-
Epilepsy Research Sep 2021Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HTR) agonist that was approved for the treatment of obesity,...
Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HTR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HTRs at therapeutic doses, we pretreated one group of mice with the selective 5-HTR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HTRs to AGSs. We also assessed lorcaserin's in vitro pharmacology at human (h) and mouse (m) 5-HTRs and 5-HTRs and its in vivo interactions at m5-HTRs and m5-HTRs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HTRs and m5-HTRs, and near full efficacy agonist activity at h5-HTRs and m5-HTRs; selectivity for activation of 5-HTRs over 5-HTRs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HTRs and 5-HTRs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HTR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HTR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HTRs as well as 5-HTRs in mice at doses as low as 3 mg/kg. The similar activity at m5-HTRs and m5-HTRs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HTRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.
Topics: Animals; Anticonvulsants; Benzazepines; Epilepsy, Reflex; Mice; Mice, Knockout
PubMed: 34130255
DOI: 10.1016/j.eplepsyres.2021.106677 -
Acta Poloniae Pharmaceutica 2015A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity....
A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses.
Topics: Animals; Anticonvulsants; Electroshock; Male; Mice; Neurotoxicity Syndromes; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures
PubMed: 25850204
DOI: No ID Found -
Molecules (Basel, Switzerland) Jul 2017Blume (), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant,... (Review)
Review
Blume (), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of and its constituents reported from 1985 onwards.
Topics: Anticonvulsants; China; Gastrodia; Humans; Medicine, Chinese Traditional; Phytotherapy; Plant Extracts
PubMed: 28698450
DOI: 10.3390/molecules22071137 -
Seizure Dec 2004Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan.... (Review)
Review
Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan. Identified as an anticonvulsant during exploratory research, zonisamide has since been characterized as having broad-spectrum antiepilepsy and neuroprotective effects. Early clinical studies in Japan demonstrated that zonisamide has a long elimination half-life and is well tolerated; Phase II and III clinical trials established the drug's efficacy and safety for the treatment of partial and generalized seizures. In 1989, zonisamide was approved and marketed in Japan under the trade name of Excegran. Data from postmarketing surveillance studies and clinical observations over 10 years of use have continued to support zonisamide's efficacy and safety, identified its usefulness as monotherapy, and characterized its effectiveness for various seizure types and epilepsy syndromes.
Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Epilepsy; Humans; Isoxazoles; Japan; Product Surveillance, Postmarketing; Zonisamide
PubMed: 15511683
DOI: 10.1016/j.seizure.2004.04.015 -
Neurosurgery Clinics of North America Oct 2020Seizures represent a common and debilitating complication of central nervous system metastases. The use of prophylactic antiepileptic drugs (AEDs) in the preoperative... (Review)
Review
Seizures represent a common and debilitating complication of central nervous system metastases. The use of prophylactic antiepileptic drugs (AEDs) in the preoperative period remains controversial, but the preponderance of evidence suggests that it is not helpful in preventing seizure and instead poses a significant risk of adverse events. Studies of postoperative seizure prophylaxis have not shown substantial benefit, but this practice remains widespread. Careful analysis of the risk of seizure based on patient-specific factors, such as tumor location and primary tumor histology, should guide the physician's decision on the initiation and cessation of prophylactic AED therapy.
Topics: Anticonvulsants; Brain Neoplasms; Humans; Seizures; Treatment Outcome
PubMed: 32921354
DOI: 10.1016/j.nec.2020.06.008 -
Molecules (Basel, Switzerland) Mar 2018In this study, a novel series of 4-(2-(alkylthio)benzo[]oxazol-5-yl)-2,4-dihydro-3-1,2,4-triazol-3-ones (-) was designed and synthesized. The anticonvulsant activities...
In this study, a novel series of 4-(2-(alkylthio)benzo[]oxazol-5-yl)-2,4-dihydro-3-1,2,4-triazol-3-ones (-) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED values of 23.7 and 18.9 mg/kg, respectively. The TD value of was 284.0 mg/kg, which resulted in a higher protective index (PI = TD/ED) value than that of carbamazepine and valproate. In an ELISA test, compound significantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of in the MES model, which suggests that the mechanism through which compound elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; Mice; Molecular Structure; Pentylenetetrazole; Seizures; Structure-Activity Relationship; Triazoles; Up-Regulation; gamma-Aminobutyric Acid
PubMed: 29587394
DOI: 10.3390/molecules23040756 -
Molecules (Basel, Switzerland) Jun 2022Seizures and epilepsy are some of the most common serious neurological disorders, with approximately 80% of patients living in developing/underdeveloped countries.... (Review)
Review
Seizures and epilepsy are some of the most common serious neurological disorders, with approximately 80% of patients living in developing/underdeveloped countries. However, about one in three patients do not respond to currently available pharmacological treatments, indicating the need for research into new anticonvulsant drugs (ACDs). The GABAergic system is the main inhibitory system of the brain and has a central role in seizures and the screening of new ACD candidates. It has been demonstrated that the action of agents on endocannabinoid receptors modulates the balance between excitatory and inhibitory neurotransmitters; however, studies on the anticonvulsant properties of endocannabinoids from plant oils are relatively scarce. The Amazon region is an important source of plant oils that can be used for the synthesis of new fatty acid amides, which are compounds analogous to endocannabinoids. The synthesis of such compounds represents an important approach for the development of new anticonvulsant therapies.
Topics: Anticonvulsants; Endocannabinoids; Epilepsy; Humans; Plant Oils; Plants; Seizures
PubMed: 35684543
DOI: 10.3390/molecules27113595 -
CNS Drugs Sep 2023γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain and has been found to play an important role in the pathogenesis or... (Review)
Review
New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System.
γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain and has been found to play an important role in the pathogenesis or the expression of many neurological diseases, including epilepsy. Although GABA can act on different receptor subtypes, the component of the GABA system that is most critical to modulation of seizure activity is the GABA-receptor-chloride (Cl) channel complex, which controls the movement of Cl ions across the neuronal membrane. In the mature brain, binding of GABA to GABA receptors evokes a hyperpolarising (anticonvulsant) response, which is mediated by influx of Cl into the cell driven by its concentration gradient between extracellular and intracellular fluid. However, in the immature brain and under certain pathological conditions, GABA can exert a paradoxical depolarising (proconvulsant) effect as a result of an efflux of chloride from high intracellular to lower extracellular Cl levels. Extensive preclinical and clinical evidence indicates that alterations in GABAergic inhibition caused by drugs, toxins, gene defects or other disease states (including seizures themselves) play a causative or contributing role in facilitating or maintaning seizure activity. Conversely, enhancement of GABAergic transmission through pharmacological modulation of the GABA system is a major mechanism by which different antiseizure medications exert their therapeutic effect. In this article, we review the pharmacology and function of the GABA system and its perturbation in seizure disorders, and highlight how improved understanding of this system offers opportunities to develop more efficacious and better tolerated antiseizure medications. We also review the available data for the two most recently approved antiseizure medications that act, at least in part, through GABAergic mechanisms, namely cenobamate and ganaxolone. Differences in the mode of drug discovery, pharmacological profile, pharmacokinetic properties, drug-drug interaction potential, and clinical efficacy and tolerability of these agents are discussed.
Topics: Animals; Humans; Chlorides; Epilepsy; Brain; Anticonvulsants; Seizures; Mammals
PubMed: 37603262
DOI: 10.1007/s40263-023-01027-2 -
Molecular Neurobiology Oct 2014Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the... (Review)
Review
Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the brain caused by a disruption of the delicate balance between excitation and inhibition. Neuropeptides can contribute to such misbalance by modulating the effect of classical excitatory and inhibitory neurotransmitters. In this review, we discuss 21 different neuropeptides that have been linked to seizure disorders. These neuropeptides show an aberrant expression and/or release in animal seizure models and/or epilepsy patients. Many of these endogenous peptides, like adrenocorticotropic hormone, angiotensin, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, are able to suppress seizures in the brain. Other neuropeptides, such as arginine-vasopressine peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive properties. For oxytocin and melanin-concentrating hormone both pro- and anticonvulsive effects have been reported, and this seems to be dose or time dependent. All these neuropeptides and their receptors are interesting targets for the development of new antiepileptic drugs. Other neuropeptides such as nesfatin-1 and vasoactive intestinal peptide have been less studied in this field; however, as nesfatin-1 levels change over the course of epilepsy, this can be considered as an interesting marker to diagnose patients who have suffered a recent epileptic seizure.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Humans; Neurons; Neuropeptides
PubMed: 24705860
DOI: 10.1007/s12035-014-8669-x -
CNS Drug Reviews 2007Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of... (Review)
Review
Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.
Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsy; Humans; Intercellular Signaling Peptides and Proteins; Lacosamide; Models, Biological; Nerve Tissue Proteins; Pain
PubMed: 17461888
DOI: 10.1111/j.1527-3458.2007.00001.x