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Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs.

ABSTRACT: Epilepsy is a chronic neurological disorder caused by abnormal changes in the functions of neuronal circuits and manifested by seizures. It affects patients of all age, substantially worsens the quality of life for the patients as well as their families, and imposes a huge economic burden on the healthcare system. Historically, efforts for discovering and developing antiseizure therapies have been focused on modulating the functions of receptors, transporters, and enzymes expressed by neurons. These drug development efforts have paid off, as we have over 25 antiseizure drugs available in the clinic. However, these drugs mainly provide symptomatic relief from seizures and often cause serious adverse effects. Importantly, almost one-third of patients with epilepsy do not have their seizures adequately controlled by available drugs. To address this problem, researchers are investigating cellular and molecular mechanisms fundamental to the optimal function of neuronal circuits. Evidence shows that disruptions in these mechanisms cause impairment in neuroglial interactions, uncontrolled inflammation, aberrant synaptogenesis, and neurodegeneration in genetic and acquired epilepsies. Many novel therapeutic targets have been identified to target these mechanisms for developing new antiseizure drugs. In addition, the field is exploring new drug targets which may impede the development of epilepsy. We have summarized some of these novel targets in this brief review.

SUBMITTER: Patel DC

PROVIDER: S-EPMC5716500 | biostudies-literature | 2017 Sep-Oct

REPOSITORIES: biostudies-literature

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Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs.

Patel Dipan C DC Wilcox Karen S KS Metcalf Cameron S CS

Epilepsy currents 20170901 5

Epilepsy is a chronic neurological disorder caused by abnormal changes in the functions of neuronal circuits and manifested by seizures. It affects patients of all age, substantially worsens the quality of life for the patients as well as their families, and imposes a huge economic burden on the healthcare system. Historically, efforts for discovering and developing antiseizure therapies have been focused on modulating the functions of receptors, transporters, and enzymes expressed by neurons. T ...[more]

PMID: 29225544

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Project description:A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferator-activated receptors ? pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brain-derived neurotrophic factor signaling; and blockade of ?2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1? signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the ?2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

Project description:Drug-resistant epilepsy occurs in 25-30% of patients. Furthermore, treatment with a first-generation antiseizure drug (ASD) fails in 30-40% of individuals because of their intolerable adverse effects. Over the past three decades, 20 newer- (second- and third-)generation ASDs with unique mechanisms of action and pharmacokinetic profiles have been introduced into clinical practice. This advent has expanded the therapeutic armamentarium of epilepsy and broadens the choices of ASDs to match the individual patient's characteristics. In recent years, research has been focused on defining the ASD of choice for different seizure types. In 2017, the International League Against Epilepsy published a new classification for seizure types and epilepsy syndrome. This classification has been of paramount importance to accurately classify the patient's seizure type(s) and prescribe the ASD that is appropriate. A year later, the American Academy of Neurology published a new guideline for ASD selection in adult and pediatric patients with new-onset and treatment-resistant epilepsy. The guideline primarily relied on studies that compare the first-generation and second-generation ASDs, with limited data for the efficacy of third-generation drugs. While researchers have been called for investigating those drugs in future research, epilepsy specialists may wish to share their personal experiences to support the treatment guidelines. Given the rapid advances in the development of ASDs in recent years and the continuous updates in definitions, classifications, and treatment guidelines for seizure types and epilepsy syndromes, this review aims to present a complete overview of the current state of the literature about the efficacy and tolerability of ASDs and provide guidance to clinicians about selecting appropriate ASDs for initial treatment of epilepsy according to different seizure types and epilepsy syndromes based on the current literature and recent US and UK practical guidelines.

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Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs.

Publications

Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs.

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