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Key Event Title
Occurrence, Epileptic seizure
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Blocking iGABA receptor ion channel leading to seizures||AdverseOutcome||Cataia Ives (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Key Event Description
Blockage of the GABA-gated chloride channel reduces neuronal inhibition and induces focal seizure. This may further lead to generalized seizure, convulsions and death (Bloomquist 2003; De Deyn et al. 1990; Werner and Covenas 2011). For instance, exposure to fipronil produces hyperexcitation at low doses and convulsion or tonic-clonic seizure and seizure-related death at high doses (Gunasekara et al. 2007; Tingle et al. 2003; Jackson et al. 2009).
As described in Bromfield et al. (2006), seizure propagation, the process by which a partial seizure spreads within the brain, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum. The propagation of bursting activity is normally prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Of equal interest, but less well understood, is the process by which seizures typically end, usually after seconds or minutes, and what underlies the failure of this spontaneous seizure termination in the life-threatening condition known as status epilepticus (Bromfield et al. 2006).
How It Is Measured or Detected
Electrophysiological measurements and physical (visual) observation (for mortality) are the methods often used to detect epileptic seizure-related effects (Ulate-Campos et al. 2016). One may also visit http://www.mayoclinic.org/diseases-conditions/epilepsy/diagnosis-treatment/diagnosis/dxc-20117234 for more information on how medical doctors diagnose epilepsy in patients.
Recently, a new technique called micro-electrode array (MEA) recording has been developed and tested both in vitro (Novellino et al. 2011) and ex vivo (Dossi et al. 2014). MEAs, which are microfabricated devices embedding an array of spatially arranged microelectrodes, provide a unique opportunity to simultaneously stimulate and record field potentials, as well as action potentials of multiple neurons from different areas of the tissue (Dossi et al. 2014). Thus, MEAs recordings constitute an excellent tool for studying the spatio-temporal patterns of spontaneous interictal and evoked seizure-like events, the mechanisms underlying seizure onset and propagation, and electrophysiological activity of the neurons in response to chemical exposures (Novellino et al. 2011; Dossi et al. 2014).
Domain of Applicability
Substance-induced epileptic seizures have been documented in a wide range of species including invertebrates and vertebrates (see Tingle et al. (2003) and Gunasekara et al. (2007) for reviews on the list of aquatic and terrestrial species affected by fipronil). For instance, fipronil can induce seizures in fruit flies (Stilwell et al. 2006) and house flies (Gao et al. 2007).
Regulatory Significance of the Adverse Outcome
As a neurotoxicity endpoint, information with regard to the seizure or epilepsy is often used by regulators such as EPA, FDA and DHS for human and environmental health assessment and regulation of chemicals, drugs and other materials. For instance, the Office of Pesticide Programs (OPP) in US EPA, regulates, monitors and investigates the use of all pesticides in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (https://www.epa.gov/laws-regulations/summary-federal-insecticide-fungicide-and-rodenticide-act). Many pesticides like fipronil target the iGABAR causing seizure and mortality. Another example is the regulatory actions of US FDA to ensure drug safety (see https://www.fda.gov/Drugs/DrugSafety/ucm436494.htm).
Bloomquist JR. 2003. Chloride channels as tools for developing selective insecticides. Arch. Insect Biochem. Physiol 54(4), 145-156.
Bromfield EB, Cavazos JE, Sirven JI, editors. 2006. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society. Chapter 1 Basic Mechanisms Underlying Seizures and Epilepsy. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2510/
De Deyn PP, Marescau B, Macdonald RL. 1990. Epilepsy and the GABA-hypothesis a brief review and some examples. Acta Neurol. Belg. 90(2), 65-81.
Dossi E, Blauwblomme T, Nabbout R, Huberfeld G, Rouach N. 2014. Multi-electrode array recordings of human epileptic postoperative cortical tissue.J Vis Exp. (92):e51870.
Gao JR, Kozaki T, Leichter CA, Rinkevich FD, Shono T, Scott JG. 2007. The A302S mutation in Rdl that confers resistance to cyclodienes and limited crossresistance to fipronil is undetectable in field populations of house flies from the USA. Pestic. Biochem. Physiol. 88, 66−70.
Gunasekara AS, Truong T, Goh KS, Spurlock F, Tjeerdema RS. 2007. Environmental fate and toxicology of fipronil. J. Pestic. Sci. 32(3), 189-199.
Jackson D, Cornell CB, Luukinen B, Buhl K, Stone D. 2009. Fipronil Technical Fact Sheet. National Pesticide Information Center, Oregon State University Extension Services,
Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. 2011. Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals.Front Neuroeng. 4:4.
Stilwell GE, Saraswati S, J. Troy Littleton JT, Chouinard SW. 2006. Development of a Drosophila seizure model for in vivo high-throughput drug screening. European J Neurosci. 24, 2211-2222.
Tingle CC, Rother JA, Dewhurst CF, Lauer S, King WJ. 2003. Fipronil: environmental fate, ecotoxicology, and human health concerns. Rev. Environ. Contam Toxicol. 176, 1-66.
Ulate-Campos A, Coughlin F, Gaínza-Lein M, Fernández IS, Pearl PL, Loddenkemper T. 2016. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure. 40:88-101.
Werner FM, Covenas R. 2011. Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs. Curr. Med. Chem. 18(32), 4933-4948.