Evaluation of the effects of liraglutide on the development of epilepsy and behavioural alterations in two animal models of epileptogenesis

Abstract

Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300 g/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300 µg/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognised neuroprotective properties.

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…In addition, during this study we narrowed our focus on the influence of ketone supplement-evoked effects to the adenosinergic system. Nevertheless, this WAG/Rij rat strain is extensively used for investigation of different drugs on CNS diseases [1,[67][68][69][70][71], and the present study further supports our previous experiments [23] on the role of the adenosinergic system. It has been suggested that the ketosis/βHB-evoked increase in adenosine levels [14] can modulate influence of ketone supplements not only on different CNS diseases [8,32,36], but also sleep and sleep-like effects [20,21,[28][29][30] via adenosinergic system (likely through A1Rs).…”

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…In addition, during this study we narrowed our focus on the influence of ketone supplement-evoked effects to the adenosinergic system. Nevertheless, this WAG/Rij rat strain is extensively used for investigation of different drugs on 13 CNS diseases [1,[67][68][69][70][71], and the present study further supports our previous experiments [23] on the role of the adenosinergic system. It has been suggested that the ketosis/βHB-evoked increase in adenosine levels [14] can modulate influence of ketone supplements not only on different CNS diseases [8,32,36], but also sleep and sleep-like effects [20,21,[28][29][30] via adenosinergic system (likely through A1Rs).…”

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models

“…Thus, the main goal of the present study was to determine if specific ketogenic supplements and/or combinations would improve motor performance in rodents with pathology (Wistar Albino Glaxo/Rijswijk, WAG/Rij/WR rats and Glut1 Deficiency Syndrome/G1D mice) and without pathology (Sprague-Dawley/SPD rats) [ 36 , 37 ] and to test whether they are able to offset the postexercise induced blood glucose elevation. WR rat strain is an accepted model of absence epilepsy with comorbidity of low-grade depression, but without pathological changes in locomotor activity/motor performance [ 38 , 39 , 40 ], while G1D mice are models of Glut1 Deficiency Syndrome and show motor dysfunction [ 37 , 41 ]. We hypothesized that nutritional ketosis induced by various ketone therapeutics (KD and exogenous ketone supplements) can improve motor performance in rodent models, as defined by latency to fall from the accelerated rotarod and can offset blood glucose elevation in postexercised states.…”