Current Antiepileptic Drugs Research Articles

Recent Advances in Bioactive Flavonoids-based Nanotherapeutics as Promising Neuroprotectants in Epilepsy

Background: Epilepsy is a prevalent neurological disorder that can be characterized by seizures and can be caused by abnormal electrical impulses in the brain. Various genetic, environmental, age-related, and lifestyle factors are associated with its pathogenesis, which causes neuronal cells to degenerate over time. Methodology: Epilepsy often results from an imbalance between excitatory neurotransmitters, such as glutamate, and inhibitory neurotransmitters, such as GABA. Abnormalities in glutamate receptors like N-methyl-D-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) can lead to excessive neuronal excitation, while dysfunctions in GABA receptors can result in insufficient inhibition, both of which can provoke seizures. Additionally, a variety of receptors and pathways like NF-κB, DAPK, Trκb, COX-2, etc. are associated with the expression of epilepsy. This disorder often faces various limitations in treatment with current anti-epileptic drugs (AEDs), such as drug resistance, adverse effects, and high costs. In context, flavonoids exhibit significant neuroprotective properties in epilepsy through various mechanisms such as antioxidant activity, anti-inflammatory effects, neurotransmitter systems, and receptor modulation. Results: Flavonoids communicate with different signaling pathways and adjust their activities, prompting valuable neuroprotective impacts. Essential flavonoids such as quercetin, rutin, apigenin, luteolin, genistein, fisetin, chrysin, vitexin, naringin, baicalin, catechin, morin, hesperetin, kaempferol, gallic acid, silibinin, wogonin, etc. have shown promising results in channel regulation, reduced oxidative stress and neuroinflammation, and neuronal excitability in experimental models of epilepsy. Given their inherent neuroprotective properties and ability to modulate multiple pathways involved in epilepsy, flavonoids hold considerable promise as multitargeted, accessible, and low-cost alternatives to conventional AEDs. Although there are challenges with target specificity and bioavailability, innovative approaches such as nanotechnology and chemical modifications are being developed to enhance these aspects. Conclusion: Focusing on the mechanisms of action and neuroprotective benefits the paper highlights the promising role of flavonoids and flavonoid-based nanotherapeutics as a beneficial addition to epilepsy treatment strategies.

Therapeutic Efficacy of Lavandula dentata's Oil and Ethanol Extract in Regulation of the Neuroinflammation, Histopathological Alterations, Oxidative Stress, and Restoring Balance Treg Cells Expressing FoxP3+ in a Rat Model of Epilepsy.

Background/Objectives: Despite the availability of antiepileptic drugs (AEDs) that can manage seizures, they often come with cognitive side effects. Furthermore, the role of oxidative stress and neuroinflammatory responses in epilepsy and the limitations of current AEDs necessitate exploring alternative therapeutic options. Medicinal plants, e.g., Lavandula dentata L., are rich in phenolic compounds and may provide neuroprotective and anti-inflammatory benefits. However, limited research evaluates their effectiveness in modulating neuroinflammation and histopathological changes in epilepsy models. Therefore, the current study hypothesized that treating Lavandula dentata L. extract or essential oils may reduce neuroinflammatory responses and mitigate histopathological changes in the brain, providing a natural alternative or adjunct therapy for epilepsy management. Methods: Five groups of male Wistar rats were used: control, pilocarpine-treated epileptic, valproic acid (VPA-treated epileptic), L. dentata extract, and essential oils. Numerous electrolyte levels, monoamine levels, neurotransmitter levels, and the mRNA expression of specific gate channel subtypes were evaluated in homogenate brain tissue. Additionally, histological changes in various brain regions were investigated. Results: The investigation revealed that the extract and essential oils obtained from L. dentata L. exhibited the ability to improve the modulation of electrolytes and ions across voltage- and ligand-gated ion channels. Furthermore, it was revealed that they could decrease neuronal excitability by facilitating repolarization. Moreover, L. dentata's oil and ethanol extract re-balances T-reg/Th-17 cytokines, restoring the pro/anti-inflammatory cytokines and Treg markers, e.g., FOXP3 and CTLA-4, to their normal level. Conclusions: The present work confirms that the extract and essential oils of L. dentata L. have different activities to ameliorate the progression of histopathological alterations. Therefore, when used in conjunction with other AEDs, the extract and essential oils of L. dentata can slow the progression of epileptogenesis.

D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity.

Current antiepileptic drugs are ineffective in one-third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D-2-hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium-independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy-related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant-based treatments for refractory epilepsy.

Necrostatin-1 as a Potential Anticonvulsant: Insights from Zebrafish Larvae Model of PTZ-Induced Seizures.

Epilepsy is a common neurological disorder affecting around 70 million people worldwide. Despite significant research and advancements in pharmaceutical therapies, the exact mechanisms underlying epileptogenesis remain unclear. As a result, current antiepileptic drug treatments are ineffective for approximately 30% of patients, providing only symptomatic relief. The epileptic process is influenced by the signaling of tumor necrosis factor alpha (TNFα), which affects neuronal excitability. The TNFα/TNFR1 signaling pathway and the role of RIPK1 in initiating inflammatory cell death pathways are well studied in human disorders. Dysregulation of RIPK1 is linked to inflammation and neurodegenerative diseases. Necrostatin-1 (Nec-1) selectively inhibits RIPK1 in various pathological conditions. The current study aimed to investigate the anticonvulsant properties of Nec-1 (a selective RIPK1 inhibitor) in PTZ-induced seizures in zebrafish larvae. Before the onset of seizures, zebrafish were treated with Nec-1 (15µM) for 24h at 6days post-fertilization (dpf), followed by exposure to 15mM of PTZ for 30min. Behavioral assessments were conducted to observe changes in locomotor activity. Additionally, c-Fos expression was measuredas an indicator of neuronal activation and analyzed mRNA levels of the astrocyte activation marker (GFAP) along with various inflammatory cytokines. Western blot analysis was conducted to evaluate GABAA receptor expression. Pretreatment with Nec-1 restored normal behavior and reversed the expression of c-Fos in zebrafish larvae induced by PTZ. Additionally, Nec-1 reduced the elevated mRNA expression of inflammatory cytokines and significantly suppressed TNF/TNFR1 signaling, thereby inhibiting the enhanced internalization of GABAA receptors. Our findings indicate that Nec-1 reduced the severity of PTZ-induced seizures in zebrafish by regulating behavior changes, suppressing inflammatory mediators, and enhancing the expression of GABAA receptors, suggesting potential anticonvulsant properties.

Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet.

Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms.

An Update on the Pathways and Aspects of Epilepsy Treatment Targets

Abstract: Epilepsy is a neurological disorder characterized by spontaneously occurring seizures known for several decades. Despite the availability of current anti-epileptic drugs, including Phenytoin, Valproate, Carbamazepine, Lamotrigine, Gabapentin, Vigabatrin, etc., a considerable 30 % of the epileptic population are drug-resistant to the available conventional medications. This suggests a need to find new drug therapy for the management of epilepsy. Moreover, prolonged use of a single drug or monotherapy can also lead to therapeutic failure owing to the inability of a single drug to exert the desired anti-epileptic effect. Hence, on the basis of the knowledge and understanding regarding the existing targets, novel agents having the ability to show therapeutic effects should be studied and investigated further. This article emphasizes the need to investigate and repurpose drug molecules for the management of epilepsy. The review elaborates on the potential targets, including Glutamate, EAAT (Excitatory nucleotide) Channel and mTOR (Mammalian Target of Rapamycin) pathway. Moreover, the discussion on the EAAT (Excitatory Amino Acid Transporters), RAS (Renin Angiotensin System), NHE (Na+/H+ exchangers), HCN (Hyperpolarization-activated cyclic nucleotide) targets and treatment approach has been supported by literature that sheds light on evidence which is validated via suitable preclinical and clinical studies.

Unravelling the neurochemical maze: neurotransmitters, neuropeptides and novel drug modes of action based on epilepsy pathophysiology

The brain is extremely complicated three dimensional structures made up of interconnected neurons and neuroglia cells. It entails all type of functions of our body whether we are healthy or in disease conditions. Brain is accountable for our connectivity with the surroundings; all this is performed by an organized and systemic electrical activity of neurons by which they communicate messages to and from the brain. The abnormal electrical activity leading to the intense outburst of impulses, results in the development of epilepsy. Epilepsy is typified by recurrent, unprovoked seizures as a result excessive, hypersynchronous discharge of neurons occurs in the brain. Nearly 1% of the population throughout the worldwide is suffering from epilepsy and almost 75% begins at childhood. The patients almost one third are resistant to current available antiepileptic drugs. We don’t have the deep knowledge of the pathophysiology of the disease which can prove useful in further research for drugs with new mechanisms of action for diseases. This paper covers the role various neurotransmitters and neuropeptides in the pathophysiology of epilepsy. Our objective is to introduce the scientists with that aspect of the disease which may prove useful for further development of new drugs of epilepsy to overcome the resistance shown by the patientsorithm.

Anticonvulsant Properties of 1-Diethylamino-3-phenylprop-2-en-1-one.

There is a need for novel antiepileptic agents whose modes of action differ from those of current antiepileptic drugs. The objective of this study was to determine whether 1-diethylamino-3-phenylprop-2-en-1-one (2) could prevent or at least diminish convulsions caused by different mechanisms. This amide afforded protection in the maximal electroshock and subcutaneous pentylenetetrazole screens when given intraperitoneally to both mice and rats. A number of specialized tests in mice were conducted and are explained in the text. They revealed (2) to have efficacy in the 6 Hz psychomotor seizure test, the corneal kindling model, the mouse temporal epilepsy screen and a peripheral neuronal transmission test using formalin. Three screens in rats were undertaken, which revealed that (2) blocked chloride channels, inhibited peripheral neuronal transmission (tested using sciatic ligation and von Frey fibres) and afforded protection in the lamotrigine-resistant kindled rat model. The biodata generated reveal that (2) is an important lead molecule in the quest for novel structures to combat epilepsy.

Recent Progress in the Development of New Antiepileptic Drugs with Novel Targets.

Epilepsy is a chronic neurological disorder that affects approximately 50-70 million people worldwide. Epilepsy has a significant economic and social burden on patients as well as on the country. The recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy. The current antiepileptic drugs provide symptomatic relief by restoring the balance of excitatory and inhibitory neurotransmitters. Besides, about 30% of epileptic patients do not achieve seizure control. The prevalence of adverse drug reactions, including aggression, agitation, irritability, and associated comorbidities, is also prevalent. Therefore, researchers should focus on developing more effective, safe, and disease-modifying agents based on new molecular targets and signaling cascades. This review overviews several clinical trials that help identify promising new targets like lactate dehydrogenase inhibitors, c-jun n-terminal kinases, high mobility group box-1 antibodies, astrocyte reactivity inhibitors, cholesterol 24-hydroxylase inhibitors, glycogen synthase kinase-3 beta inhibitors, and glycolytic inhibitors to develop a new antiepileptic drug. Approximately 30% of epileptic patients do not achieve seizure control. The current anti-seizure drugs are not disease modifying, cure or prevent epilepsy. Lactate dehydrogenase inhibitor, cholesterol 24-hydroxylase inhibitor, glycogen synthase kinase-3 beta inhibitors, and mTOR inhibitors have a promising antiepileptogenic effect.

Eucalyptol prevents pilocarpine-induced seizure and neuronal damage in mice, through the cholinergic, monoaminergic and antioxidant pathways

Current antiepileptic drugs can inhibit seizure occurrence but are not effective in preventing its onset. Moreover, they produce several side effects, which may impact the efficacy of the treatment. In addition, it has been stimulating the prospection of new molecules isolated from aromatic plants, with potential anticonvulsant and neuroprotective activities and less side effects. This study aimed to evaluate, though behavioural and neurochemical methodologies, the anticonvulsant, and neuroprotective effects of eucalyptol on mice subjected to the pilocarpine-induced seizure model. Eucalyptol (100, 200 and 400 mg/kg, p.o.) was administered in mice prior to pilocarpine (350 mg/kg, i.p.) and the following behavioural parameters were assessed: Latency to First Seizure (LFS), Seizure Intensity (SI) and Latency to Death (LD). In addition, an oxotremorine-induced tremors test was performed to evaluate the cholinergic system involvement on the eucalyptol effects. Neurochemical tests were also performed, including determination of hippocampal (HC) concentration of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate and striatal (ST) concentration of noradrenaline, dopamine, and serotonin. Lastly, histopathological, and morphometric hippocampal analysis were conducted. Eucalyptol increased the latency to first seizure and latency to death, inhibited oxotremorine-induced tremors, decreased hippocampal TBARS and nitrite/nitrate overproduction, increased striatal noradrenaline and dopamine levels and prevented hippocampal neurodegeneration. These results demonstrate the potential anticonvulsant, neuroprotective and antioxidant effects of eucalyptol, probably through a conjunction of mechanisms including muscarinic cholinergic antagonism, oxidative stress mitigation and the monoaminergic system modulation, which appears to effectively control the seizure onset.

Metabolic Derangements with Anticonvulsants in Children with Generalised Tonic-clonic Epilepsy: A Cross-sectional Study

Introduction: Epilepsy is one of the most prevalent noncommunicable neurologic conditions, accounting for significant disability and mortality. The effects of Antiepileptic Drugs (AEDs) on total cholesterol, triglycerides, High-Density Lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and apolipoprotein levels have been demonstrated in many studies, mainly conducted with adults. However, there have been very few studies in children. Derangement of lipid profile and other metabolic abnormalities could lead to the development of metabolic syndrome in children. The adverse metabolic effects of anti-epileptics are underestimated, as only a few studies have been done in this area, which is a legitimate concern. Aim: To assess the impact of AEDs on metabolic parameters in children with epilepsy. Materials and Methods: This was a descriptive, crosssectional study conducted in the Department of Paediatrics and Pharmacology at Pt. BD Sharma PGIMS, Rohtak, Haryana, India. The study included 100 children with epilepsy from May 2022 to October 2022. A predefined case record form, including demographic and clinical characteristics, was filled for each participant. The parameters recorded were age, gender, outpatient number, type of epilepsy, history of duration of epilepsy, current AED history, and seizure frequency over the preceding six months, as per the case record form. Guidelines from the International Diabetes Federation were used for diagnosing metabolic syndrome in children. The data was entered into Microsoft excel and presented using descriptive statistics. The chi-square test was used to differentiate between categorical variables. Results: The mean age of the study participants was 10.2±2.97 years. There were more males (62%) than females (38%). A 48% of the patients received monotherapy, while 52% received polytherapy. A total of 24% of the patients had derangement in lipid profile (increased triglycerides and decreased HDL), with 14% of patients on monotherapy and 10% on polytherapy. The difference in metabolic derangements between monotherapy and polytherapy was not statistically significant (p=0.25). Out of 100 participants, 3% fulfilled the criteria for metabolic syndrome, with a predominance in males. Conclusion: Metabolic derangements are known with 1st generation AEDs, but 2nd generation AEDs can also lead to significant metabolic abnormalities.

Brain Imaging in Epilepsy-Focus on Diffusion-Weighted Imaging.

Epilepsy is a common neurological disorder; 1% of people worldwide have epilepsy. Differentiating epileptic seizures from other acute neurological disorders in a clinical setting can be challenging. Approximately one-third of patients have drug-resistant epilepsy that is not well controlled by current antiepileptic drug therapy. Surgical treatment is potentially curative if the epileptogenic focus is accurately localized. Diffusion-weighted imaging (DWI) is an advanced magnetic resonance imaging technique that is sensitive to the diffusion of water molecules and provides additional information on the microstructure of tissue. Qualitative and quantitative analysis of peri-ictal, postictal, and interictal diffusion images can aid the differential diagnosis of seizures and seizure foci localization. This review focused on the fundamentals of DWI and its associated techniques, such as apparent diffusion coefficient, diffusion tensor imaging, and tractography, as well as their impact on epilepsy in terms of differential diagnosis, epileptic foci determination, and prognosis prediction.

Reducing the shock factor with new anti-epilepsy drugs

Epilepsy is one of the most common serious neurological conditions, affecting 1 in 131 people in the UK. Patients with epilepsy suffer recurrent spontaneous seizures when neuronal activity elevates beyond physiological limits. Although current anti-epileptic drugs can effectively prevent seizures in some patients, up to 20% of paediatric and 40% of adult patients are refractory to treatment. One therapeutic avenue that has not yet been pursued for epilepsy is targeting neuronal homeostasis. PUMILIO (PUM) is a transcriptional repressor that maintains neuron action potentials within physiological limits and, importantly, is abnormally reduced in patients with epilepsy. In their recent article, Richard Baines and colleagues, therefore, investigated PUM as a therapeutic target for epilepsy.The authors identified a new compound, 4-tert-butyl-benzaldehyde (4-TBB), which could increase expression and stability of PUM in Drosophila and mice, and had physiochemical properties compatible with clinical use. They pre-treated diverse Drosophila and mouse models of epilepsy with 4-TBB prior to electrical or chemical induction of seizures. The team found that 4-TBB acts as an anticonvulsant, significantly reducing behavioural and physiological signs of seizure. The authors also confirmed that 4-TBB acts – at least in part – through modulation of PUM, as protein levels of downstream targets of PUM were reduced in treated mouse brains and because RNAi-induced reduction of PUM significantly diminished the anticonvulsant activity of 4-TBB in Drosophila.The authors then identified RAB216, a more-potent analogue of 4-TBB, which also increased PUM expression, and induced anticonvulsant activity in Drosophila and mice, at significantly lower concentrations than 4-TBB. Moreover, RAB216 also reduced the duration of seizures in an electrically induced seizure assay within a murine model that recapitulates drug-refractory epilepsy.The Baines lab identified two anticonvulsant compounds that modulate PUM expression and activity to oppose the high neuronal activity associated with seizures. This approach modulates neuronal homeostasis, which may incur fewer side effects, as these mechanisms are tightly controlled to avoid under- or over-activation. Interestingly, although mice were pre-treated with 4-TBB for 3 days prior to seizure induction, there were no overt signs of side effects. However, future work is required to investigate the full mode of action of the new compounds, beyond the modulation of PUM activity. Moreover, as PUM is expressed systemically, the development of compounds targeting central nervous system-specific downstream targets or co-factors of PUM could further minimise potential side effects. Nevertheless, the authors have demonstrated the potential of a novel approach to treating epilepsy, which may reduce the proportion of drug-refractory patients.

Efficacy of Lacosamide Add-on Therapy on Refractory Focal Epilepsies in Children and Adolescents: An Open-Label Clinical Trial.

Epilepsy is a chronic neurological disorder that affects 0.5%-1% of children. 30%-40% of patients are resistant to current anti-epileptic drugs. Lacosamide (LCM) appeared to be effective, safe, and well tolerated in children and adolescents. This study was aimed to evaluate whether LCM could be an effective add-on therapy in children with refractory focal epilepsies. This study was conducted from April 2020 to April 2021 in Imam Hossein Children Hospital, Isfahan, Iran. We included 44 children aged 6 months to 16 years with refractory focal epilepsy (based on International League Against Epilepsy criteria). LCM was given in divided doses of 2 mg/kg/day, increasing by 2 mg/kg every week. The first follow-up visit was 6 weeks later, when all patients had reached the therapeutic dose. The average age of the patients was 89.9 months. 72.5% of children had focal motor seizures. Evaluation of percent change in seizure frequency and duration before and after treatment showed a 53.22% reduction in seizure frequency and 43.72% reduction in seizure duration after treatment. Our study group tolerated LCM well, with few side effects. Headache, dizziness, and nausea were common side effects. In line with other studies, none of the suspected risk factors could predict response to LCM treatment. LCM appears to be an effective, safe, and well-tolerated medication in children with uncontrolled drug-resistant focal epilepsy.

Statins as antiepileptogenic drugs: Analyzing the evidence and identifying the most promising statin.

Many brain insults and injuries are “epileptogenic”: they increase the risk of developing epilepsy. It is desirable to identify treatments that are “antiepileptogenic”: treatments that prevent the development of epilepsy, if administered after the occurrence of an epileptogenic insult. Current antiepileptic drugs are not antiepileptogenic, but evidence of antiepileptogenic efficacy is accumulating for a growing number of other compounds. From among these candidate compounds, statins are deserving of particular attention because statins are reported to be antiepileptogenic in more published studies and in a wider range of brain insults than any other individual or class of compounds. Although many studies report the antiepileptogenic effect of statins, it is unclear how many studies provide evidence that statins exhibit the following two essential features of a clinically viable antiepileptogenic drug: the drug must exert an antiepileptogenic effect even if it is initiated after the epileptogenic brain insult has already occurred, and the antiepileptogenic effect must endure even after the drug has been discontinued. In the current work, we interrogate published preclinical and clinical studies, to determine if statins fulfill these essential requirements. There are eight different statins in clinical use. To enable the clinical use of one of these statins for antiepileptogenesis, its antiepileptogenic effect will have to be established through future time‐ and resource‐intensive clinical trials. Therefore, it is desirable to review the published literature to determine which of the statins emerges as the most promising candidate for antiepileptogenic therapy. Hence, in the current work, we also collate and analyze published data—clinical and pre‐clinical, direct and indirect—that help to answer the question: Which statin is the most promising candidate to take forward into an antiepileptogenesis clinical trial?

The diverse role of the raphe 5-HTergic systems in epilepsy.

The raphe nuclei comprise nearly all of 5-hydroxytryptaminergic (5-HTergic) neurons in the brain and are widely acknowledged to participate in the modulation of neural excitability. "Excitability-inhibition imbalance" results in a variety of brain disorders, including epilepsy. Epilepsy is a common neurological disorder characterized by hypersynchronous epileptic seizures accompanied by many psychological, social, cognitive consequences. Current antiepileptic drugs and other therapeutics are not ideal to control epilepsy and its comorbidities. Cumulative evidence suggests that the raphe nuclei and 5-HTergic system play an important role in epilepsy and epilepsy-associated comorbidities. Seizure activities propagate to the raphe nuclei and induce various alterations in different subregions of the raphe nuclei at the cellular and molecular levels. Intervention of the activity of raphe nuclei and raphe 5-HTergic system with pharmacological or genetic approaches, deep brain stimulation or optogenetics produces indeed diverse and even contradictory effects on seizure and epilepsy-associated comorbidities in different epilepsy models. Nevertheless, there are still many open questions left, especially regarding to the relationship between 5-HTergic neural circuit and epilepsy. Understanding of 5-HTergic network in a circuit- and molecule-specific way may not only be therapeutically relevant for increasing the drug specificity and precise treatment in epilepsy, but also provide critical hints for other brain disorders with abnormal neural excitability. In this review we focus on the roles of the raphe 5-HTergic system in epilepsy and epilepsy-associated comorbidities. Besides, further perspectives about the complexity and diversity of the raphe nuclei in epilepsy are also addressed.

Malondialdehyde and superoxide dismutase levels in patients with epilepsy: a case–control study

BackgroundOxidative stress has a significant influence in the initiation and progression of epileptic seizures. It was reported that inhibiting oxidative stress could protect against epilepsy. The aim of the current research is to estimate some biomarkers that reflect the oxidative stress in epileptics, its relation to seizure control as well as to study the impact of antiepileptic drugs (AEDs) on these biomarkers. This case–control study included 62 epileptic patients beside 62 age and gender-matched healthy controls. The epileptic patients subjected to detailed history taking with special regards to disease duration, seizure frequency, and the current AEDs. Laboratory evaluation of serum malondialdehyde (a lipid peroxidation byproduct) and superoxide dismutase (an endogenous antioxidant) were done.ResultsMalondialdehyde (MDA) was significantly higher, and superoxide dismutase (SOD) was lower in epileptic patients than in the controls (p < 0.001). Seizure frequency was directly correlated with MDA (r = 0.584, p < 0.001) while inversely correlated with SOD (r = − 0.432, p = 0.008). High MDA and low SOD were recorded in epileptic patients receiving polytherapy as compared to monotherapy (p < 0.001).ConclusionsEpileptic patients had higher oxidative stress biomarkers than healthy individuals. Frequent seizures, long disease duration, and AEDs were associated with higher MDA and lower SOD that reflects an imbalance in the oxidant–antioxidant status among these patients.

The role of astrocytes in epileptic disorders.

Epilepsy affects about 1% of the population and approximately 30% of epileptic patients are resistant to current antiepileptic drugs. As a hallmark in epileptic tissue, many of the epileptic patients show changes in glia morphology and function. There are characteristic changes in different types of glia in different epilepsy models. Some of these changes such as astrogliosis are enough to provoke epileptic seizures. Astrogliosis is well known in mesial temporal lobe epilepsy (MTLE), the most common form of refractory epilepsy. A better understanding of astrocytes alterations could lead to novel and efficient pharmacological approaches for epilepsy. In this review, we present the alterations of astrocyte morphology and function and present some instances of targeting astrocytes in seizure and epilepsy.

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention.

Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.

Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment.&#x0D; This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications.&#x0D; Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.