Objective Cognitive impairment is common in patients with chronic drug‐resistant temporal lobe epilepsy (TLE). Hyperphosphorylated tau (pTau) and amyloid‐β (Aβ) plaques, pathological hallmarks of Alzheimer disease, have been hypothesized to play a mechanistic role. We investigated Aβ plaques and pTau prevalence in TLE patients who underwent resective surgery and correlated their presence with preoperative psychometric test scores and clinical factors. Methods Patients were retrospectively selected from the epilepsy surgery register of the Royal Melbourne Hospital, Australia. Sections from the resected temporal lobe were immunostained for pTau and Aβ plaques (antibodies: AT8, 1E8). The presence and severity of pathology were correlated with clinical characteristics, and verbal and visual learning functions as measured by the Verbal Pair Associates (VPA) test and Rey Complex Figure Test. Results Fifty‐six patients (55% female) aged 20–68 years (median = 34 years) at surgery were included. Aβ plaques were detected in four patients (7%), all at the moderate level. There was no difference in duration, age at onset of epilepsy, or side of resection between patients with and without Aβ plaques. Sparse pTau was found in two patients (3.5%). Both had moderate Aβ plaques and were >50 years of age. Patients with Aβ plaques had a lower median score for the VPA hard assessment compared to those without (0 vs. 4; p = .02). There was otherwise no correlation between pathology and psychometric test scores. Significance Aβ plaques and pTau were uncommon in the resected brain tissue of patients who have undergone temporal lobectomy, and did not correlate with clinical characteristics or preoperative psychometric test scores, except for a lower VPA median score in patients with Aβ plaques. Therefore, considering the low prevalence of Aβ plaques and pTau herein observed, it is unlikely that cognitive impairment in TLE is driven by the same mechanisms as in Alzheimer disease.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.