VEGF Modulates Neurogenesis and Microvascular Remodeling in Epileptogenesis After Status Epilepticus in Immature Rats

Neurogenesis and angiogenesis are widely recognized to occur during epileptogenesis and important in brain development. Because vascular endothelial growth factor (VEGF) is a critical neurovascular target in neurological diseases, its effect on neurogenesis, microvascular remodeling and epileptogenesis in the immature brain after lithium-pilocarpine-induced status epilepticus (SE) was investigated. The dynamic changes in and the correlation between hippocampal neurogenesis and microvascular remodeling after SE and the influence of VEGF or SU5416 injection into the lateral ventricles at different stages after SE on neurogenesis and microvascular remodeling through regulation of VEGF expression were assessed by immunofluorescence and immunohistochemistry. Western blot analysis revealed that the VEGFR2 signaling pathway promotes phosphorylated ERK and phosphorylated AKT expression. The effects of VEGF expression regulation at different stages after SE on pathological changes in hippocampal structure and spontaneous recurrent seizures (SRS) were evaluated by Nissl staining and electroencephalography (EEG). The results showed that hippocampal neurogenesis after SE is related to microvascular regeneration. VEGF promotion in the acute period and inhibition in the latent period after SE alleviates loss of hippocampal neuron, abnormal vascular regeneration and inhibits neural stem cells (NSCs) ectopic migration, which may effectively alleviate SRS severity. Interfering with VEGF via the AKT and ERK pathways in different phases after SE may be a promising strategy for treating and preventing epilepsy in children.

New Insights Into the Role of Aberrant Hippocampal Neurogenesis in Epilepsy

Data accumulated over the past four decades have confirmed that adult hippocampal neurogenesis (HN) plays a key role in the wide spectrum of hippocampal pathology. Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although neurogenesis in persistent germinative zones is altered in the adult rodent models of epilepsy, the effects of seizure-induced neurogenesis in the epileptic brain, in terms of either a pathological or reparative role, are only beginning to be explored. In this review, we described the most recent advances in neurogenesis in epilepsy and outlooked future directions for neural stem cells (NSCs) and epilepsy-in-a-dish models. We proposed that it may help in refining the underlying molecular mechanisms of epilepsy and improving the therapies and precision medicine for patients with epilepsy.

The Role of Brain-Derived Neurotrophic Factor in Epileptogenesis: an Update

Epilepsy, which is characterized by spontaneous recurrent seizures, is one of the most common and serious chronic neurological diseases in the world. 30% patients failed to control seizures with multiple anti-seizure epileptic drugs, leading to serious outcomes. The pathogenesis of epilepsy is very complex and remains unclear. Brain-derived neurotrophic factor (BDNF), as a member of the neurotrophic factor family, is considered to play an important role in the survival, growth and differentiation of neurons during the development of the central nervous system. Recent years, a series of studies have reported that BDNF can maintain the function of the nervous system and promotes the regeneration of neurons after injury, which is believed to be closely related to epileptogenesis. However, two controversial views (BDNF inhibits or promotes epileptogenesis) still exist. Thus, this mini-review focuses on updating the new evidence of the role of BDNF in epileptogenesis and discussing the possibility of BDNF as an underlying target for the treatment of epilepsy.

Clustering of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling

Acute repetitive seizures or seizure clusters are common in epileptic patients. Seizure clusters are associated with a high risk of developing status epilepticus and increased morbidity and mortality. Seizure clusters are also recognizable in spontaneous recurrent seizures (SRS) that occur in animal models of epilepsy. The electrical kindling of a limbic structure is a commonly used model of temporal lobe epilepsy. Although classic kindling over the course of a few weeks does not generally induce SRS, extended kindling over the course of a few months can induce SRS in several animal species. SRS in kindled cats often occur in clusters, but the existence of seizure clusters in rodent models of extended kindling remains to be demonstrated. We explored the existence of seizure clusters in mice following extended hippocampal kindling. Adult male mice (C57BL/6) experienced twice daily hippocampal stimulations and underwent continuous 24-hour electroencephalogram (EEG)-video monitoring after ≥80 stimulations. SRS events were recognized by EEG discharges and associated motor seizures. Seizure clusters, defined as ≥4 seizures per cluster and intra-cluster inter-seizure intervals ≤ 120 min, were observed in 19 of the 20 kindled mice. Individual mice showed variable seizure clusters in terms of cluster incidence and circadian-like expression patterns. For clusters consisting of 4–7 seizures and intra-seizure intervals ≤ 20 min, no consistent changes in inter-seizure intervals, EEG discharge duration, or motor seizure severity scores were observed approaching cluster termination. These results suggested that seizure clustering represents a prominent feature of SRS in hippocampal kindled mice. We speculate that, despite experimental limitations and confounding factors, systemic homeostatic mechanisms that have yet to be explored may play an important role in governing the occurrence and termination of seizure clusters.

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis

Vigabatrin (VGB), a potent selective γ-aminobutyric acid transaminase (GABA-T) inhibitor, is an approved non-traditional anti-seizure drug for patients with intractable epilepsy. Nevertheless, its effect on epileptogenesis, and whether this effect is correlated with post-epileptogenic cognitive function remain unclear. Based on lithium-pilocarpine-induced seizure modeling, we evaluated the effect of VGB on epileptogenesis and neuronal damage following status epilepticus in Sprague–Dawley rats. Cognitive evaluations were performed with the aid of inhibitory avoidance testing. We found that VGB could interrupt epileptogenesis by reducing spontaneous recurrent seizures, hippocampal neuronal damage, and chronic mossy fiber sprouting. Nevertheless, VGB did not help with the retention of cognitive performance. Our findings suggest that further research into the role of VGB in epileptogenesis and the treatment of epilepsy in clinical practice is warranted.

Proteins related to ictogenesis and seizure clustering in chronic epilepsy

Seizure clustering is a common phenomenon in epilepsy. Protein expression profiles during a seizure cluster might reflect the pathomechanism underlying ictogenesis. We performed proteomic analyses to identify proteins with a specific temporal expression pattern in cluster phases and to demonstrate their potential pathomechanistic role. Pilocarpine epilepsy model mice with confirmed cluster pattern of spontaneous recurrent seizures by long-term video-electroencpehalography were sacrificed at the onset, peak, or end of a seizure cluster or in the seizure-free period. Proteomic analysis was performed in the hippocampus and the cortex. Differentially expressed proteins (DEPs) were identified and classified according to their temporal expression pattern. Among the five hippocampal (HC)-DEP classes, HC-class 1 (66 DEPs) represented disrupted cell homeostasis due to clustered seizures, HC-class 2 (63 DEPs) cluster-onset downregulated processes, HC-class 3 (42 DEPs) cluster-onset upregulated processes, and HC-class 4 (103 DEPs) consequences of clustered seizures. Especially, DEPs in HC-class 3 were hippocampus-specific and involved in axonogenesis, synaptic vesicle assembly, and neuronal projection, indicating their pathomechanistic roles in ictogenesis. Key proteins in HC-class 3 were highly interconnected and abundantly involved in those biological processes. This study described the seizure cluster-associated spatiotemporal regulation of protein expression. HC-class 3 provides insights regarding ictogenesis-related processes.

Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.