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Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Temporal lobe epilepsy (TLE) remains pharmacoresistant in 30–40% of patients. Peroxisome proliferator-activated receptor alpha (PPARα) agonists like fenofibrate exhibit anti-inflammatory and neuroprotective properties, but their region-specific effects during epileptogenesis and on behavioral comorbidities are unknown. We investigated fenofibrate (100 mg/kg, 7 days) in the lithium-pilocarpine rat model during the latent phase. Fenofibrate (1) reduced anxiety-like behaviors and improved exploratory deficits; (2) decreased plasma short-chain fatty acids (butyric, pentanoic, hexanoic acids); (3) exerted region-specific modulation of glutamate receptors: restored N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit gene expression in temporal cortex but failed to reverse and further exacerbated the downregulation of AMPAR subunits in the dorsal hippocampus; (4) prevented the upregulation of cortical neuroinflammation markers (reduced Nlrp3, Il1rn); and (5) enhanced the A2 astrocyte marker Ptx3 in the hippocampus while reducing the M2 microglial marker Arg1 in the temporal cortex. No effects on astrogliosis (Gfap), microgliosis (Aif1), or trophic factors (Bdnf, Tgfb1) were observed. This first comprehensive study demonstrates that fenofibrate differentially modulates neuroinflammation and synaptic plasticity across brain regions during epileptogenesis, providing behavioral benefits but highlighting potential hippocampal drawbacks. Its PPARα-mediated actions support further investigation as a complementary strategy for TLE, pending optimization of dosing/timing to mitigate regional disparities.

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. This study aimed to analyze the changes in gene expression of mGluR subtypes (1–5, 7, 8) in various rat brain regions in the latent and chronic phases of a lithium–pilocarpine model of epilepsy. For this study, multiplex test systems were selected and optimized to analyze mGluR gene expression using RT-qPCR. Region- and phase-specific changes in expression were revealed. During the latent phase, mGluR5 mRNA levels were increased in the dorsal and ventral hippocampus, and expression of group III genes was decreased in the hippocampus and temporal cortex, which could contribute to epileptogenesis. Most of the changes in expression detected in the latent stage were absent in the chronic stage, but mGluR8 mRNA production remained reduced in the hippocampus. Moreover, we found that gene expression of group II mGluRs was altered only in the chronic phase. The study deepened our understanding of the mechanisms of epileptogenesis and suggested that agonists of group III mGluRs are the most promising targets for preventing epilepsy.

A variety of clinical observations and studies in animal models of temporal lobe epilepsy (TLE) reveal dysfunction of blood-brain barrier (BBB) during seizures. It is accompanied by shifts in ionic composition, imbalance in transmitters and metabolic products, extravasation of blood plasma proteins in the interstitial fluid, causing further abnormal neuronal activity. A significant amount of blood components capable of causing seizures get through the BBB due to its disruption. And only thrombin has been demonstrated to generate early-onset seizures. Using the whole-cell recordings from the single hippocampal neurons we recently showed the induction of epileptiform firing activity immediately after the addition of thrombin to the blood plasma ionic media. In the present work, we mimic some effects of BBB disruption in vitro to examine the effect of modified blood plasma artificial cerebrospinal fluid (ACSF) on the excitability of hippocampal neurons and the role of serum protein thrombin in seizure susceptibility. Comparative analysis of model conditions simulating BBB dysfunction was performed using the lithium-pilocarpine model of TLE, which most clearly reflects the BBB disruption in the acute stage. Our results demonstrate the particular role of thrombin in seizure-onset in conditions of BBB disruption.

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.

The lithium–pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset, and we assessed brain glucose metabolism using [18F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, at 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by a VOI analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrogliosis but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated limbic–cortical hypometabolism when evaluated by SPM and normalized to whole brain tracer uptake and microglia-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on the brain’s response to SE.

Reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) is a commonly used tool for gene expression analysis. The selection of stably expressed reference genes is required for accurate normalization. The aim of this study was to identify the optimal reference genes for RT-qPCR normalization in various brain regions of rats at different stages of the lithium–pilocarpine model of acquired epilepsy. We tested the expression stability of nine housekeeping genes commonly used as reference genes in brain research: Actb, Gapdh, B2m, Rpl13a, Sdha, Ppia, Hprt1, Pgk1, and Ywhaz. Based on four standard algorithms (geNorm, NormFinder, BestKeeper, and comparative delta-Ct), we found that after pilocarpine-induced status epilepticus, the stability of the tested reference genes varied significantly between brain regions and depended on time after epileptogenesis induction (3 and 7 days in the latent phase, and 2 months in the chronic phase of the model). Pgk1 and Ywhaz were the most stable, while Actb, Sdha, and B2m demonstrated the lowest stability in the analyzed brain areas. We revealed time- and region-specific changes in the mRNA expression of the housekeeping genes B2m, Actb, Sdha, Rpl13a, Gapdh, Hprt1, and Sdha. These changes were more pronounced in the hippocampal region during the latent phase of the model and are thought to be related to epileptogenesis. Thus, RT-qPCR analysis of mRNA expression in acquired epilepsy models requires careful selection of reference genes depending on the brain region and time of analysis. For the time course study of epileptogenesis in the rat lithium–pilocarpine model, we recommend the use of the Pgk1 and Ywhaz genes.

Oxidative stress and membrane damage are believed to be principally involved in the pathogenesis of epilepsy. This study aimed to assess the effects of phenosanic acid (PA), an antioxidant and membrane protector, in acute pentylenetetrazole and chronic lithium–pilocarpine seizure models in male Wistar rats. PA was administered acutely (ip, 120 mg/kg BW ip, or 240 mg/kg BW per os) or chronically (80 mg/kg BW/day per os). Indices of free radical oxidation, the hypothalamo–pituitary–adrenocortical axis, and the nitrergic system were assessed in blood and brain regions. Morphological analysis of the hippocampus was performed in the lithium–pilocarpine model. PA exerted an acute anti-seizure effect in the pentylenetetrazole model. In the lithium–pilocarpine model, acute PA treatment decreased the death rate and corticosterone levels in the neocortex and brainstem. In contrast, the level of free radical oxidation products reacting with thiobarbituric acid declined in the brain stem in response to chronic PA treatment. In the lithium–pilocarpine model, the neuronal density in the dentate gyrus was elevated, and the proliferating cell nuclear antigen positive (PCNA+) cell counts in the subgranular zone did not differ between groups. Doublecortin positive (DCX+) cell count was significantly increased after chronic PA treatment. PA-induced reduction in mortality in the lithium–pilocarpine epilepsy model may be partially mediated by decreasing the lipid peroxidation and corticosterone levels in different brain regions. Chronic PA treatment may affect adult hippocampal neurogenesis by either prolonging the action of factors that increase neurogenesis after status epilepticus or by slowing down the neuronal differentiation rate. These data suggest that PA may be a disease-modifying AED able to hamper epileptogenesis.

Chronic experiments on male Wistar and Krushinskii–Molodkina rats, the latter having an inherited predisposition for audiogenic convulsions, addressed the effects of glutamate receptor antagonist IEM-1925 – which acts on both NMDA and Ca2+-permeable AMPA/kainate receptors – on brain electrical activity during the development of pilocarpine-induced status epilepticus (SE). Electrograms were recorded from the caudate nucleus, hippocampus, and the somatosensory, visual, and auditory areas of the cortex. The sequence of SE phase changes identified from electrogram patterns was found not to change on exposure to this blocker. In addition, IEM-1925 weakened the behavioral motor convulsive signs of SE in rats, decreasing seizure intensity from 8 to 4 points on the Pinel and Rovner [1978] scale. Furthermore, the latent period of onset of epileptiform activity in Krushinskii–Molodnika rats after administration of pilocarpine increased by 40% on the background of IEM-1925 at a dose of 10 mg/kg (on average from 12.8 ± 1.1 to 18.0 ± 2.1 min), with an almost two-fold increase in Wistar rats (from 22.5 ± 0.2 to 43.5 ± 3.7 min). The mean durations of SE after IEM-1925 (10 mg/kg) in Krushinskii–Molodnika and Wistar rats were 4.5–5 times shorter than without blocker. The data obtained here provide evidence that combined blockade of NMDA and Ca2+-permeable AMPA/kainate glutamate receptors, although unable to prevent onset of pilocarpine-induced SE, increased the latent period of the onset of status and significantly decreased both individual phase durations and the total duration of SE.