Article Summaries for Non-Specialists
Zahra Shiri, Maxime Levesque, Guillaume Etter, Frederic Manseau, Sylvain Williams, and Massimo Avoli
Objective – Seizures are caused by abnormal electrical activity in the brain. The brain includes of excitatory and inhibitory neurons (with a multitude of cell types under this broad classification). Excitatory and inhibitory neurons work in concert, and seizures are thought to arise when this balance goes awry. Anti-epileptic medications limit seizures in approximately two-thirds of the patient population, but the rest may have to resort to aggressive procedures like surgery (these patients are said to have “refractory” epilepsy). Low-frequency stimulation (LFS) is a procedure that could potentially be used for refractory epilepsy, because it has been shown to modify the behavior of neurons. However, one drawback of LFS is its non-specificity i.e. not being able to turn on and off specific cell types. Optogenetics is an experimental technique where certain neuronal populations can be turned on and off at will because the specific proteins they contain react to light of different wavelengths.
In the current study, the authors investigated effects of LFS with optogenetics in a part of the brain called the entorhinal cortex (EC). The EC was chosen because of its potential role in seizure generation. LFS with optogenetics was used to control the excitability of specific neuronal populations over time. All experiments were done in mice â€“ after anesthesia, mice brain slices were made, and a drug called 4-AP was used to simulate seizures.
Results – The authors first confirmed that their technique of using optogenetics in mice could successfully target specific neuronal populations - Â they targeted one type of principal cell (excitatory neuron), and two types of interneurons (inhibitory neurons). The authors then found that LFS with optogenetics targeted to all three cell types reduced the rate of experimental seizures. The effect lasted for a longer time when principal cells were specifically targeted.
Interpretation – In this study of “in vitro” seizures (seizures produced outside the body; in this case, 4-AP was used in slices from a mouse brain), the authors found that LFS along with optogenetics reduced seizures. The authors checked just one model of seizure, and one question is whether LFS and optogenetics would reduce seizures caused by other techniques as well. Whether, and how this technique may help people with refractory seizures will require extensive experimentation.
Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury
Ali Erturk, Susanne Mentz, Erik E. Stout, Maj Hedehus, Sara L. Dominguez, Lisa Neumaier, Franziska Krammer, Gemma Llovera, Karpagam Srinivasan, David V. Hansen, Arthur Liesz, Kimberly A. Scearce-Levie, and Morgan Sheng
Objective: Traumatic brain injury (TBI) is the cause of considerable disability, and has been shown to contribute to conditions like epilepsy, and dementia. TBI causes changes in the brain immediately (acute), and sometime after (chronic) the initial event. The characteristics of acute changes in neurons are somewhat better understood, but the features of the neurons that survive, and whether (and how) they contribute to long-term deleterious effects is not fully known. Hence, the authors of this paper used a model of TBI called the closed-head model in mice, to study these chronic alterations. In this model, mice are anesthetized, and an injury of measured magnitude is applied to the exposed skull. This gives the opportunity to not only study what happens to the brain over time, but also what happens in areas near and far away from the injury site. The authors looked at inflammatory mediators in mice that were subjected to the closed-head model.
Results: In mice subjected to the closed-head model, abnormal inflammation was found as long as a year after the initial injury. Since the life span of mice is considerably shorter than that of humans, one year represents a long time in their lives. Abnormal inflammation was found in areas of the brain both near to, and farther away from, the site of injury. After observing these general changes in the brains of mice that were subject to TBI, the authors then studied a specific molecule called CX3CR1, which is a mediator of inflammation in the brain. Experiments in transgenic mice revealed that deletion of one allele of CX3CR1 prevents the chronic, inflammatory cascade in mice caused by TBI. This effect was more pronounced in female mice as compared to male mice.
Interpretation: The current study shows that inflammatory reactions can persist for a long time after the injury, and that they might be a critical component of neurodegeneration. The authors also discovered that a molecule called CX3CR1 might mediate these long-term effects (in female mice, at least). The authors hence propose that chronic inflammation may be a potential target to develop therapies for subjects with TBI.
Tight Coupling of Astrocyte pH Dynamics to Epileptiform Activity Revealed by Genetically Encoded pH Sensors
Raimondo JV, Tomes H, Irkle A, Kay L, Kellaway L, Markram H, Millar RP, Akerman CJ
Objective: The brain consists of two types of cells, neurons and glia. Considerable research in epilepsy has focused on neurons, but the role of glia in seizure disorders is just beginning to be understood. Astrocytes are star-shaped glial cells that are extremely responsive to changes in the environment, and are important for supplying the brain with nutrients, forming the blood-brain barrier and for repairing the brain after injury.
pH is a measure of how acidic or alkaline (basic) something is, and pH changes have been noticed during seizure activity. Specifically, pH changes in neurons during seizures have been examined, but glial pH during a seizure has not been explored in detail. Hence, the scientists wanted to examine changes in astrocytic pH during a seizure and the timeframe in which these pH changes occur. This study is unique because the authors used genetically-coded pH sensitive proteins to observe pH changes in real time while measuring the electrical activity during a seizure. Seizures were elicited in tissue obtained from rodents. The hope is that by tracking pH changes, we can study their contribution to seizures and potentially find therapies to limit these changes and stop seizures.
Results: Earlier results have shown that pH in neurons during a seizure tends towards acidification. The mechanisms that regulate pH in astrocytes are different from those in neurons, and the authors found that astrocytes become alkaline during seizure-like events. The change in pH in astrocytes was much more rapid and more tightly coupled to network dynamics as compared to neuronal pH changes.
Interpretation: This study highlights notable differences between neurons and astrocytes in the way they regulate pH and possibly seizures. Since astrocytes seem to be more responsive than neurons to changes in local environment, targeting them could provide novel therapies for seizures and epilepsies.
Eissa TL, Tryba AK, Marcuccilli CJ, Ben-Mabrouk F, Smith EH, Lew SM, Goodman RR, McKhann GM Jr, Frim DM,
Objective: A third of the population with epilepsy fails to achieve seizure freedom with anti-epileptic drugs. These patients have to resort to vagus nerve stimulation, deep brain stimulation or surgical removal of areas that initiate seizures. For surgical removal of brain tissue, finding out where the seizure onset zone (SOZ) is located is critical. In some patients this requires electrocorticography (ECoG), the placement of electrodes on the brain surface. But it is thought that ECoG sometimes overestimates the SOZ, thereby potentially making the neurosurgeons resect more brain tissue than just the SOZ. Hence, there is a need to find a better biomarker to identify the SOZ. The authors of a recent paper looked at high gamma (HG) activity as a potential biomarker. HG activity is observed at the network level; at the neuronal level, paroxysmal depolarizing shifts (PDSs) are also thought to be important for seizure generation. The hypothesis of this paper was that HG activity at the network level is linked to PDSs at the neuronal level. Experiments were done in tissue resected from patients with intractable epilepsy and by looking at seizure activity in the patients in vivo.
Results: On experiments done on resected tissue from patients with intractable epilepsy, the authors recorded electrical activity from outside neurons (extracellular) and inside neurons (intracellular). In vivo seizures were measured with microelectrodes placed with ECoG grids. By simulating seizure activity in resected tissue, the authors found an increase in HG activity. In vivo seizures exhibited a higher HG activity in parts of the seizure. This HG activity was correlated to PDSs.
Interpretation: These experiments show that HG and PDSs are indeed correlated, and that HG activity could be a more accurate determinant of the SOZ for resection surgery than what is currently done.
Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures
Awad PN, Sanon NT, Chattopadhyaya B, Carriço JN, Ouardouz M, Gagné J, Duss S, Wolf D, Desgent S, Cancedda L, Carmant L, Di Cristo G
Objective: A specific type of febrile seizure known as ‘atypical febrile seizures’ can be associated with temporal lobe epilepsy later in life. Individuals with a defect in architecture of the brain called cortical dysplasia are more susceptible to such seizures. Studies have shown a link between cortical dysplasia, the presence of atypical febrile seizures and temporal lobe epilepsy later in life, but why this is the case is not fully understood. The authors of a recent paper had developed an experimental model to study this process in rat pups (these rats are called ‘LHS rats’). Inhibitory neurotransmission in the brain is regulated by gamma amino butyric acid (GABA). GABAergic neurotransmission critically depends on the gradient of chloride inside vs. outside of neurons, and KCC2 is a chemical that regulates this gradient. In this study, the authors studied KCC2 in LHS rats to see if changes in KCC2 can cause the seizures and epilepsy.
Results: Neurons communicate with each other using electricity, and dendritic spines are small protrusions that help in transmission of electrical signals. The scientists examined dendritic spines in LHS rats and their normal counterparts in a part of the brain called the hippocampus. They found an increase in KCC2, reduced number and abnormal maturation of dendritic spines. By reducing the amount of KCC2, the scientists were able of correct deficits in dendritic spines and reduce the incidence of seizures.
Interpretation: The results suggest that an increase in KCC2 in the developing brain may lead to abnormal dendritic spines and an increase in incidence of febrile seizures.
Objective: Status epilepticus (SE) is a medical emergency defined as unrelenting seizures that last longer than 5 minutes and can be associated with mortality. The first line of treatment is benzodiazepines (e.g. diazepam) but these drugs stop working in more than half of the individuals with SE as seizures progress. Drugs like diazepam act on the inhibitory neurotransmitter gamma amino butyric acid (GABA). GABAergic neurotransmission is controlled by the level of chloride (Cl−) ions inside vs. outside neurons (the Cl− gradient) which is maintained by ion channels. Given the specific expression of ion channels in the immature brain, experiments have shown that a drug called bumetanide is effective in reducing seizures in neonates. In the current study, the authors wanted to know whether there is a breakdown of the GABAergic system during SE in the adult brain and whether bumetanide would allow diazepam to retain its function even as seizures progress. Mice were used for these experiments, and both in vitro (brain slices) and in vivo (in the intact animal) experiments were done.
Results: Bumetanide reduced seizure-like events in the brain slice and seizures in the intact mice.
Interpretation: Previous studies have suggested that bumetanide can be useful in neonates because of its action on the immature GABAergic system. This study shows that dysfunction of Cl- homeostasis and GABEergic neurotransmission can take place in SE as well, and that bumetanide can decrease seizures in SE by potentially restoring this imbalance.
Postictal immobility and generalized EEG suppression are associated with the severity of respiratory dysfunction
Objective: The mechanisms underlying SUDEP (sudden unexpected death in epilepsy) are not known, but a few parameters of potential importance have been recognized. SUDEP has been shown to occur mostly after a generalized tonic clonic seizure, and individuals are for the most part found in a prone position i.e. with the chest down and the back up. Respiratory dysfunction (an increase in blood CO2), postictal immobility (loss of movement right after a seizure) and postictal generalized EEG suppression (PGES) could play a role. The authors of a recent study examined whether postictal immobility was associated with PGES and with SUDEP. To do this, they chose patients that had tonic-clonic seizures and measured a number of parameters.
Results: There were no correlations between postictal immobility and the duration of the seizures or the location in the brain where seizures were originating. However, there was a correlation between respiratory dysfunction, PGES and postictal immobility.
Interpretation: This study shows a link between PGES, respiratory dysfunction and postictal immobility and sheds light on the possible sequence of events that could lead to SUDEP. It could be that after a tonic-clonic seizure, an individual in the prone position experiences a positive feedback between respiratory dysfunction and postictal immobility. This would mean that the more a person is immobile, the more respiratory dysfunction would occur, which could continue until the person is unable to move the head, ultimately leading to death. This study is important because something that reverses or targets postictal immobility may help reverse SUDEP.
Marguet SL, Le-Schulte VT, Merseburg A, Neu A, Eichler R, Jakovcevski I, Ivanov A, Hanganu-Opatz IL, Bernard C, Morellini F, Isbrandt D.
Nature Medicine; vol 21 no. 12, December 2015, pp 1436-1444. doi:10.1038/nm.3987
Objective: Proper functioning of the brain is dependent on transfer of ions in and out of neurons which is mediated by ion channels situated on neuronal membranes. One such ion channel is the potassium (K+) channel called Kv7 channel. A defect in this ion channel can lead to epilepsy.
The incidence of epilepsy is high during the first few years of life as the brain is developing and is more susceptible to insults. Since there is a narrow time window where Kv7 K+ channels are formed in the brain, the authors of a recent paper investigated whether administering a drug only during that specific time window would decrease seizures. Bumetanide, a drug that has been shown to normalize ionic imbalance in neurons and reduce seizures in lab experiments, was used. The authors used mice with a mutation in Kv7 K+ channels, as previous experiments had shown that these mice develop seizures and abnormalities in structure and function during the first two weeks of life and for the rest of the adult life.
Results: Bumetanide showed no ill-effects on normal, healthy mice suggesting a possible lack of side-effects. Then, bumetanide was administered to mutant mice for the first two weeks of life; this transient treatment was enough to restore structure and function and to prevent seizure development.
Interpretation: At present, drugs for epilepsy target seizures and not epileptogenesis. This study shows administration of bumetanide before overt seizures develop can restore abnormalities in structure and function caused by deficient Kv7 K+ channels in mutant mice. A similar strategy could also be useful for individuals with hypoxia or traumatic brain injury, both of which can lead to epilepsy.
Objective: Glutamate is an excitatory neurotransmitter in the brain and acts via the NMDA receptor (NMDAR; N-methyl D-aspartate receptor). Like other receptors, the NMDAR is made up of various submits. One cause of inflammation in the brain (or, encephalitis) is an autoimmune reaction to a NMDAR subunit. This condition, known as "NMDA receptor antibody encephalitis" is associated with psychosis, agitation and violent behavior which may be followed by seizures. A recent book recounts the experience of a young journalist with this condition. How the NMDAR antibody causes seizures is not fully known; hence, in this study, the authors injected the human antibody directly into the brains of experimental mice. The antibody was injected by itself and then with a drug that produces seizures (i.e. a chemoconvulsant- in this case, pentylenetetrazol or PTZ).
Results: Mice injected with the antibody did not show spontaneous seizures. However, they were more susceptible to seizures caused by PTZ as compared to those given the sham (inactive) antibody. The antibody bound preferentially to the hippocampus – a part of the brain important for seizures, and the level of antibody bound to NMDARs correlated with the seizures that the mice experienced.
Interpretation: This study showed that the antibody against NMDARs injected directly into the brain can worsen seizures caused by PTZ. This study forms one of the first studies to understand the seizure-inducing capacity of the NMDAR antibody.
Objective: Glia are supporting cells of the brain that serve essential functions. Microglia are a type of glia that respond to seizures by changing their shape and releasing free radicals called Reactive Oxygen Species (ROS). Studies showing this have been done in the lab using a chemical called a chemoconvulsant to produce seizures. Thus, it is not possible to know whether the effects are because of the seizures or the drug itself. In a recent paper, the authors used electrical stimulation to produce seizures in rats and looked at production of ROS in microglial cells. The rationale was that knowing this can help guide design of therapeutic strategies for epilepsy.
Results: Acquired epilepsies can be caused by an event like stroke or meningitis, which may be followed by a phenomenon called “epileptogenesis” (the quiet period where the normal brain becomes epileptic). Hence, the disease process is divided into three parts: the period right after the injury, epileptogenesis and epilepsy. In the rats subjected to electrical stimulation, the authors found an increase in production of microglial ROS right after the stimulation but not during epileptogenesis or epilepsy.
Interpretation: Since an increase in microglial ROS was seen only during the initial phase, therapies to decrease ROS should probably be restricted to just the initial phase. More studies need to be done to study how microglial ROS affects seizures, but this study forms a good start.
Shen HY, van Vliet EA, Bright KA, Hanthorn M, Lytle NK, Gorter J, Aronica E, Boison D
Objective: One third of people with epilepsy respond poorly to existing anti-epileptic drugs (AEDs); besides, these drugs can be associated with side-effects. Hence, there is an urgent need to discover newer targets that AEDs can work on to decrease seizures. The authors of a recent paper studied a neurotransmitter called glycine and its role in epilepsy. Neuronal function depends on a fine balance between excitation and inhibition, and glycine plays a key role in maintaining this balance. Since seizures are can result from an imbalance between excitation and inhibition, it is reasonable to think that the role of glycine in epilepsy is valuable to investigate. The authors looked at the hippocampus because the hippocampus is greatly affected in temporal lobe epilepsy (TLE). Seizures were generated in experimental rats and mice and glycine in the hippocampus was observed.
Results: The effects of glycine in the hippocampus are mediated by the glycine transporter 1 (GlyT1). An increase in GlyT1 was observed in two experimental models of TLE and also in tissue from people with TLE. Since epilepsy was found to be associated with an increase in GlyT1, the question that followed was what would happen if GlyT1 action was decreased. In response to a drug that inhibits GlyT1, experimental animals were found to be protected from seizures.
Interpretation: This study showed that targeting glycine and GlyT1 could be investigated further for epilepsy. Of course, more research needs to be done, but the findings of this study provide a promising lead.
Nina Dupuis, Niccolo Curatolo, Jean-François Benoist and Stéphane Auvin
Objective: Anti-epileptic drugs (AEDs) are effective in only two-thirds of the population with epilepsy and alternative therapies need therefore to be explored. The ketogenic diet,a high-fat, low-carbohydrate diet, was found to be useful in refractory epilepsy (i.e. seizures that do not respond well to medication) and has been shown to improve cognition in people with epilepsy. However, the mechanism by which the ketogenic diet has an effect on seizures is not fully understood. Since a role for inflammation in seizure disorders has been proposed, the authors of a recent study sought to determine whether the ketogenic diet might be beneficial by reducing inflammation in the brain.
Results: The scientists used experimental rats to test this hypothesis. Rats were divided into two groups – those given a normal diet and those on a ketogenic diet. In order to study inflammation and effects of the ketogenic diet on inflammation, the scientists injected all rats with lipopolysaccharide (LPS) – this compound increases body temperature and causes inflammation. Of interest is the fact that high body temperature can sometimes lead to a seizure. The authors found that LPS injected increased body temperature in rats given a normal diet, but not in those on the ketogenic diet. Injection of LPS causes an increase in inflammatory molecules and rats on the ketogenic diet showed a reduction in these inflammatory molecules.Interpretation: The experiments show that the ketogenic diet decreases inflammation; this is perhaps the reason for its efficacy in epilepsy.
Objective: Anecdotal reports in the clinic show that stress can exacerbate seizures in people with epilepsy. One reason for this could be a subjective bias in how events are recalled i.e. something as unpredictable as a seizure can be viewed as stressful when looking back. However, scientists have shown a correlation of seizure frequency with stress even in laboratory animals, suggesting that perhaps there are neurobiological mechanisms as play. Stress causes activation of two pathways – the sympathetic nervous system responsible for the “fight or flight” reaction we're familiar with, and the hypothalamic-pituitary-adrenal (HPA)-axis. The latter is a slower response and involves release of a stress hormone called cortisol. Both systems can cause an increase in excitability of neurons, potentially leading to seizures. Authors of a recent study studied the relationship between stress and seizures in children with epilepsy; children without epilepsy were controls. Children were given a seizure diary to capture daily seizures and were administered a test that produced acute stress and the level of cortisol in their saliva was measured.
Results: The diaries showed a positive relationship between stress and seizures in a subset of children with epilepsy. In this subset of children, the acute stressor test revealed a decreased cortisol response to stress compared to healthy children and to epileptic children in whom seizures were not associated with stress.
Interpretation: A positive relationship between stress and seizures could have been attributed to a subjective recall bias, or due to factors like fatigue or a lack of sleep. This study shows that children whose seizures are facilitated by stress in fact have a blunted physiological response to stress.
Short summary for scientists: A positive relationship between stress and seizures in subjects with epilepsy has been observed, but not entirely understood. In this study in children with epilepsy, the authors administered the Trier Social Stress Test for Children – a standardized acute psychosocial test – and found a blunted cortisol response in children with epilepsy that had stress-sensitive seizures. Children with epilepsy without stress-sensitive seizures did not show the blunted cortisol response and neither did controls. By unraveling the biological mechanism of stress-related seizures, one can envision novel therapies for stress-related seizures.
Objective: Anti-epileptic drugs usually act on neurons, and can be associated with side-effects and refractoriness. Recently, the role of glia (non-electrically excitable cells in the brain) in epilepsy is being examined. One type of glia called astrocytes (star-shaped glial cells) has been shown to undergo tremendous changes in the epileptic brain; hence, examining its role in epilepsy could lead to the development of newer and better therapies for epilepsy. In a recent study, the authors studied astrocytes in tissue resected from the brain of people with epilepsy. To understand the role of astrocytes in epilepsy in greater detail, they also used a mouse model of epilepsy.
Results: One of the ways astrocytes keep excitability of neurons under check is by buffering potassium (K+) ions. Tight regulation of K+ concentration is important because an increase in K+ ions can cause seizures. Astrocytes are connected to each other and astrocytes help clearance of K+ ions by distributing K+ ions throughout the astrocytic network. The authors of this study found that astrocytes were no longer connected or coupled in tissue from a subset of patients with epilepsy. In a mouse model of epilepsy where seizures were elicited by administration of a chemoconvulsant, the authors found that uncoupling of astrocytes is a relatively early phenomenon.Interpretation: There is a great interest in the role of astrocytes in epilepsy. The results of this study suggest that since uncoupling of astrocytes occurs in epilepsy, targeting astrocytes may be a novel therapeutic strategy.
A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy model
Neurobiology of Disease 76(2015) 87-97
Objective: Current anti-epileptic drugs act through only a few known mechanisms and can be associated with refractoriness (failure of medication to decrease seizures) and side-effects. Hence, one area of epilepsy research is identification of new therapies for epilepsy. Since seizures can be associated with activation of the immune system leading to inflammation, mechanisms that cause inflammation are studied in the lab. One component of the immune system is called complement peptide C5a; in the current study, the authors studied the role of C5a in experimental seizures in mice. In the lab, investigators can study both acute seizures and chronic seizures (epilepsy consists of spontaneous, chronic, recurrent seizures).
Results: The complement C5a acts through a receptor called C5ar1. Mice were given drugs called chemoconvulsants to cause seizures experimentally, and the levels of C5ar1 were checked. The levels of C5ar1 were increased in the brains of mice that had seizures. The researchers then asked if (or how) decreasing C5a would affect seizures. A decrease in function of C5a was found to decrease seizures. Inhibiting or decreasing complement C5a also reduced seizure-induced injury in the brain. The next question was how exactly inhibition of C5a decreases seizures in mice? The researchers found that blocking C5a reduces excitability and inflammation, explaining how blockade of C5ar1 receptor could be beneficial in acute seizures and chronic seizures (epilepsy).
Interpretation: This study was done in experimental animals in the lab, and whether or not it applies to people with epilepsy in the clinic still remains to be seen. However, the authors found that decreasing activity of the complement system C5a decreased seizures – eventually, this may be a novel mechanism that could be targeted by drugs to help people with refractory epilepsy.
The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma
Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC
Objective – The ketogenic diet has been used with success for refractory epilepsy (when anti-epileptic drugs are unable to effectively stop seizures). Administration of the ketogenic diet leads to formation of ketone bodies – normal brains cells can use ketone bodies as an energy source but tumor cells cannot. Hence, in addition to the role of the ketogenic diet in epilepsy, there may also be a role of the diet in shrinking the tumor. The authors of a recent study asked whether the ketogenic diet is beneficial in one kind of brain tumor called glioma in mice. In this model, glioma cells were implanted into the brains of mice (mice were anesthetized and care was taken so that the mice do not feel undue pain). KetoCal, a commercially available ketogenic diet for pediatric epilepsy patients was used, and was compared to the standard diet. If the ketogenic diet is found to be useful in mice, it is expected that it will be tested in a subset of brain tumor patients. But it is unlikely that it will be tested without an adjuvant therapy. Hence, in this study, the authors observed the efficacy of KetoCal in glioma in mice along with radiation.
Results - Mice with glioma that were administered the ketogenic diet had a higher survival rate than those that were on the standard diet. Ketogenic diet along with radiation had a highly beneficial effect on survival and tumor growth. Indeed, Ketocal along with radiation led to a marked decrease in tumor volume; this effect was more pronounced than radiation alone.
Interpretation - The ketogenic diet has been used with success in refractory epilepsy, but its use in brain tumors is just being investigated. This study showed that the ketogenic diet along with radiation was beneficial in shrinking tumor volume in mice with glioma and in increasing survival.
Ania L. Gheyara MD, PhD, Ravikumar Ponnusamy PhD, Biljana Djukic PhD, Ryan J. Craft BS, Kaitlyn Ho BS, Weikun Guo MS, Mariel M. Finucane PhD, Pascal E. Sanchez PhD, and Lennart Mucke MD
Objective: Tau, a protein found in neurons, is important for providing them mechanical support and structure. Disruptions in tau have been implicated in neurological disorders like dementia and Alzheimer's disease. Previous studies with experimental rodents have shown that reduction of tau protein is beneficial in epilepsy. The current study was done to observe whether reduction of tau would be beneficial in Dravet Syndrome (DS). DS is a disorder caused by a mutation in the SCN1A gene – this gene codes for a sodium channel called NaV1.1. DS is characterized by severe, intractable seizures (seizures that do not respond well to anti-epileptic drugs) and behavioral and cognitive deficits. Indeed, DS is one of the most drug-resistant forms of epilepsy. Since the gene responsible for DS is known, it is possible to simulate the exact deficit in mice in order to study their characteristics to eventually find better drugs for DS. To study the role of tau in DS mice, the scientists used a genetic technique to reduce tau. The hypothesis was that mice with DS and reduced tau would have fewer seizures as compared to DS mice with normal amounts of tau.
Results: Individuals with DS can experience SUDEP (sudden unexpected death in epilepsy). Similarly, mice with DS exhibit mortality. Remarkably, mice with DS and reduced tau showed reduced mortality suggesting the protective effects of tau reduction. Interictal spikes in the electroencephalogram have been shown to be hallmarks of the epileptic brain both in the clinic and in the lab. Mice with DS and reduced tau had fewer interictal spikes and seizures, as well as fewer behavioral abnormalities as compared to mice with DS and intact tau. When the scientists looked at the brains of DS mice with reduced tau, there were fewer markers indicative of epilepsy as compared to DS mice with intact tau.
Interpretation: This study shows that reduction of tau in DS mice is protective against seizures and behavioral abnormalities. These results are quite exciting not only for DS but also for refractory epilepsy. Approximately one-third of individuals with epilepsy do not respond well to currently available antiepileptic drugs; in these cases, reduction of tau could be useful. However, how to reduce tau in a safe way needs to be further investigated.
Short summary for scientists: Preclinical studies have shown that ablation of tau is protective against seizures in Alzheimer's disease- a neurological condition where seizures are not uncommon. In this study, the scientists wanted to see if reduction of tau would be beneficial in Dravet Syndrome (DS) as well. Using in vivo and ex vivo physiology, behavioral studies and seizure monitoring, it was found that reduction of tau was indeed protective against seizures and associated behavioral comorbidites in DS mice.
Doeser A, Dickhof G, Reitze M, Uebachs M, Schaub C, Pires NM, Bonifácio MJ, Soares-da-Silva P, Beck H
Objective – Drugs used to treat epilepsy are known as anti-epileptic drugs (AEDs) but AEDs effectively reduce seizures in only two-thirds of patients, the remaining third not gaining sufficient relief from seizures. This is known as refractoriness and is an issue that epilepsy researchers are actively trying to solve. In acquired epilepsies, an initiating event like meningitis or stroke can eventually lead to development of spontaneous seizures (i.e. epilepsy). The process by which a normal brain transforms into one capable of generating seizures is known as ‘epileptogenesis.’ Unfortunately, at present, there are no drugs that can effectively halt this phenomenon.
One can imagine that a drug that can stop refractoriness and epileptogenesis would be important clinically. The authors of a recent study asked whether eslicarbazepine acetate (shortened to ESL) could address both these issues. Eslicarbazepine acetate is converted to eslicarbazepine in the body; and its use in Europe and the US has been approved in partial-onset epilepsy. For this study, the authors used experimental animals that had been given a convulsant to make them epileptic and resected tissue from individuals with refractory epilepsy.
Results: A number of AEDs work by blocking sodium (Na+) channels, hence suppressing neuronal activity. If AEDs cannot block Na+ channels effectively, one can see how they may not be able to block seizures either. Indeed, this has been proposed to be one of the mechanisms of refractoriness. In this study, the authors found ESL was able to block Na+ channels effectively again. Hence, one could say that ESL might effectively overcome refractoriness.
In another set of experiments, the scientists found that ESL blocked a particular type of calcium channels known as CaV3.2. These channels allow calcium to enter into neurons and are thought to contribute to epileptogenesis. ESL was shown to decrease two other proposed markers of epileptogenesis – mossy fiber sprouting and neurodegeneration. Additionally, ESL decreased the number of spontaneous seizures in animals that were given a convulsant. These results allude to the anti-epileptogenic actions of ESL.
Interpretation: The clinical implications of a drug that not only decreases refractoriness but also halts epileptogenesis are substantial. One interpretation of this study is that ESL could be used as a general anti-epileptogenic agent. At present, clinicians have no way of stopping epilepsy after a stroke or meningitis. Although more experiments need to be done, it could be that people who have had stroke or meningitis could be given ESL to stop epileptogenesis and hence, epilepsy. No such drug exists at this time.
Objective – Anti-epileptic drugs (AEDs) manage seizures reasonably well, but they can be associated with refractoriness and side-effects. AEDs work via only a few known mechanisms, hence it is worthwhile putting in the effort to find additional targets for drug action. New drugs hold the promise of not only being more effective in stopping seizures, but also having fewer side effects. A novel target in the field of epilepsy is adenosine – a molecule that has anticonvulsant effects. The authors of a recent study investigated whether gene therapy targeting adenosine kinase (ADK) would be effective in an experimental model of seizures in rats. ADK is the enzyme that causes breakdown of adenosine; the thought being, blockade of the enzyme would allow more adenosine to be available for action
Results – The scientists first confirmed that the gene therapy approach did what it was meant to do – i.e. a substantial reduction in expression of ADK. Drugs used to simulate seizures in the lab are known as chemoconvulsants – one such drug is kainate. Using the gene therapy approach, the scientists found that rats with a reduction in ADK (and hence more adenosine) showed a reduction in seizures caused by kainate. Rats that experience kainate-induced seizures show a loss of neurons in a part of the hippocampus known as the hilus (as do people with epilepsy). Rats that had an increase in ADK showed that these neurons were protected.
Interpretation – This preclinical study has possible implications for discovery of newer AEDs. Gene therapy could be of special importance in a chronic disorder like epilepsy because of the potential to provide long-term beneficial effects with minimal side-effects. This study shows preliminary evidence that gene therapy targeting of adenosine may be beneficial in epilepsy.