Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the brain caused by a disruption of the delicate balance between excitation and inhibition. Neuropeptides can contribute to such misbalance by modulating the effect of classical excitatory and inhibitory neurotransmitters. In this review, we discuss 21 different neuropeptides that have been linked to seizure disorders. These neuropeptides show an aberrant expression and/or release in animal seizure models and/or epilepsy patients. Many of these endogenous peptides, like adrenocorticotropic hormone, angiotensin, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, are able to suppress seizures in the brain. Other neuropeptides, such as arginine-vasopressine peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive properties. For oxytocin and melanin-concentrating hormone both pro- and anticonvulsive effects have been reported, and this seems to be dose or time dependent. All these neuropeptides and their receptors are interesting targets for the development of new antiepileptic drugs. Other neuropeptides such as nesfatin-1 and vasoactive intestinal peptide have been less studied in this field; however, as nesfatin-1 levels change over the course of epilepsy, this can be considered as an interesting marker to diagnose patients who have suffered a recent epileptic seizure.

Quantitative real-time PCR (qPCR) is a commonly used technique to quantify gene expression levels. Validated normalization is essential to obtain reliable qPCR data. In that context, normalizing to multiple reference genes has become the most popular method. However, expression of reference genes may vary per tissue type, developmental stage and in response to experimental treatment. It is therefore imperative to determine stable reference genes for a specific sample set and experimental model. The present study was designed to validate potential reference genes in hippocampal tissue from rats that had experienced early-life febrile seizures (FS). To this end, we applied an established model in which FS were evoked by exposing 10-day old rat pups to heated air. One week later, we determined the expression stability of seven frequently used reference genes in the hippocampal dentate gyrus.

A growing societal awareness is calling upon scientists to reconsider the use of animals in research, which stimulates the development of translational in vitro models. The physiological and architectural interactions between different cell types within an organ present a challenge to these models, particularly for a complex organ such as the brain. Thus far, in vitro brain models mostly consist of a single cell type and demonstrate little predictive value. Here, we present a co-culture of an epileptic human neocortical biopsy on a layer of human induced pluripotent stem cell (hiPSC)-derived cortical neurons. The activity of the cortical neurons was recorded by a 120-electrode multi-electrode array. Recordings were obtained at 0, 3, and 6 days after assembly and compared to those obtained from cortical neurons without a biopsy. On all three recording days, the hybrid model displayed a firing rate, burst behavior, number of isolated spikes, inter-spike interval, and network bursting pattern that aligns with the characteristics of an epileptic network as reported by others. Thus, this novel model may be a non-animal, translational alternative for testing new therapies up to six days after resection.

By clearing GABA from the synaptic cleft, GABA transporters (GATs) play an essential role in inhibitory neurotransmission. Consequently, in vivo visualization of GATs can be a valuable diagnostic tool and biomarker for various psychiatric and neurological disorders. Not surprisingly, in recent years several research attempts to develop a radioligand have been conducted, but so far none have led to suitable radioligands that allow imaging of GATs. Here, we provide an overview of the radioligands that were developed with a focus on GAT1, since this is the most abundant transporter and most of the research concerns this GAT subtype. Initially, we focus on the field of GAT1 inhibitors, after which we discuss the development of GAT1 radioligands based on these inhibitors. We hypothesize that the radioligands developed so far have been unsuccessful due to the zwitterionic nature of their nipecotic acid moiety. To overcome this problem, the use of non-classical GAT inhibitors as basis for GAT1 radioligands or the use of carboxylic acid bioisosteres may be considered. As the latter structural modification has already been used in the field of GAT1 inhibitors, this option seems particularly viable and could lead to the development of more successful GAT1 radioligands in the future.