Development of a Rat Model for Glioma-Related Epilepsy

Abstract

Seizures are common in patients with high-grade gliomas (30–60%) and approximately 15–30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures.

Comparison of In Vivo and Ex Vivo Magnetic Resonance Imaging in a Rat Model for Glioblastoma-Associated Epilepsy

“…In vivo MRI provides a general representation of the tumor mass and peritumoral tissue changes, ex vivo MRI allows a delineation of the tumor mass, and histology allows the visualization and characterization of the tumor mass, the peritumoral GB cell infiltrations and inflammatory cells. As a rat model for GB-associated epilepsy [16] was used in the current study, further optimization of in vivo MRI protocols, in combination with extensive histological analyses, may allow achieving a more detailed characterization of the model and help to understand the process of epileptogenesis in GB. The implantation of MRI-compatible electrodes would allow researchers to continuously record EEG for the detection of epileptic seizures and study their relation to glioma-induced anatomical and functional changes on follow-up (functional) MRI scans during GB progression.…”

“…Several rodent models for GB have been developed [15]. The syngeneic Fischer/F98 rat model of GB, characterized as a GB-related epilepsy model [16] at Ghent University, has characteristics that closely resemble those of human GB with regard to its aggressiveness, histological appearance and lack of immunogenicity [17], and this model was used in the current study.…”

Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

“…Depending on the number of cells injected, the animals survive for about 2–5 weeks after glioma implantation [ 169 , 185 , 186 , 187 ]. Recently, the model was reported to develop a tumor-associated seizure during glioma progression [ 169 , 170 ]. In line with own data from video-EEG analyses ( Figure 3 B), Bouchaert et al (2020) observed seizures in all tumor-bearing animals in their study.…”

“…In line with own data from video-EEG analyses ( Figure 3 B), Bouchaert et al (2020) observed seizures in all tumor-bearing animals in their study. However, the model shows a heterogeneous distribution of the seizures, with some animals suffering from more seizures per day and others having only a few seizures over the entire period of the experiment [ 169 , 170 ]. Between the seizures, interictal events can be found in the EEG (black traces in Figure 3 B).…”

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

“…Gliomas are the most common malignant tumors of the central nervous system, accounting for more than 80% of cases, and have complex survival outcomes ( Lin et al, 2017 ; Bouckaert et al, 2020 ). Existing therapeutic strategies and regimens have proven inadequate ( Qin et al, 2017 ).…”