Aug 2026· Current Issues in Molecular Biology· Vol 48, pp. 842· 0 citations· 174 references
Medicine
TL;DR
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.
Abstract
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.
Status epilepticus (SE) is a serious neurological emergency defined by
prolonged or recurring seizures that frequently do not respond to standard antiepileptic medications.
Recent revelations into the molecular underpinnings of SE, including neuroinflammation,
oxidative stress, angiogenesis, and disruption of the blood-brain barrier, have stimulated research
into targeted therapeutics. Lenvatinib, a multi-kinase inhibitor sanctioned for many cancers,
has demonstrated potential neuroprotective and anti-inflammatory effects by targeting the
VEGFR, FGFR, and PDGFR pathways, which are also involved in epileptogenesis.
This review examines the therapeutic potential of repurposing lenvatinib in the pilocarpine-
induced status epilepticus model, a well-established preclinical framework that simulates
human temporal lobe epilepsy. Preclinical evidence, mechanistic relevance, pharmacodynamics,
blood-brain barrier permeability, and safety profiles were reviewed to determine the
viability of lenvatinib as an adjunct or alternative therapy.
Furthermore, the function of angiogenic signaling in the advancement of seizures and
how lenvatinib's multitargeted mechanism may influence critical pathogenic pathways were also
examined.
Although existing evidence is insufficient, in silico and in vivo investigations indicate
that lenvatinib may disrupt neuroinflammatory and vascular alterations essential to SE
pathogenesis. Additional preclinical validation is necessary to verify its efficacy and safety.
This review seeks to establish a thorough basis for subsequent research on the repurposing
of lenvatinib in neurotherapeutics.
V. B., Asha Nayak, D. L.M. et al.· Current Signal Transduction...· 0 citations
This study demonstrates that FLX provides neuroprotective and cognitive benefits in murine epilepsy models by inhibiting neuronal ferroptosis, highlighting its therapeutic potential for epilepsy and other ferroptosis-related neurological disorders.
Yuxiang Li, Cong Wang, Meng-Ying Huang et al.· Journal of Advanced Research· 0 citations
Epilepsy is a chronic non-communicable brain disease affecting approximately 50 million people of all ages worldwide. Antiepileptic drugs (AEDs) are used to manage epileptic seizures. However, AEDs may fail to control seizure activity in some patients and may cause unwanted effects of varying severity, including impairment of central nervous system (CNS) functions. Oxidative stress and imbalances between the excitatory and inhibitory neurotransmitters glutamate and GABA have been implicated in epileptic seizures, highlighting the need for acceptable treatments with fewer adverse effects. S-allyl-L-cysteine (SAC), a natural antioxidant compound, may help prevent epileptic seizures at lower cost and with fewer adverse effects. This study investigated the neuroprotective role of SAC in pentylenetetrazol (PTZ)-induced epileptic seizures in rats. Sixty male Wistar rats were divided into six groups of 10 animals each. Four groups were pretreated with SAC at 100, 200, or 400 mg/kg or with valproic acid (VPA) at 150 mg/kg before PTZ administration. Hippocampal tissues were harvested, homogenised, and centrifuged, and the supernatants were assayed for MDA, SOD, CAT, GSH, glutamate, and GABA. SAC reduced MDA and increased SOD, CAT, and GSH, indicating attenuation of oxidative stress and enhancement of antioxidant defence. Reduced glutamate and increased GABA concentrations suggest improved neurochemical balance and reduced neuronal hyperexcitability. These combined effects support the neuroprotective action of SAC in PTZ-induced seizures and its potential to limit seizure-associated oxidative and excitotoxic brain damage.
P. Mshelia, S. Alhaji, F. Musa et al.· Journal of Advances in Medic...· 0 citations
Simple Summary Epilepsy is a common neurological disorder in which abnormal electrical activity in the brain causes recurrent seizures. Increasing evidence suggests that oxidative damage and excessive production of nitric oxide, a signaling molecule that can become harmful in large amounts, contribute to brain injury during seizures. This study investigated whether combining the widely used anti-seizure medicine valproate with deferoxamine, a drug that removes excess iron from the body, alters markers of oxidative and nitrosative stress in the brain, in addition to its effects on seizure-related electrical activity. Using an experimental model of epilepsy in rats, we found that both treatments reduced seizure-related electrical activity. Although the combination did not suppress seizures more effectively than valproate alone, it was associated with lower nitrite/nitrate surrogate markers of nitric oxide metabolism and higher hippocampal antioxidant status, while its effects on other oxidative stress markers were mixed. These findings indicate that combining these two agents produces measurable, marker-specific biochemical changes in this acute experimental model. However, the combination did not provide additional suppression of epileptiform activity compared with valproate alone, and whether the biochemical changes have functional significance remains to be determined in future studies.
A growing body of literature describes the anti-inflammatory, neuroprotective, and anti-epileptic properties of the cannabis sativa constituent cannabidiol, suggesting that it might play a useful role in the treatment of neurodegenerative diseases. Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare pediatric neurodegenerative disorder resulting from an inherited dysfunction of the lysosome. CLN2 disease, and its representative animal models, display neuroimmune response, neuroinflammation, neurodegeneration, and epileptic seizures, and these symptoms are all touted as potential targets of cannabidiol therapeutic benefit. Here, we treated a valid model of CLN2 disease with long-term daily cannabidiol (300 mg/kg) from 1 month of age until disease end stage and evaluated epileptic seizures, lifespan, and markers of neuroimmune response. Chronic cannabidiol treatment significantly delayed or fully eliminated seizures in CLN2 model mice compared to those treated with vehicle only, and the treatment led to a non-significant extension of lifespan. These effects occurred in the absence of any therapeutic benefit to physiological markers of disease such as GFAP, CD68, and cytokine/chemokine reactivity. Taken together, we show that chronic treatment with cannabidiol confers significant anti-seizure benefit to the mouse model of CLN2 disease, and that it does not appear to do so by altering the inflammatory and neuroimmune markers traditionally used to track CLN2 disease progression.
Joshua T. Dearborn, Keigo Takahashi, N. Rensing et al.· PLoS ONE· 0 citations
Epilepsy is a chronic neurological disorder marked by recurrent seizures caused by abnormal electrical discharges and neuronal hyperexcitability. Besides the neuroelectrical component, the active involvement of the immune system in the pathophysiology of this disease has been recognized. In this study, we evaluated whether DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an effective drug in refractory epilepsy, presents an immunomodulatory effect on microglia cells in a murine model of pentylenetetrazole (PTZ)-induced status epilepticus.
Three groups of five C57BL/6 mice were formed: control, epileptic untreated, and epileptic treated with HEPP. The behavioral assessment was conducted using the Racine scale. Flow cytometry was used to analyze microglial activation, cytokine production, and cell infiltration.
We corroborated that animals with status epilepticus showed a sustained progression towards severe convulsive stages. In contrast, those treated with HEPP showed a significant decrease in the mean score, indicating a strong anticonvulsant effect of the compound. At the cellular level, we found a significant increase in the proportion of activated microglial cells in the brains of status epilepticus animals, as well as increased infiltration of peripheral cells; these findings were attenuated in the HEPP-treated group, suggesting a neuroprotective effect. Likewise, we identified an increase in the expression of TNF-α, IL-6, and IL-4 cytokines in activated microglia of the group of mice with status epilepticus, while treatment with HEPP decreased the expression of these cytokines, although it did not favor a transition towards an anti-inflammatory phenotype type M2, given the lack of statistical significance in CD206 cells.
Our findings suggest that HEPP not only modulates seizure activity but also provides immunomodulatory and neuroprotective effects, positioning itself as a promising therapeutic alternative for epilepsy associated with chronic inflammation.
The National Polytechnic Institute of Mexico provides the SIP20253908, SIP20254383, and SIP20253809 grants for this research.
Neuroimmunology (NEUR)
Carlos Wong Baeza, S. Gómez-Manzo, Edgar Rundquist-Sánchez et al.· Journal of Immunology· 0 citations
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