Neuroinflammation plays a pivotal role in the onset and progression of epilepsy. In this review, we critically examine: (1) the dual roles of astrocytes and microglia in maintaining a chronic inflammation and its contribution to epileptogenesis and seizures; (2) the crosstalk between the histamine released by mast cells and the brain histaminergic neurotransmission, an underexplored mechanism for seizures; (3) the potential of inflammatory mediators as biomarkers for predicting prognosis and risk stratification; (4) the shared inflammatory pathways linking epilepsy and Alzheimer's disease, with special attention to reactive astrocyte and ferroptosis markers in identifying individuals at risk; (5) emerging therapeutic strategies, including conventional anti-inflammatory drugs and traditional medicine, for seizure control through modulation of neuroinflammation. With these carefully chosen topics, we introduce new molecular findings reinforcing the crucial role of neuroinflammation in epilepsy and as a marker for epileptogenesis, a topic of special interest for the acquired epilepsies such as hippocampal sclerosis. Moreover, we explored other mechanisms that received far less attention, especially those linking epilepsy with Alzheimer's disease, and the potential role of mast cells in seizures.

Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.

Current treatments fail to prevent long-term consequences induced by a severe traumatic brain injury (TBI). This study aimed to evaluate the efficacy of repetitive intranasal administration of NeuroEPO (a derivative of erythropoietin) on long-term alterations after a severe TBI induced by the application of a lateral fluid percussion in male rats. A otal of 30–31 days after the trauma, TBI+vehicle group showed sensorimotor dysfunction (Neuroscore, p < 0.0009; beam walking test, p < 0.0001 vs. Sham+vehicle group) and depressive-like behavior suggested by increased immobility (p = 0.0009 vs. baseline) during the forced swim test. Rats also showed increased production of malondialdehyde (a marker of oxidative damage), increased catalase activity (an antioxidant enzyme), and atrophy of brain areas evaluated with Magnetic Resonance Imaging 31 days after the trauma. TBI+NeuroEPO group received intranasal administration of NeuroEPO (0.136 mg/kg) starting 3 h post-TBI and continued every 8 h for four days. This group showed less sensorimotor dysfunction (Neuroscore, p = 0.020; beam walking test, p = 0.001, vs. TBI+vehicle group) and normal immobility behavior (p = 0.998 vs. Sham+vehicle group). Levels of malondialdehyde and catalase as well as the volume of brain structures of this group were like the Sham+vehicle group. These findings support the potential of NeuroEPO as a therapeutic agent to reduce long-term consequences of TBI.