What we have learned from non-human primates as animal models of epilepsy.

Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.

High Concentrations of Cannabidiol Induce Neurotoxicity in Neurosphere Culture System.

Recent studies have demonstrated that cannabinoids are potentially effective in the treatment of various neurological conditions, and cannabidiol (CBD), one of the most studied compounds, has been proposed as a non-toxic option. However, the adverse effects of CBD on neurodevelopmental processes have rarely been studied in cell culture systems. To better understand CBD's influence on neurodevelopment, we exposed neural progenitor cells (NPCs) to different concentrations of CBD (1 µM, 5 µM, and 10 µM). We assessed the morphology, migration, differentiation, cell death, and gene expression in 2D and 3D bioprinted models to stimulate physiological conditions more effectively. Our results showed that CBD was more toxic at higher concentrations (5 µM and 10 µM) and affected the viability of NPCs than at lower concentrations (1 µM), in both 2D and 3D models. Moreover, our study revealed that higher concentrations of CBD drastically reduced the size of neurospheres and the number of NPCs within neurospheres, impaired the morphology and mobility of neurons and astrocytes after differentiation, and reduced neurite sprouting. Interestingly, we also found that CBD alters cellular metabolism by influencing the expression of glycolytic and ß-oxidative enzymes in the early and late stages of metabolic pathways. Therefore, our study demonstrated that higher concentrations of CBD promote important changes in cellular functions that are crucial during CNS development.

Posttraumatic epilepsy: Integrating clinical, inflammatory, and genetic profiles in traumatic brain injury patients.

OBJECTIVE: This study aims to assess the clinical, inflammatory, and genetic profiles of traumatic brain injury (TBI) patients over a 2-year follow-up period, focusing on the development of posttraumatic epilepsy (PTE). METHODS: Fifty-nine patients with acute TBI were recruited in the emergency unit of a hospital in Brazil. Clinical data and blood samples were collected after 10 days of hospitalization for posterior genetic profile (Apolipoprotein E- ApoE and Glutamic Acid Descarboxylase-GAD sequencing) analyses. A subset of 19 patients were assessed for cytokine markers (mRNA expression). The development of PTE was investigated for two years following TBI. Statistical analyses including univariate analysis, multiple correspondence analysis, and Mann-Whitney test were performed. RESULTS: Analysis revealed an association between severe TBI and requirement for neurosurgery and polytrauma (p<0.05), as well as the development of PTE over a two-year follow-up period (p<0.05). Multiple correspondence analysis identified two distinct profiles associated with PTE and Non-PTE outcomes. The PTE profile showed a higher prevalence of the ApoE genotype E3/E3 and GAD1 SNP (rs769391) genotype AA in our study, while the Non-PTE profile showed a higher presence of E3/E4. mRNA expression analysis demonstrated acute elevated levels of TNF-α in the PTE group as compared to Non-PTE patients (6.70±1.53 vs 5.31 ±0.33, p<0.01). SIGNIFICANCE: Our findings underscore the multifactorial nature of aspects potentially contributing to PTE. It is unlikely that any single factor might in isolation have a strong causative influence over the development of epilepsy after TBI. Our results provide a suggestion of potential clustering that might be relevant as prognostic factors for PTE.

Distinctive Neuroanatomic Regions Involved in Cocaine-Induced Behavioral Sensitization in Mice.

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon.

Anticholinergics: A potential option for preventing posttraumatic epilepsy.

Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.

Hormonal and biochemical changes in female Proechimys guyannensis, an animal model of resistance to pilocarpine-induced status epilepticus.

The Amazon rodent Proechimys guyannensis is widely studied for hosting various pathogens, though rarely getting sick. Previous studies on male Proechimys have revealed an endogenous resistance to epilepsy. Here, we assess in female Proechimys, whether sex hormones and biochemical aspects can interfere with the induction of status epilepticus (SE). The lithium-pilocarpine ramp-up protocol was used to induce SE, and blood sera were collected at 30 and 90 min after SE, alongside brains, for biochemical, western blot and immunohistochemical analyses. Results from non-ovariectomised (NOVX) Proechimys were compared to ovariectomised (OVX) animals. Data from female Wistars were used as a positive control of SE inductions. SE latency was similar in NOVX, OVX, and female Wistars groups. However, the pilocarpine dose required to induce SE in Proechimys was higher (25- to 50-folds more). Despite a higher dose, Proechimys did not show strong SE like Wistars; they only reached stage 2 of the Racine scale. These data suggest that female Proechimys are resistant to SE induction. Glucose and progesterone levels increased at 30 min and returned to normal at 90 min after SE. A relevant fact because in humans and rodents, SE leads to hypoglycaemia after 30 min of SE and does not return to normal levels in a short time, a typical adverse effect of SE. In OVX animals, a decrease in GABAergic receptors within 90 min of SE may suggest that ovariectomy produces changes in the hippocampus, including a certain vulnerability to seizures. We speculate that progesterone and glucose increases form part of the compensatory mechanisms that provide resistance in Proechimys against SE induction.

Characterization of the estrous cycle in the Amazon spiny rat (Proechimys guyannensis).

Males of Proechimys guyannensis, a rodent living in the Amazon rainforest are studied in biomedical research because of their antiepileptogenic mechanism. Females are usually taken from experimental designs, because of limited data of this sex. This study aimed to characterize the estrous cycle to include females together with males in research in a more balanced approach. The estrous cycle of P. guyannensis based through exfoliative cytology, determination of the vaginal occlusion membrane state, and hormonal analysis. In this study, cytological analyses of vaginal smears were performed for three months, three times a day. The observed length of the estrous cycle was 247 ± 81 h (mean ± SD) with a reproductive phase of 27.08 ± 17.39 h (estrus stage). We observed a frequent presence of both the open and closed states of the vaginal membrane in the estrus stage (fertile period) although only the open stage is a prerequisite for successful copulation. High levels of progesterone and estradiol were detected in proestrus. Levels of follicle-stimulating hormone peaked at the estrus stage. These data will establish the parameters and subsidies to set the grounds for future research either for investigating the biology of this species or to use P. guyannensis in research that previously excluded females. Information regarding female Proechimys is relevant to not only describe the species but also explain the interaction between sex hormones and physiological responses. Moreover, the present results will enhance rigor and reproducibility in preclinical studies. In conclusion, P. guyannensis reproductive cycles can occur spontaneously and cyclically independent of mating stimulation and the high levels of FSH in the estrus stage, suggest that ovulation occurs in the late phase of the estrus.