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Epilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may not be etiologically relevant for genetic epilepsies. Mutations in SCN1A are a common cause of Dravet Syndrome, a severe epileptic encephalopathy. Dravet syndrome typically begins in infancy with seizures provoked by fever and then progresses to include afebrile pleomorphic seizure types. Affected children respond poorly to available anticonvulsants. Scn1a+/- heterozygous knockout mice recapitulate features of Dravet syndrome and provide a potential screening platform to investigate novel therapeutics. In this study, we conducted a screening of conventional anticonvulsants in Scn1a+/- mice to establish assays that most closely correlate with human response data.
Embryofetal development is a critical process that needs a strict epigenetic control, however, perturbations in this balance might lead to the occurrence of congenital anomalies. It is known that anticonvulsants potentially affect epigenetics-related genes, however, it is not comprehended whether this unbalance could explain the anticonvulsants-induced fetal syndromes. In the present study, we aimed to evaluate the expression of epigenetics-related genes in valproic acid, carbamazepine, or phenytoin exposure. We selected these three anticonvulsants exposure assays, which used murine or human embryonic stem-cells and were publicly available in genomic databases. We performed a differential gene expression (DGE) and weighted gene co-expression network analysis (WGCNA), focusing on epigenetics-related genes. Few epigenetics genes were differentially expressed in the anticonvulsants' exposure, however, the WGCNA strategy demonstrated a high enrichment of chromatin remodeling genes for the three drugs. We also identified an association of 46 genes related to Fetal Valproate Syndrome, containing SMARCA2 and SMARCA4, and nine genes to Fetal Hydantoin Syndrome, including PAX6, NEUROD1, and TSHZ1. The evaluation of stem-cells under drug exposure can bring many insights to understand the drug-induced damage to the embryofetal development. The candidate genes here presented are potential biomarkers that could help in future strategies for the prevention of congenital anomalies.
AMPA receptors are responsible for fast excitatory synaptic transmission in the mammalian brain. Post-translational protein S-palmitoylation of AMPA receptor subunits GluA1-4 reversibly regulates synaptic AMPA receptor expression, resulting in long-lasting changes in excitatory synaptic strengths. Our previous studies have shown that GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice exhibited hyperexcitability in the cerebrum and elevated seizure susceptibility without affecting brain structure or basal synaptic transmission. Moreover, some inhibitory GABAergic synapses-targeting anticonvulsants, such as valproic acid, phenobarbital, and diazepam, had less effect on these AMPA receptor palmitoylation-deficient mutant mice. This work explores pharmacological effect of voltage-gated ion channel-targeted anticonvulsants, phenytoin and trimethadione, on GluA1C811S mice. Similar to GABAergic synapses-targeting anticonvulsants, anticonvulsive effects were also reduced for both sodium channel- and calcium channel-blocking anticonvulsants, which suppress excess excitation. These data strongly suggest that the GluA1C811S mice generally underlie the excessive excitability in response to seizure-inducing stimulation. AMPA receptor palmitoylation site could be a novel target to develop unprecedented type of anticonvulsants and GluA1C811S mice are suitable as a model animal for broadly evaluating pharmacological effectiveness of antiepileptic drugs.
Behavioral and psychological symptoms of dementia (BPSD) are present in a majority of patients with dementia contributing to increased morbidity, health care costs, and caregiver burden. While there are no United States Food and Drug Administration (FDA)-approved medications for these symptoms, off-label use of medications such as antipsychotics have been shown to have significant adverse effects including increased mortality. The goal of this review is to examine the efficacy and safety of anticonvulsants in the treatment of BPSD.
In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, KA-104, that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds 53 and 60 displayed the following pharmacological profile: ED50 = 89.7 mg/kg (MES), ED50 = 29.9 mg/kg (6 Hz, 32 mA), ED50 = 68.0 mg/kg (6 Hz, 44 mA), and ED50 = 73.6 mg/kg (MES), ED50 = 24.6 mg/kg (6 Hz, 32 mA), and ED50 = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, 53 and 60 were effective in the ivPTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for 53 and 60. These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for 53 and 60 (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, 53 and 60 seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel.
Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.
1. Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. 2. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 microg per 100 microl, respectively. 3. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. 4. Hill slope coefficients for the tested anticonvulsants indicate that the dose-response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. 5. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics.
30% of epilepsy patients receiving antiepileptic drugs (AEDs) are not fully controlled by therapy. The drug transporter hypothesis for refractory epilepsy proposes that P-gp is over expressed at the epileptic focus with a role of P-gp in extruding AEDs from the brain. However, there is controversy regarding whether all AEDs are substrates for this transporter. Our aim was to investigate transport of phenytoin, lamotrigine and carbamazepine by using seven in-vitro transport models. Uptake assays in CEM/VBL cell lines, oocytes expressing human P-gp and an immortalised human brain endothelial cell line (hCMEC/D3) were carried out. Concentration equilibrium transport assays were performed in Caco-2, MDCKII ±P-gp and LLC-PK1±P-gp in the absence or presence of tariquidar, an inhibitor of P-gp. Finally, primary porcine brain endothelial cells were used to determine the apparent permeability (Papp) of the three AEDs in the absence or presence of P-gp inhibitors. We detected weak transport of phenytoin in two of the transport systems (MDCK and LLC-PK1 cells transfected with human P-gp) but not in the remaining five. No P-gp interaction was observed for lamotrigine or carbamazepine in any of the seven validated in-vitro transport models. Neither lamotrigine nor carbamazepine was a substrate for P-gp in any of the model systems tested. Our data suggest that P-gp is unlikely to contribute to the pathogenesis of refractory epilepsy through transport of carbamazepine or lamotrigine.
Aim: Anticonvulsant medications are frequently used in clinical practice to treat psychiatric disorders in children and adolescents, but the evidence for their efficacy is uncertain. We conducted a systematic review of published randomized controlled trials (RCT) that assessed the psychiatric benefit of anticonvulsants in patients under 18 years of age. Method: The Medline, Scopus, Web of Science, and ClinicalTrials.gov databases were systematically searched for peer-reviewed primary publications of RCTs with a minimum of 10 patients per treatment arm through December 2017. Results: Out of 355 identified non-duplicative publications, 24 met the inclusion criteria. Most RCTs were to treat bipolar disorder (n = 12) or manage recurrent aggression (n = 9). Few (n = 3) had both a multisite design and adequate statistical power. Valproate was the most frequently studied anticonvulsant (n = 15). Out of three placebo-controlled RCTs of valproate in bipolar disorder, none showed efficacy. In four RCTs, valproate was inferior to the antipsychotic risperidone. In several small, single-site RCTs, valproate and sulthiame were better than placebo for the management of recurrent aggression. Conclusions: Currently available RCTs do not support the efficacy of anticonvulsants as mood stabilizers in children. There is some preliminary evidence from small RCTs of the efficacy of some anticonvulsants in the control of aggression and behavioral dyscontrol in conduct disorder, autism, and intellectual disability.
The acute hippocampal brain slice preparation is an important in vitro screening tool for potential anticonvulsants. Application of 4-aminopyridine (4-AP) or removal of external Mg(2+) ions induces epileptiform bursting in slices which is analogous to electrical brain activity seen in status epilepticus states. We have developed these epileptiform models for use with multi-electrode arrays (MEAs), allowing recording across the hippocampal slice surface from 59 points. We present validation of this novel approach and analyses using two anticonvulsants, felbamate and phenobarbital, the effects of which have already been assessed in these models using conventional extracellular recordings. In addition to assessing drug effects on commonly described parameters (duration, amplitude and frequency), we describe novel methods using the MEA to assess burst propagation speeds and the underlying frequencies that contribute to the epileptiform activity seen. Contour plots are also used as a method of illustrating burst activity. Finally, we describe hitherto unreported properties of epileptiform bursting induced by 100 microM 4-AP or removal of external Mg(2+) ions. Specifically, we observed decreases over time in burst amplitude and increase over time in burst frequency in the absence of additional pharmacological interventions. These MEA methods enhance the depth, quality and range of data that can be derived from the hippocampal slice preparation compared to conventional extracellular recordings. It may also uncover additional modes of action that contribute to anti-epileptiform drug effects.
Epilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2-5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-current, which suppresses neuronal excitability, protecting against seizures. Here, in silico docking, mutagenesis and cellular electrophysiology reveal that two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Correspondingly, MTX and IVA combine to suppress pentylene tetrazole-induced tonic seizures in mice, whereas individually they are ineffective. Co-administering MTX and IVA with the modern, synthetic anticonvulsant retigabine creates a further synergy that voltage independently locks KCNQ2/3 open. Leveraging this synergy, which harnesses ancient and modern medicines to exploit differential KCNQ isoform preferences, presents an approach to developing safe yet effective anticonvulsants.
Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program was therefore established by the National Institutes of Health (NIH) to discover novel treatments that may be administered adjunctively with the currently approved medical countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program utilizes in vivo EEG recordings and Fluoro-JadeB (FJB) histopathology in two established rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered at 20 or 60 min after the induction of OP-induced SE. Here we report the results of multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining demonstrated that none of the tested drugs had widespread neuroprotective abilities. Overall these data suggest that neurosteroids may represent the most promising anticonvulsant option for OP-induced SE out of the seven unique mechanisms tested here. Additionally, these results suggest that drugs that provide significant neuroprotection from OP-induced SE without some degree of anticonvulsant activity are elusive, which further highlights the necessity to continue screening novel adjunct treatments through the CNS program.
Purpose This study investigated clinical practice patterns for admissions due to FS at a national level. Method Discharge records were extracted for patients with FS aged < 6 years for the years 2010-16 using national inpatient database in Japan. We ascertained antiepileptic drug use, diagnostic procedures, healthcare costs, and length of hospital stays (LOS), using mixed effect linear or logistic regression models. We also investigated correlations between performance of lumbar puncture (LP), and use of head computed tomography (CT) and antibiotics. Results We identified a total of 94,452 eligible patients. Hospitalization costs and LOS in days decreased from 19,027 JPY and 4.6 days in 2010 to 18,753 JPY and 4.1 days in 2016. Phenytoin use decreased from 1.6% in 2010 to 0.5% in 2016, whereas fosphenytoin use increased from 0% in 2010 to 6.7% in 2016. Decreasing trends were observed in CT use (from 32.8% to 16.9%) and LP performance (16.9% to 13.5%). For the analyses at hospital levels, CT use and LP performance was positively correlated (r = 0.63). No correlations were observed between total and extremely broad-spectrum antibiotic use and CT use or LP performance in hospitals without cases of intensive care. Wide variations were observed across hospitals for performance of LP (0%-88%), use of CT (0%-84%) and antibiotics (10%-99%). Conclusion We provided novel insights into the current practice patterns for children with FS at individual levels, and delineated wide variations of LP, CT, and antibiotic use for the practices at hospital levels.
Acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is a common complication in critical illness and has a significant impact on pharmacokinetic factors determining drug exposure, including absorption, distribution, transport, metabolism, and clearance. In this review, we provide a practical guide to drug dosing considerations in critically ill patients undergoing CRRT, focusing on the most commonly used analgesic, anticonvulsant, and psychotropic medications in the clinical care of critically ill patients. A literature search was conducted to identify articles in which drug dosing was evaluated in adult patients receiving CRRT between the years 1980 and 2020. We included articles with pharmacokinetic/pharmacodynamic analyses and those that described medication clearance via CRRT. A summary of the data focused on practical pharmacokinetic and pharmacodynamic principles is presented, with recommendations for drug dosing of analgesics, anticonvulsants, and psychotropic medications. Pharmacokinetic and pharmacodynamic studies to guide drug dosing of analgesics, anticonvulsants, and psychotropic medications in critically ill patients receiving CRRT are sparse. Considering the widespread use of these medications, narrow therapeutic index of these drug classes, and risks of over- and underdosing, additional studies in patients receiving CRRT are needed to inform drug dosing.
Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection.
Risk exists for civilian exposure to nerve agents (NA), and exposure can produce prolonged seizures. Pediatric populations are at greater risk for injury or death due to the central nervous system effects of NAs. To address the need to evaluate the effectiveness of anticonvulsants, pediatric and adult animal models were established to test the effectiveness of anticonvulsant drugs for treating NA-induced seizures in pediatric populations. In this paper, median effective dose (ED50) and neuroprotective effectiveness were determined for the first-line anticonvulsant treatments diazepam and midazolam in pediatric and adult rats against sarin- and VX-induced seizures. Comparisons between treatments were made across postnatal days (PND) 21, 28, and 70 in rats of both sexes. We observed high efficacy and potency of midazolam and diazepam, with low variation in doses across the ages or sexes. These data are important for informing adult and pediatric dosing recommendations for NA-induced seizures.
Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2-K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.
Herpes zoster-associated pain [i.e., acute herpes zoster neuralgia (AHN) and postherpetic neuralgia (PHN)] has the potential to cause significant patients' burden and heath resource expenditure. PHN is refractory to the existing treatments, and the consensus is preventing the transition of AHN to PHN is better than treating PHN. Anticonvulsants (e.g., gabapentin, pregabalin) have been recommended as one of the first-line therapies for PHN. In practice, anticonvulsants have also decreased the severity and duration of AHN and reduced the incidence of PHN. Nevertheless, its clinical application to AHN is hampered by inadequate evidence for its efficacy and safety. We performed this protocol for a systematic review to explore the efficacy and safety of anticonvulsants for AHN. Besides, a benefit-risk assessment of anticonvulsants for AHN would be performed to estimate the extent to which these drugs could relieve symptoms and whether the benefits outweigh harms.
We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI=TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
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