Activating Sigma1R by fluoxetine suppresses neuronal ferroptosis in epilepsy by inhibiting MDM2-mediated GPX4 ubiquitination.

Selected Molecular Targets for Counteracting Epileptogenesis: What Do We Know About Its Effective Inhibition?

Epilptogenesis is a long-term process that involves the transformation of a healthy brain into a seizure-producing brain. Since approximately 30% of epilepsy patients suffer from drug-resistant seizures, the concept of inhibiting the epileptogenesis process and thus preventing seizures has emerged. The search for effective methods of inhibiting epileptogenesis is possible thanks to animal models, which include kindled seizures; models based on the induction of status epilepticus resulting in subsequent spontaneous recurrent seizures, or brain trauma; and genetic models. Blood–brain barrier dysfunction, inflammatory processes in the brain, and oxidative stress appear to play a major role in epileptogenesis. This prompted testing of a number of anti-inflammatory agents and antioxidants in the epileptogenic process. One noteworthy finding was that losartan (an antihypertensive drug), as a TGF-β antagonist, proved effective in inhibiting epileptogenesis due to blood–brain barrier damage. Due to the many mechanisms involved in the process of epileptogenesis, it seems that the use of a combination of drugs will be an effective method of inhibiting it. The most promising combination includes levetiracetam (a second-generation antiseizure drug), atorvastatin, and ceftriaxone (a beta-lactam antibiotic), which effectively inhibits spontaneous seizures in animals experiencing status epilepticus. Any clinical trials on the inhibition of epileptogenesis must take into account the fact that a small percentage of patients develop epileptic seizures after stroke or brain injury. Recently suggested markers predicting a high probability of epileptic seizures after brain damage may facilitate appropriate patient selection for studies on inhibition of epileptogenesis.

Current insights suggest gabapentin-induced neurodegeneration

Antiepileptic drugs (AEDs) are commonly prescribed to treat epilepsy and other neurodegenerative disorders (NDs). Gabapentin (GBP) is a newer, off-label antiepileptic/anticonvulsant for NDs that remains underexplored. Recent evidence indicates that prolonged, frequent, and high-dose use of GBP may be associated with an increased risk of various types of dementia and cognitive impairment. GBP has become 1 of the top 20 most prescribed drugs for NDs. GBP modulates voltage-gated calcium channels by binding to the alpha2delta subunit. One possible mechanism is oxidative stress, which can damage neuronal structures, impair synaptic function, and cause mitochondrial dysfunction, all of which are strongly implicated in the pathogenesis of several NDs and contribute to cognitive decline. Another factor is excitotoxicity, where abnormal glutamatergic activity causes excessive calcium influx and neuronal injury, thereby exacerbating mood problems and memory deficits. Long-term use of GBP interferes with SIRT1 (neuroprotective), CaMKII (calcium regulator), and tau phosphorylation regulation, damaging downstream signalling, disrupting central pain pathways in the spinal cord and brain (central sensitisation), damaging neuronal survival pathways, and promoting neurodegeneration. This literature review aims to synthesise current insights on GBP neurotoxic effects, including changes at the gene and protein levels, neuronal structure, function, and network connectivity, as well as strategies for managing GBP-associated NDs. Further research is needed to clarify the exact mechanisms and to develop protective strategies to reduce neurodegenerative risks, optimise seizure control, and evaluate the risks of GBP in clinical settings.

Seipin modulates Alzheimer’s disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway

Resveratrol Alleviates Epilepsy-Induced Brain Damage via the P62-Keap1-Nrf2 Pathway: A Multi-Omics Study Integrating the Pilot Cohort, In Silico Analyses, and Experimental Validation.

BACKGROUND Pediatric epilepsy is frequently associated with long-term cognitive, behavioral, and neurodevelopmental impairments. Although oxidative stress and metabolic dysfunction contribute to seizure-induced brain injury, how ferroptosis operates and is regulated within the context of pediatric epilepsy has yet to be fully elucidated. METHODS A pediatric pilot cohort of 15 pediatric patients at first seizure onset alongside age-matched neurotypical peers was established. Untargeted metabolomics, neuroimaging, biochemical assays, and gene expression analyses were performed to evaluate metabolic dysregulation, iron accumulation, oxidative stress, and ferroptosis-related alterations. Integrated bioinformatics, Mendelian randomization, external transcriptomic validation, single-cell RNA sequencing, virtual perturbation analysis, and in silico drug screening were used to identify key regulatory pathways and candidate therapeutic compounds. The effects of resveratrol were further validated in a kainic acid-based murine epilepsy model and glutamate-challenged HT22 neuronal cells. RESULTS Pediatric epilepsy was characterized by metabolic reprogramming, iron accumulation, lipid peroxidation, inflammation, and impaired antioxidant defense. Integrated bioinformatics identified SQSTM1/P62 and NFE2L2/NRF2 as key regulators linking autophagy and ferroptosis. External validation and single-cell transcriptomic analyses further confirmed ferroptosis- and autophagy-related dysregulation, particularly in neuronal populations. In silico screening identified resveratrol as a candidate therapeutic compound. In epileptic mice, resveratrol reduced seizure severity, epileptiform discharges, neurobehavioral deficits, iron accumulation, lipid peroxidation, inflammation, and hippocampal neuronal injury. CONCLUSION Pediatric epilepsy is associated with metabolic dysregulation, oxidative stress, iron accumulation, and ferroptosis-related neuronal injury. Resveratrol protects against seizure-associated brain damage by activating P62-Keap1-Nrf2 signaling and suppressing ferroptosis, suggesting a potential therapeutic strategy for pediatric epilepsy.

The translocator protein antagonist ONO-2952 attenuates neuroinflammation and neuronal apoptosis in an epilepsy rat model

Epilepsy is a globally prevalent chronic neurological disorder, and translocator protein 18 kDa (TSPO)-mediated neuroinflammation plays a critical role in epilepsy pathogenesis. This study aimed to explore the effect of the translocator protein 18 kDa antagonist ONO-2952 on neuroinflammation and cognitive function in epilepsy by establishing a mature epileptic rat model, which was divided into control group, untreated status epilepticus group and ONO-2952 intervention status epilepticus group; cognitive and behavioral tests were performed to observe the behavioral changes of rats, immunofluorescence staining was used to detect neuronal apoptosis, flow cytometry was adopted to analyze immune cell infiltration, and Western blotting was applied to measure the expression of proinflammatory cytokines. The results showed that ONO-2952 could down-regulate the expression of translocator protein 18 kDa, reduce the level of proinflammatory cytokines and peripheral immune cell infiltration, thereby inhibiting neuroinflammation in epileptic rats, and it could also relieve hippocampal neuronal apoptosis and effectively improve the cognitive dysfunction of model rats. This study confirms that ONO-2952 can regulate the expression of translocator protein 18 kDa, inhibit neuroinflammation and neuronal apoptosis, and improve cognitive function in epileptic rats, and further research is required to fully elucidate its specific biological effects.

Epilepsy-associated digenic variants affecting an actin-mitochondria-glutamate pathway promote seizure susceptibility.

Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1,000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease. By studying epilepsy-associated actin regulatory genes, we identified a conserved "actin-mitochondria-glutamate (AMG) pathway". We demonstrate that reduced actin polymerization promotes DRP1-mediated mitochondrial fission, increases reactive oxygen species (ROS) levels, and enhances glutamatergic transmission, leading to seizures. The glial innate immune pathway, a recently recognized contributor to epilepsy, is activated when the AMG pathway is affected. Reducing mitochondrial fission with the DRP1 inhibitor Mdivi-1, or suppressing ROS with N-acetyl-L-cysteine amide (NACA), significantly alleviates seizures. Importantly, digenic heterozygous loss‑of‑function variants in AMG‑pathway genes combine to cause seizures, and individuals with epilepsy of unknown etiology show an increased burden of such variants when compared to the controls. Modeling patient‑specific digenic combinations in Drosophila confirms that many combinations promote seizure susceptibility. Together, these findings establish the AMG pathway as a mechanistic framework for identifying digenic etiologies in epilepsy and highlight potential therapeutic targets.