assess hypothalamicpituitary-adrenal axis function. Next, we assessed the effects of 30-min noise stress, and cage tilt stress, on spike-wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone.Results: GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p < .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p < .05). Metyrapone, an

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“…This has been accomplished either by giving dams no, or almost no, nesting material and housing them with their litters on top of a wire mesh above the floor of the home cage (i.e., the Limited Bedding & Nesting paradigm), or more simply by restricting the amount of bedding provided on the home cage floor (i.e., the Scarcity paradigm) (for review see Walker et al., 2017). Despite methodological differences, many groups report these manipulations disturb maternal caregiving, specifically resulting in more fragmented behavioral sequencing, rough handling of the pups, and less time spent with the litter (Orso et al., 2019; Walker et al., 2017; more recently see Gallo et al., 2019; Laguna et al., 2022; Raineki et al., 2019; Rincón‐Cortés & Grace, 2022; Rupasinghe et al., 2022; Scarola et al., 2020). Other studies, however, have instead found that dams with restricted bedding spend more time or greater frequency interacting with their pups (Eck et al., 2020; Gallo et al., 2019; Granata et al., 2022; McLaughlin et al., 2011; Shupe & Clinton, 2021).…”

Section: Introductionmentioning

confidence: 99%

Anxiety, aggression, reward sensitivity, and forebrain dopamine receptor expression in a laboratory rat model of early‐life disadvantage

Lonstein,

Vitale,

Olekanma

et al. 2023

Developmental Psychobiology

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Despite early‐life disadvantage (ELD) in humans being a highly heterogenous construct, it consistently predicts negative neurobehavioral outcomes. The numerous environmental contributors and neural mechanisms underlying ELD remain unclear, though. We used a laboratory rat model to evaluate the effects of limited resources and/or heavy metal exposure on mothers and their adult male and female offspring. Dams and litters were chronically exposed to restricted (1‐cm deep) or ample (4‐cm deep) home cage bedding postpartum, with or without lead acetate (0.1%) in their drinking water from insemination through 1‐week postweaning. Restricted‐bedding mothers showed more pup‐directed behaviors and behavioral fragmentation, while lead‐exposed mothers showed more nestbuilding. Restricted bedding‐raised male offspring showed higher anxiety and aggression. Either restricted bedding or lead exposure impaired goal‐directed performance in a reinforcer devaluation task in females, whereas restricted bedding alone disrupted it in males. Lead exposure, but not limited bedding, also reduced sucrose reward sensitivity in a progressive ratio task in females. D1 and D2 receptor mRNA in the medial prefrontal cortex and nucleus accumbens (NAc) were each affected by the early‐life treatments and differently between the sexes. Most notably, adult males (but not females) exposed to both early‐life treatments had greatly increased D1 receptor mRNA in the NAc core. These results illuminate neural mechanisms through which ELD threatens neurobehavioral development and highlight forebrain dopamine as a factor.

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Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

Cited by 4 publications

References 73 publications

E2730, an uncompetitive γ‐aminobutyric acid transporter‐1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy

E2730, an uncompetitive γ‐aminobutyric acid transporter‐1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy

Metyrapone abolishes spike–wave discharge seizures in genetic absence epilepsy rats from Strasbourg by reducing stress hormones

Anxiety, aggression, reward sensitivity, and forebrain dopamine receptor expression in a laboratory rat model of early‐life disadvantage

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