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Studies have shown that glycolysis increases during seizures, and that the glycolytic metabolite lactic acid can be used as an energy source. However, how lactic acid provides energy for seizures and how it can participate in the termination of seizures remains unclear. We reviewed possible mechanisms of glycolysis involved in seizure onset. Result...
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... the epileptic discharge process, the accumulation of various metabolites that are generated by neuron misfiring during seizures leads to acidosis, and this may be involved in the process of seizure termination. Anaerobic glycolysis is known to increase seizures, and its metabolite lactic acid terminates seizures [54] (Figure 2). ...
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... promote seizures through closure of ATP-sensitive potassium (K ATP ) channels that normally act as an energy sensor to protect neurons from excessive depolarization (Karagiannis et al., 2021). Lactate is also often the initial fuel source during seizure activity; thus, excess lactate in the peritumoral environment may increase available energy and sustain increased activity in healthy peritumoral cells (Yang et al., 2013). ...
Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total cfv resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDH mut ) tumors compared to patients with IDH wildtype (IDH wt ) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDH mut vs. IDH wt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.
... A key feature of seizures is the increase in energy metabolism that occurs during abnormal neuronal firing, which leads to an increase in glucose metabolism and oxygen consumption. This increased metabolic demand evokes an increase in blood flow, while also producing an accumulation of metabolic intermediates such as lactate, adenosine, and changes in pH [10][11][12][13][14][15]. Many studies have supported the notion that energy metabolism is compartmentalized between neural cells, with astrocytes presenting a glycolytic profile and neurons an oxidative profile. ...
... The obtained signal was smoothed using a 200-point Savitzky-Golay method. Representing data of the high-frequency component corresponds to the FFT band pass (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and to the power of the FFT band pass (1-20 Hz) of the raw signal. The frequency power-spectrum was obtained by applying a short time Fourier transform to the high-frequency component, using an FFT length of 256, window length of 64, overlap of 32, and a Triangular window type for the KCl depolarization experiment and an FFT length of 256, window length of 150, overlap of 128, and an Hanning window type for the status epilepticus experiment. ...
... Despite its small size (2% of body weight), the mammalian brain receives a disproportionately high proportion of total cardiac output (20%), accounting for a significant portion of total body metabolism. Neurons utilise aerobic and anaerobic metabolism through direct and indirect pathways (through intermediates of astrocytic metabolism) to maintain optimal ATP generation (Yang et al., 2013). By continuously controlling ionic gradients, which are required for membrane excitability, much of this ATP produced supports neural network activity. ...
... During seizures, cerebral blood flow and metabolic rate of glucose and oxygen consumption increase to address enormous energy demands [6]. Nevertheless, the energy shortage due to limitations in oxygen supply enhances the relative energetic contribution of glycolytic pathway vs. oxidative phosphorylation [7]. A preventive effect of oxygen therapy in generalized convulsive seizures supports hypoxemia as an immediate result of the seizures [8]. ...
Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.
... The superoxide is further processed to produce hydroxyl radicals by a Fenton reaction or peroxynitrite by reaction with nitrogen oxide. ROS also inhibit the electron transport chain in mitochondria [51,52]. ...
The understanding of the cellular, molecular and biochemical processes that take place during the production of brain lesions has increased recently due to numerous studies of microscopy, cellular and molecular biology, performed on both human material and experimentally on a laboratory animal. Although new therapeutic methods have emerged to treat strokes and prevent them, due to the complexity of morpho-and pathophysiological processes, the beneficial effects of treatment are still far from satisfactory.
... The numerous mechanisms are associated with prolonged epileptic seizures causing neuronal injury resulting in inflammatory responses and production of reactive oxygen species involved in neuronal cell death [5,6]. These include the elevation of intracellular calcium ion concentration disrupting mitochondrial membrane-mediated neuronal death, a prominent feature of seizures-induced neuronal damage [7,8]. The increased intracellular calcium influx is a key for initiating the mitochondrial apoptotic pathway. ...
IntroductionMitochondrial dysfunction is a common denominator of neuroinflammation recognized by neuronal oxidative stress-mediated apoptosis that is well recognized by common intracellular molecular pathway-interlinked neuroinflammation and mitochondrial oxidative stress, a feature of epileptogenesis. In addition, the neuronal damage in the epileptic brain corroborated the concept of brain injury-mediated neuroinflammation, further providing an interlink between inflammation, mitochondrial dysfunction, and oxidative stress in epilepsy.Materials and methodsA systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to provide evidence of preclinical and clinically used drugs targeting such nuclear, cytosolic, and mitochondrial proteins suggesting that the correlation of mechanisms linked to neuroinflammation has been elucidated in the current review. Despite that, the evidence of elevated levels of inflammatory mediators and pro-apoptotic protein levels can provide the correlation of inflammatory responses often concerned with hyperexcitability attributing to the fact that mitochondrial redox mechanisms and higher susceptibilities to neuroinflammation result from repetitive recurring epileptic seizures. Therefore, providing an understanding of seizure-induced pathological changes read by activating neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, and JAK-STAT signaling further related to mitochondrial damage promoting hyperexcitability.Conclusion
The current review highlights the further opportunity for establishing therapeutic interventions underlying the apparent correlation of neuroinflammation mediated mitochondrial oxidative stress might contribute to common intracellular mechanisms underlying a future prospective of drug treatment targeting mitochondrial dysfunction linked to the neuroinflammation in epilepsy.
... The study included 7 sheep (median weight: 29 [range [26][27][28][29][30][31][32][33][34][35] Cerebral measures. The ictal Eγ increased of a median of + 11 [7][8][9][10][11][12][13][14][15][16][17] % of the pre-ictal value and a statistically significant positive trend was noticed with recurring seizures (Spearman's ρ coefficient 0.31, P < 0.001, Fig. 1a). ...
... It has to be noted that the extent of these events was not sufficient to impair neuronal function since the last seizures had a prominent EEG power and lasted longer than the early ones. As proposed by others authors, in the context of pathologic stress, auxiliary sources of energy than mitochondrial oxidative respiration, such as glycolysis, might support neuronal activity 27,29 . ...
The increase in neuronal activity induced by a single seizure is supported by a rise in the cerebral blood flow and tissue oxygenation, a mechanism called neurovascular coupling (NVC). Whether cerebral and systemic hemodynamics are able to match neuronal activity during recurring seizures is unclear, as data from rodent models are at odds with human studies. In order to clarify this issue, we used an invasive brain and systemic monitoring to study the effects of chemically induced non-convulsive seizures in sheep. Despite an increase in neuronal activity as seizures repeat (Spearman’s ρ coefficient 0.31, P < 0.001), ictal variations of cerebral blood flow remained stable while it progressively increased in the inter-ictal intervals (ρ = 0.06, P = 0.44 and ρ = 0.22; P = 0.008). We also observed a progressive reduction in the inter-ictal brain tissue oxygenation (ρ = − 0.18; P = 0.04), suggesting that NVC was unable to compensate for the metabolic demand of these closely repeating seizures. At the systemic level, there was a progressive reduction in blood pressure and a progressive rise in cardiac output (ρ = − 0.22; P = 0.01 and ρ = 0.22; P = 0.01, respectively), suggesting seizure-induced autonomic dysfunction.
... A specific isoform of CAs facilitate lactate transport in astrocytes as well as in neurons [66]. In addition, CAs can intervene in lactic acid-induced acidosis, that seems to be implicated in seizure termination [65,67]. Moreover, CAs provide substrates required for the function of metabolic enzymes involved in epilepsy. ...
Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer's disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as an-ticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.
... KD contains high fat content, low carbohydrate content, and adequate protein content. It alters the primary cerebral energy supply from glucose to ketone bodies, mimicking biochemical changes during starvation (11,12). KD is the most effective when taken after fasting or when the body's calorie levels are low. ...
Management of frequent epileptic seizures in febrile infection-related epilepsy (FIRES) is often challenging. FIRES is an uncommon disease condition. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes. However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES. We present the case of a previously healthy 3-year-old male with new-onset status epilepticus (SE) admitted to the paediatric intensive care unit for 55 days. Despite treatment with multiple anti-epileptic agents in addition to IV anaesthetics, the patient remained in SRSE and continued to have generalised epileptic activity on electroencephalography (EEG). KD therapy was initiated on the 14th day of the onset, and the patient achieved complete neurological recovery following the KD. Throughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. The convulsions were well controlled after discharge. We discuss the treatment strategies for FIRES and highlight the role of KD therapy in the acute phase to control disease progression and improve the prognosis, and early diagnosis of FIRES and early initiation of KD therapy combined with anti-epileptic drugs (AEDs) could improve the prognosis.
... Oxidative stress might also contribute to the high comorbidities of metabolic disturbances in patients with epilepsy [17,18]. Seizures result in the alteration of glucose metabolism, the reduction of intracellular energy metabolites, and the accumulation of metabolic intermediates, such as lactate and adenosine [18,19]. ...
... Oxidative stress might also contribute to the high comorbidities of metabolic disturbances in patients with epilepsy [17,18]. Seizures result in the alteration of glucose metabolism, the reduction of intracellular energy metabolites, and the accumulation of metabolic intermediates, such as lactate and adenosine [18,19]. Furthermore, although studies have reported that glucose dysregulation may be a predictor of the pathological outcome [20,21], little is known about the effect of glycemic control on clinical outcome in patients with DRE. ...
Drug-resistant epilepsy (DRE) is a chronic neurological disorder with somatic impacts and increased risk of metabolic comorbidities. Oxidative stress might play an important role in metabolic effects and as a regulator of seizure control, while coenzyme Q10 (CoQ10) could improve insulin sensitivity through antioxidant effects. We aimed to investigate the association between CoQ10 level and clinical outcome, represented by the seizure frequency and quality of life, in DRE patients. DRE patients (N = 33) had significantly higher serum insulin levels and lower scores on the physical domain of the World Health Organization Quality of Life questionnaire (WHOQoL) than gender-age matched controls. The serum CoQ10 level (2910.4 ± 1163.7 ng/mL) was much higher in DRE patients than the normal range. Moreover, the serum CoQ10 level was significantly correlated with the seizure frequency (r = −0.412, p = 0.037) and insulin level (r = 0.409, p = 0.038). Based on stratification by insulin resistance (HOMA-IR > 2.4), the subgroup analysis showed that patients with a greater HOMA-IR had higher CoQ10 levels and lower seizure frequency, and had a significantly worse quality of life. In summary, CoQ10 could be a mediator involved in the mechanism of epilepsy and serve as a biomarker of the clinical outcome in DER patients.
