Binding to voltage-gated sodium channel

60-56-0

PMRYVIKBURPHAH-UHFFFAOYSA-N

Methimazole

2H-Imidazole-2-thione, 1,3-dihydro-1-methyl- 1,3-Dihydro-1-methyl-2H-imidazole-2-thione 1-Methyl-1,3-dihydroimidazole-2-thione 1-Methyl-1H-imidazole-2-thiol 1-Methyl-2-mercapto-1H-imidazole 1-Methyl-2-mercaptoimidazole 1-Methyl-4-imidazoline-2-thione 1-Methylimidazole-2(3H)-thione 1-Methylimidazole-2-thiol 1-Methylimidazole-2-thione 2-Mercapto-1-methyl-1H-imidazole 2-Mercapto-1-methylimidazole 2-Mercapto-N-methylimidazole 4-Imidazoline-2-thione, 1-methyl- Basolan Danantizol Favistan Frentirox Imidazole-2-thiol, 1-methyl- Mercaptazole Mercazole Mercazolyl Metazolo Methimazol Methylmercaptoimidazole Metothyrin Metothyrine Metotirin N-Methyl-2-mercaptoimidazole N-Methylimidazolethiol NSC 38608 Strumazol Tapazole Thacapzol Thiamazol thiamazole Thycapzol Thymidazol Thymidazole tiamazol

DTXSID4020820

51-52-5

KNAHARQHSZJURB-UHFFFAOYSA-N

6-Propyl-2-thiouracil

6-Propyl-2 thiouracil (PTU) 4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo- 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone 2-Mercapto-4-hydroxy-6-n-propylpyrimidine 2-Mercapto-4-hydroxy-6-propylpyrimidine 2-Mercapto-6-propylpyrimidin-4-ol 2-Thio-4-oxo-6-propyl-1,3-pyrimidine 2-Thio-6-propyl-1,3-pyrimidin-4-one 6-n-Propyl-2-thiouracil 6-n-Propylthiouracil 6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione 6-Propylthiouracil NSC 6498 NSC 70461 Procasil Propacil propiltiouracilo Propycil Propyl-Thiorist Propylthiorit propylthiouracil Propylthiouracile Propyl-Thyracil Prothiucil Prothiurone Prothycil Prothyran Protiural Thiuragyl Thyreostat II URACIL, 4-PROPYL-2-THIO- Uracil, 6-propyl-2-thio-

DTXSID5021209

GO:0001518

GO voltage-gated sodium channel complex

GO:0005248

GO voltage-gated sodium channel activity

GO:0005272

GO sodium channel activity

GO:0007611

GO learning or memory

GO:0050890

GO cognition

WIKI disrupted

WIKI functional change

WIKI decreased

Deltamethrin

2023-02-22T08:36:00

Pyrethrins and Pyrethroids

2016-11-29T18:42:27

Methimazole

2016-11-29T18:42:19

Propylthiouracil

2016-11-29T18:42:22

Iodine deficiency

2017-03-26T11:37:44

10090

NCBI mouse

10116

NCBI rat

WCS_9606

common toxicological species human

Binding to voltage-gated sodium channel

Binding to VGSC

Molecular

Due to their critical role in neuronal function, sodium channels are known molecular targets of neurotoxins and neurotoxicants (Caterall et al., 2012; Wakeling et al., 2012). The essentiality of sodium channels in nerve conduction comes from classic literature on tetrodotoxin (TTX). TTX is a sodium channel blocker that inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels (VGSC/NaV) in nerve cell membranes. This action blocks the passage of sodium ions into the neuron, ions responsible for the rising phase of an action potential (AP). There is strong evidence implicating a similar TTX-like of pyrethroid insecticides on VGSC. This block of VGSC is supported by an extensive body of literature on the action of pyrethroid insecticides on mammalian sodium channels. Binding studies using radioactive pyrethroid demonstrated specific binding of the pyrethroid to rat brain VGSC α subunits (Trainer et al., 1997). Ion channels are integral membrane proteins that are critical for neuronal function. They form "pores" in the plasma membrane that allow certain ions to travel across the membrane along their electrochemical gradient. Ion channels that open in response to a change in membrane voltage potential are called ‘voltage-gated’ ion channels. Channels that open in response to binding using a chemical signal or molecule are ‘ligand-gated’ ion channels. In neurons, ion channels of both types are essential for chemical communication between cells, i.e., synaptic transmission. Ion channels also function to maintain membrane potential and initiate AP to propagate electrical impulses. VGSC are therefore responsible for AP initiation and propagation in most excitable cells, including nerve, muscle and neuroendocrine cell types. It is important to note that functional VGSC are present in both grey and white matter in the brain. Approximately 50% of white matter oligodendrocyte precursor cells receive synaptic inputs and can produce trains of VGSC-dependent APs (Fields, 2008). VGSC are also present on microglia where they contribute to the release of major pro-inflammatory cytokines (Hossain et al., 2017). Mammalian VGSC are composed of one α and two β subunits. Ten separate α subunits (Ogata and Ohishi, 2002) and four different β subunits (Isom, 2002) have been identified and are expressed in tissue-, region- and time- specific manners. The diverse functional roles of VGSCs depend on the numerous potential combinations of α and β subunits (Ogata and Ohishi, 2002). The type of VGSCs expressed in different cell types and regions, their sensitivity and their functional role, all contribute to the manifestation of toxicity and age-dependent sensitivity, of chemicals acting at this site.

Interaction of compounds with VGSC can be measured directly with radioligand binding (Trainer et al 1997), while the expression and localization of VGSC on different cell types can be assessed using immunohistochemical methods. The following discussion focuses on interactions between VGSC and pyrethroids, but similar data exist for other compounds that bind to VGSC. Several other approaches provide indirect evidence of interactions of chemicals with VGSC. The published literature contains hundreds of reports identifying point mutations in VGSC that alter both the effects on the channel as well as the sensitivity to pyrethroid toxicity. Both increased and decreased modification of the insect and mammalian VGSC by pyrethroids have been demonstrated, specific action dependent on the location and type of point mutations (e.g. Vais et al., 2000; 2001). Finally, the demonstration of stereo-specific effects of the pyrethroids on binding (Soderlund 1985; Brown et al., 1988) as well as electrophysiological responses (Narahashi 1982; Narahashi1996; Narahashi., 2000; Narahashi., 2002) also supports interaction of VGSC and pyrethroids. A model for binding of pyrethroids in insect VGSC has been developed (O’Reilly et al., 2006). Together, these observations provide strong evidence of pyrethroid binding to VGSC (for additional review, see Field et al 2017).

VGSCs are present in many different cell types of the nervous system (NS), including neurons, oligodendrocytes, Schwann cells (Baker, 2002; Jessen and Mirsky, 2005; Ritche, 1992; Chiu, 1991) and microglia (Jung et al., 2013; Black and Waxman reviewed in Hossain et al., 2017; Paez et al., 2009; Berret et al., 2017). Moreover, every cell within living organisms actively maintains a low intracellular sodium concentration that is 10–12 times lower than the extracellular concentration. The cells then utilize this transmembrane sodium concentration gradient as a driving force to produce electrical signals, and if the driving force is sufficiently strong, an AP is produced. The protein family comprising VGSC (Navs) is essential for such signaling and enables cells to change their electrical status in a regenerative manner and to rapidly communicate with one another. The existence of VGSC was first predicted from studies of electrical activity in squid giant axon and later identified through molecular studies in the electric eel. Since then, these proteins have been observed in organisms ranging from bacteria to humans (Chaihne, 2018). Sodium channels consist of highly processed α subunit, which is approximately 260 kDa, associated with auxiliary β subunits of 33–39 kDa. Sodium channels in the adult CNS and heart contain a mixture of β1–β4 subunits, while sodium channels in adult skeletal muscle have only the β1 subunit. Nine different VGSC have been identified using electrophysiological recording, biochemical purification, and cloning (Catterall, 2007; Catterall, 2012). Nomenclature of the different sodium channel alpha (pore-forming) subunits is based on a numerical system to define subfamilies and subtypes based on similarities between the amino acid sequences of the channels. In this nomenclature system, the name of an individual channel consists of the chemical symbol of the principal permeating ion (Na) with the principal physiological regulator (voltage) indicated as a subscript (Nav). The number following the subscript indicates the gene subfamily (currently only Nav 1), and the number following the full point identifies the specific channel isoform (e.g. Nav 1.1). This last number has been assigned according to the approximate order in which each gene was identified. Splice variants of each family member are identified by lower-case letters following the numbers (e.g. Nav 1.1a).  (Catterall, 2012). In mammals, numerous neuronal VGSC are expressed in the adult and developing brain. Evidence from mutation and knockout animal models demonstrates that perturbation of VGSC function during development impairs nervous system structure and function, disrupts muscle function, pain reception, and cardiac rhythm (Chahine, 2018). VGSCs show complex regional and temporal ontogeny in mammals. Table 1, from Shafer et al., 2005 provides an overview about the alpha subunits and their developmental and tissue expression pattern. Pyrethroid interactions with Nav1.1 (James et al., 2017), Nav1.3 (Meacham et al., 2008; Tan and Soderlund 2009), Nav1.6 (Tan and Soderlund, 2010), Nav1.7 (Tan and Soderlund, 2011) and Nav1.9 (Nutter and Cooper, 2014; Bothe et al., 2021) channels. <img alt="" src="https://aopwiki.org/system/dragonfly/production/2022/03/21/2gkpopb51s_Table_1._Sodium_channel_a_subunit.jpg" style="height:691px; width:940px" /> ß1b and ß3 expression is high during prenatal and early postnatal period in nervous system mammals, followed by increased expression of ß1, ß2 and ß4 in the first postnatal week which then persists through adulthood. While different cell types in the brain express different ß subunits, the ß1 subunit is ubiquitously expressed with moderate heterogeneity. Its subcellular localization provides specific functionalities, e.g. high density of ß1 at the nodes of Ranvier modulates surface expression and gating of the VGSCα subunit  while in the paranodal region ß1 mediates axonal-glial cell adhesion. The ß2 protein shares some similar expression pattern with ß1 and appears to provide responsiveness to inflammatory and neuropathic pain in the peripheral nervous system (PNS). In contrast ß3 mRNA and protein are expressed ubiquitously thought the developing CNS and in adult mice it is greatly reduced except for some structures like the hippocampus. This differs in human brain, where ß3 remains highly expressed throughout adulthood. The expression profile of ß4 is mostly restricted among the ß subunits, and often related to neurons with spontaneous or burst firing APs.  Finally, β subunits are also expressed in various glia where they may function as cell adhesion guides and cues for neurodevelopment, including coordinating neurite outgrowth, axonal fasciculation, and neuronal migration (Hull et Isom 2018). Importantly, co-expression of β subunits with the α subunit modulates the function of the α subunit and can influence the binding of various ligands to the α subunit (Tan et al., 2011). In general, embryonically expressed forms of VGSCs are replaced by expression of adult forms as neurodevelopment proceeds. Due to this complex ontogeny of VGSCs it is currently not possible to specify which VGSCs subtypes and which developmental stages are particularly essential and thus important for this AOP.

UBERON:0000119

UBERON cell layer

CL:0000255

CL eukaryotic cell

High Male High Female

High

All life stages

High High High

Baker MD, 2002. Electrophysiology of mammalian Schwann cells. Progress in Biophysics and Molecular Biology, 78(2–3), 83–103. https://doi.org/10.1016/S0079–6107(02)00007-X Berret E, Barron T, Xu J, Debner E, Kim EJ and Kim JH, 2017. Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation. Nature Communications, 8(1), 1–15. https://doi.org/10.1038/s41467–017–00688–0 Black JA and Waxman SG, 2012. Sodium channels and microglial function. Experimental Neurology, 234(2), 302–315. https://doi.org/10.1016/j.expneurol.2011.09.030 Bothe SN and Lampert A,2021. <a href="https://pubmed.ncbi.nlm.nih.gov/34389319/">The insecticide deltamethrin enhances sodium channel slow inactivation of human Nav1.9, Nav1.8 and Nav1.7.</a> Toxicol Appl Pharmacol. 428,115676.<a href="https://doi.org/10.1016/j.taap.2021.115676">https://doi.org/10.1016/j.taap.2021.115676</a> Brown GB, Gaupp JE and Olsen RW, 1988. <a href="https://pubmed.ncbi.nlm.nih.gov/2455860/">Pyrethroid insecticides: stereospecific  allosteric interaction with the batrachotoxinin-A benzoate binding site of mammalian voltage-sensitive sodium channels.</a> Molecular Pharmacology.34(1),54-9. Catterall WA, 2012. Voltage‐gated sodium channels at 60: structure, function and pathophysiology. Journal of Physiology, 590(11), 2577–2589. https://doi.org/10.1113/jphysiol.2011.224204 Catterall WA, Cestèle S, Yarov-Yarovoy V, Frank HY, Konoki K and Scheuer T, 2007. Voltage-gated ion channels and gating modifier toxins. Toxicon, 49(2), 124–141. doi: 10.1016/j.toxicon.2006.09.022 Chahine M (ed.), 2018. Voltage-gated Sodium Channels: Structure, Function and Channelopathies.246. Springer. Chiu SY, 1991. Functions and distribution of voltage‐gated sodium and potassium channels in mammalian Schwann cells. Glia, 4(6), 541–558. https://doi.org/10.1002/glia.440040602 EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), Hernández-Jerez A, Adriaanse P, Aldrich A, Berny P, Coja T, Duquesne S, Focks A, Marinovich M, Millet M, Pelkonen O, Pieper S, Tiktak A, Topping C, Widenfalk A, Wilks M, Wolterink G, Crofton K, Hougaard Bennekou S, Paparella M and Tzoulaki I, 2021. Scientific Opinion on the development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment. EFSA Journal 2021;19(6):6599, 63 pp. <a href="https://doi.org/10.2903/j.efsa.2021.6599">https://doi.org/10.2903/j.efsa.2021.6599</a> Field LM, Emyr Davies TG, O'Reilly AO, Williamson MS and Wallace BA,2017. <a href="https://pubmed.ncbi.nlm.nih.gov/28070661/">Voltage-gated sodium channels as targets for pyrethroid insecticides.</a> Eur Biophysics Journal. 46(7):675-679. https://doi.org/10.1007/s00249-016-1195-1 Fields RD, 2008. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. The Neuroscientist, 14(6), 540–543. <a href="https://doi.org/10.1177/1073858408320294">https://doi.org/10.1177/1073858408320294</a> Hossain MM, Liu J and Richardson JR, 2017. Pyrethroid insecticides directly activate microglia through interaction with voltage-gated sodium channels. Toxicological Sciences, 155(1), 112–123. Oxford Academic, https://doi.org/10.1093/toxsci/kfw187 Hull JM, Isom LL,2018. Voltage-gated sodium channel β subunits: The power outside the pore in brain development and disease. Neuropharmacology,132:43-57. <a href="https://doi.org/10.1016/j.neuropharm.2017.09.018" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.neuropharm.2017.09.018</a> Isom LL, 2002. β subunits: Players in neuronal hyperexcitability? Novartis Found Symp. 2002; 241:124-38; discussion 138-43, 226-32. James TF, Nenov MN, Tapia CM, Lecchi M, Koshy S, Green TA and Laezza F, 2017. <a href="https://pubmed.ncbi.nlm.nih.gov/28007400/">Consequences of acute Nav1.1 exposure to deltamethrin.</a> Neurotoxicology, 60:150-160. <a href="https://doi.org/10.1016/j.neuro.2016.12.005" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.neuro.2016.12.005</a> Jessen KR and Mirsky R, 2005. The origin and development of glial cells in peripheral nerves. Nature Reviews in Neuroscience, 6, 671–682. https://doi.org/10.1038/nrn1746 Jung GY, Lee JY, Rhim H, Oh TH and Yune TY, 2013. An increase in voltage‐gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury. Glia, 61(11), 1807–1821. https://doi.org/10.1002/glia.22559 Meacham CA, Brodfuehrer PD, Watkins JA and Shafer TJ,2008. <a href="https://pubmed.ncbi.nlm.nih.gov/18538810/">Developmentally regulated sodium channel subunits are differentially sensitive to alpha-cyano containing pyrethroids.</a> Toxicology and Applied Pharmacology,231(3):273-81. <a href="https://doi.org/10.1016/j.taap.2008.04.017" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.taap.2008.04.017</a> Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14. Narahashi T, 2000. Neuroreceptors and ion channels as the basis for drug action: past, present, and future. J Pharmacol Exp Ther, 294, 1–26. Narahashi T,1982. Cellular and molecular mechanisms of action of insecticides: neurophysiological approach. Neurobehavioral toxicology and teratology,4(6),753-8. Narahashi T. 2002. Nerve membrane ion channels as the target site of insecticides. Mini Rev Med Chem. Aug;2(4):419-32. Nutter TJ and Cooper BY, 2014. <a href="https://pubmed.ncbi.nlm.nih.gov/24732443/">Persistent modification of Nav1.9 following chronic exposure to insecticides and pyridostigmine bromide.</a> Toxicology and Applied Pharmacolocy,277(3),298-309. <a href="https://doi.org/10.1016/j.taap.2014.04.005" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.taap.2014.04.005</a> OECD, 2022. Case study for the integration of in vitro data in the developmental neurotoxicity hazard identification and characterisation using deltamethrin as a prototype chemical; Series on Testing and Assessment No. 362. Available at: <a href="https://one.oecd.org/document/env/cbc/mono(2022)24/en/pdf">https://one.oecd.org/document/env/cbc/mono(2022)24/en/pdf</a> OECD, 2023. Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery; Series on Testing and Assessment No. 377. Available at: <a href="https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf">https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf</a> Ogata N and Ohishi Y, 2002. Molecular diversity of structure and function of the voltage-gated Na+ channels. Japanese Journal of Pharmacology, 88(4), 365–377. https://doi.org/10.1254/jjp.88.365 O'Reilly AO, Khambay BP, Williamson MS, Field LM, Wallace BA and Davies TG,2006. <a href="https://pubmed.ncbi.nlm.nih.gov/16475981/">Modelling insecticide-binding sites in the voltage-gated sodium channel.</a> Biochemical Journal.396(2):255-63. <a href="https://doi.org/10.1042/BJ20051925">https://doi.org/10.1042/BJ20051925</a> Paez PM, Fulton D, Colwell CS and Campagnoni AT, 2009. Voltage‐operated Ca2+ and Na+ channels in the oligodendrocyte lineage. Journal of Neuroscience Research, 87(15), 3259–3266. <a href="https://doi.org/10.1002/jnr.21938">https://doi.org/10.1002/jnr.21938</a> Ritchie JM, 1992. Voltage-gated ion channels in Schwann cells and glia. Trends in Neurosciences, 15(9), 345–351. https://doi.org/10.1016/0166–2236(92)90052-A Soderlund DM,1985. <a href="https://pubmed.ncbi.nlm.nih.gov/2410831/">Pyrethroid-receptor interactions: stereospecific binding and effects on sodium channels in mouse brain preparations.</a> Neurotoxicology. 1985 Summer;6(2):35-46. Tan J, Choi JS and Soderlund DM, 2011. <a href="https://pubmed.ncbi.nlm.nih.gov/22577241/">Coexpression with Auxiliary β Subunits Modulates the Action of Tefluthrin on Rat Na(v)1.6 and Na(v)1.3 Sodium Channels.</a> Pesticide Biochemistry and Physiology,101(3),256-264. https://doi.org/10.1016/j.pestbp.2011.10.003   Tan J, Soderlund DM, 2011. <a href="https://pubmed.ncbi.nlm.nih.gov/21966053/">Actions of Tefluthrin on Rat Na(v)1.7 Voltage-Gated Sodium Channels Expressed in Xenopus Oocytes.</a> Pestic Biochem Physiol,101(1):21-26. <a href="https://doi.org/10.1016/j.pestbp.2011.06.001">https://doi.org/10.1016/j.pestbp.2011.06.001</a> Tan J, Soderlund DM, 2009. <a href="https://pubmed.ncbi.nlm.nih.gov/19026681/">Human and rat Nav1.3 voltage-gated sodium channels differ in inactivation properties and sensitivity to the pyrethroid insecticide tefluthrin.</a> Neurotoxicology,30(1),81-9. doi: 10.1016/j.neuro.2008.10.008. Tan J, Soderlund DM, 2010. <a href="https://pubmed.ncbi.nlm.nih.gov/20624410/">Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Na(v)1.6 sodium channels.</a> Toxicology and Applied Pharmacology,247(3),229-37. <a href="https://doi.org/10.1016/j.taap.2010.07.001" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.taap.2010.07.001</a> Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D,and Catterall WA, 1997. High affinity binding of pyrethroids to the α subunit of brain sodium channels. Molecular Pharmacology, 51(4), 651–657. doi: https://doi.org/10.1124/mol.51.4.651 Vais H, Atkinson S, Eldursi N, Devonshire AL, Williamson MS and Usherwood PN,2000. <a href="https://pubmed.ncbi.nlm.nih.gov/10734222/">A single amino acid change makes a rat neuronal sodium channel highly sensitive to pyrethroid insecticides.</a> FEBS Lett,470(2):135-8.<a href="https://doi.org/10.1016/S0014-5793(00)01305-3">https://doi.org/10.1016/S0014-5793(00)01305-3</a> Vais H, Williamson MS, Devonshire AL, and Usherwood PN, 2001. <a href="https://pubmed.ncbi.nlm.nih.gov/11695180/">The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels.</a> Pest Management Science ,57(10),877-88. <a href="https://doi.org/10.1002/ps.392">https://doi.org/10.1002/ps.392</a> Wakeling EN, Neal AP and Atchison WD, 2012. Pyrethroids and their effects on ion channels. Pesticides—Advances in Chemical and Botanical Pesticides. Rijeka, Croatia: InTech, pp. 39–66. Available at: http://dx.doi.org/10.5772/50330. AOPWiki 2017-04-14T15:25:30

2024-07-31T11:33:42

Disruption of sodium channel gating kinetics

Altered kinetics of sodium channel

Cellular

Action potentials (AP) are a temporary shift (from negative to positive) in the neuron’s membrane potential caused by ions flowing in and out of the neuron. During the resting state, before an action potential occurs, voltage-gated sodium and potassium channels are predominantly closed. These gated channels only open once when an action potential has been triggered. They are called ‘voltage-gated’ because they are open and close depending on the voltage difference across the cell membrane. VGSCs have two gates (gate m and gate h), while the potassium channel only has one (gate n). Gate m (the activation gate) is normally closed and opens when the cell membrane potential starts to get more positive (depolarizes). Gate h (the deactivation gate) is normally open, and swings shut when the cell membrane potential gets too positive. Gate n is normally closed, but slowly opens when the cell is depolarised (very positive). VGSCs exist in one of three states: Deactivated/closed (closed), activated (open) and inactivated (closed) – at rest, channels are (Figure 1) . Modifications of the sodium channel gating have been studied using voltage and patch clamp experiments in different models (Ruigt et al., 1987). Prolongation of the sodium current is mainly due to the reduced rate of closure of a fraction of the sodium channel population and is characterized by a ‘tail current’. In neuroblastoma cell preparations, chemical stressors including deltamethrin and other type II pyrethroids, induce a slow tail current with a relatively long time constant. The rate at which sodium channels close during the pyrethroid-induced slow tail current depends not only on pyrethroid structure, but also on the duration of exposure, temperature and membrane potential (Ruigt et al., 1987; Narahashi., 2002; Soderlund., 2002). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/07/25/4xxhl53i4_1977_picture.jpg" /> Figure 1.  The three existing states of the VGSCs: Deactivated (closed), activated (open) and inactivated (closed). Figure extracted from Wakeling et al., 2012).

Typically, VGSC function is measured using electrophysiological approaches, as only these have sufficient temporal resolution to evaluate channel function. Voltage-clamp techniques typically use two microelectrodes, allowing control of the membrane potential (‘clamping’) and recording of transmembrane currents that result from ion channel opening and closing (Guan et al., 2013). Pharmacological approaches and modifications of the ionic composition of the solution are used to isolate currents passing through VGSC from other types of current in the neuron. In the patch-clamp technique, a highly sensitive version of the voltage-clamp technique, a single glass microelectrode is attached to a neuron to form a tight seal between the glass pipette tip and the cell membrane. In this case, a single electrode controls voltage and passes current (Molleman, 2003).  Typically, the current measured is the sum of currents flowing through the entire population of channels in this patch of membrane, the ‘whole cell’ patch configuration (Hamill et al., 1981). Some configurations of patch clamp technique can measure current flowing through a single ion channel. Most studies utilizing this technique involve in vitro or ex vivo measurements. Other approaches can be used to indirectly measure VGSC function, including radiotracer flux, fluorescent approaches, and calcium imaging. While these approaches can provide useful information in many cases, they are not direct, nor do they have sufficient resolution to fully describe VGSC function (Molleman A, 2003).

Ion channels are essential for the initiation and propagation of AP in excitable cells in both vertebrate and invertebrate species. In neurons, ion channels are essential for chemical communication between cells, or synaptic transmission. Ion channels also function to maintain membrane potential and initiate and propagate electrical impulses. VGSC are a target of natural and synthetic chemicals and disruption of the gate kinetics has been characterized in insects and mammalian cells (Soderlund et al., 2002). For more details and references see also the description in MIE: KE 1353 Binding to Voltage Gated Sodium Channel.

UBERON:0001016

UBERON nervous system

CL:0000255

CL eukaryotic cell

High Male High Female

High

All life stages

High High High

Guan B, Chen X and Zhang H, 2013. Two-electrode voltage clamp. Methods in Molecular Biology, 998, 79–89. doi: 10.1007/978-1-62703-351-0_6 Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Pflugers. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Archiv: European journal of physiology, 391(2), 85–100. https://doi.org/10.1007/BF00656997 Molleman A, 2003. Patch Clamping: An Introductory Guide to Patch Clamp Electrophysiology. John Wiley and Sons. DOI:10.1002/0470856521 Narahashi T. (2002). Nerve membrane ion channels as the target site of insecticides. Mini reviews in medicinal chemistry, 2(4), 419–432. <a href="https://doi.org/10.2174/1389557023405927">https://doi.org/10.2174/1389557023405927</a> OECD,2023 Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery; Series on Testing and Assessment No. 377. Available at: <a href="https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf">https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf</a> Ruigt GS, Neyt HC, Van der Zalm JM, and Van den Bercken J,1987. Increase of sodium current after pyrethroid insecticides in mouse neuroblastoma cells. Brain research, 437(2), 309–322. <a href="https://doi.org/10.1016/0006-8993(87)91645-3">https://doi.org/10.1016/0006-8993(87)91645-3</a> Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo V J, Sargent D, Stevens JT and Weiner ML ,2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59. https://doi.org/10.1016/s0300-483x(01)00569-8 AOPWiki 2022-03-15T10:57:55

2024-07-24T22:37:26

Decreased, oligodendrocyte differentiation

Oligodendrocyte differentiation

Cellular

AOPWiki 2023-02-22T06:53:43

2023-02-22T09:37:37

Hypomyelination

Tissue

AOPWiki 2023-02-21T10:48:49

2023-02-21T10:48:49

Altered, white brain matter

Tissue

AOPWiki 2023-02-21T10:50:02

2023-02-21T10:50:02

Cognitive function, decreased

Individual

Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition or retrieval of a learned event, the hippocampal-based memory systems have received the most study. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990; Squire, 2004; Gilbert., 2006).  In humans, the hippocampus is involved in recollection of an event’s rich spatial-temporal contexts and distinguished from simple semantic memory which is memory of a list of facts (Burgess et al., 2000). Hemispheric specialization has occurred in humans, with the left hippocampus specializing in verbal and narrative memories (i.e., context-dependent episodic or autobiographical memory) and the right hippocampus, more prominently engaged in visuo-spatial memory (i.e., memory for locations within an environment). The hippocampus is particularly critical for the formation of episodic memory, and autobiographical memory tasks have been developed to specifically probe these functions (Eichenbaun, 2000; Willoughby et al., 2014). In rodents, there is obviously no verbal component in hippocampal memory, but reliance on the hippocampus for spatial, temporal and contextual memory function has been well documented. Spatial memory deficits and fear-based context learning paradigms engage the hippocampus, amygdala, and prefrontal cortex (Eichenbaum, 2000; Shors et al., 2001; Samuels et al., 2011; Vorhees and Williams, 2014; D’Hooge and DeDeyn, 2001; Lynch, 2004; O’Keefe and Nadal, 1978). These tasks are impaired in animals with hippocampal dysfunction (O’Keefe and Nadal, 1978; Morris and Frey, 1987; Gilbert et al., 2016).

In rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, and most commonly, the Morris water maze (MWM). Tests such as novel object recognition, and fear-based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. The text below provides brief descriptions of the most used tasks. <ol> <li>RAM, Barnes Maze, and MWM are examples of spatial tasks in which animals are required to learn: the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze); or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014). </li> <li>Novel Object Recognition (NOR) and its variants are widely used in neuroscience, although their suitability for safety assessment remains unclear (Vorhees and Williams, 2024). NOR and novel place recognition (NPR) are examples of ‘incidental learning’ and rely on the dorsal hippocampus. They are simple tasks and are used to probe recognition memory. Two objects are presented to animals in an open field on trial 1, and animals are allowed time to briefly explore them. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention (i.e., one of these objects is familiar, the other is novel (Cohen and Stackman, 2015). In novel place recognition, the objects are shifted to a location within the arena. Compared to tests of spatial learning, the learning event is transient, the results often variable, and the test has a very narrow dynamic range.</li> <li>Contextual Fear Conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event (unconditional stimulus, US). The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009). </li> <li>Trace Fear Conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, e.g., a light or a tone) and an aversive stimulus (US, e.g., a foot shock). The unconditioned response (CRUR) that is elicited upon delivery of the foot shock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2004). </li> </ol> Most methods used in animals are well established in the published literature, and many have been engaged to evaluate the effects of developmental neurotoxicants. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD 426) both require testing of learning and memory (USEPA, 1998; OECD, 2007). These DNT Guidelines have been deemed valid to identify DNT and adverse neurodevelopmental outcomes (Makris et al., 2009).  A variety of standardized learning and memory tests have been developed for human neuropsychological testing. These include episodic autobiographical memory, word pair recognition memory; object location recognition memory. Some components of these tests have been incorporated in general tests of adult intelligence (IQ) such as the Wechsler Adult Intelligence Scale (WAIS) which calculates four composite scores that examine various domains within an individual’s overall cognitive ability: Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) (Climie and Rostad, 2011). Modifications have been made and norms developed for incorporating tests of learning and memory in children. Examples of some of these tests include:  <ol> <li>Rey Osterieth Complex Figure (RCFT) which probes a variety of functions including visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006). </li> <li>Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1994; Talley, 1986).  </li> <li>Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994). </li> <li>Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neuropsychological test designed to measure memory functions (Lezak, 1994; Talley, 1986). </li> <li>Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2011). </li> <li>Staged AM Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buying lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014). </li> </ol>

Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans.Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans.

High Male High Female

High

All life stages

High High High

Alexander RD (1990) Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development. Ethology and Sociobiology 11:241-303.  Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 120:501-507.  Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080.  Climie, E. A., & Rostad, K. (2011). Test Review: Wechsler Adult Intelligence Scale. Journal of Psychoeducational Assessment, 29(6), 581–586. https://doi.org/10.1177/0734282911408707  Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176.  Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents. In: Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009  D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60-90.  Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41-50.  Fivush R. The development of autobiographical memory. Annu Rev Psychol. 2011. 62:559-82.  Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.  Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.  Herold, C, Lässer, MM, Schmid, LA, Seidl, U, Kong, L, Fellhauer, I, Thomann, PA, Essig, M and Schröder, J. (2015). Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia. Front. Psychiatry, 6: 53.  Lezak MD (1984) Neuropsychological assessment in behavioral toxicology--developing techniques and interpretative issues. Scand J Work Environ Health 10 Suppl 1:25-29.  Lezak MD (1994) Domains of behavior from a neuropsychological perspective: the whole story. Nebr Symp Motiv 41:23-55.  Lynch, M.A. (2004). Long-Term Potentiation and Memory. Physiological Reviews. 84:87-136.  Makris SL, Raffaele K, Allen S, Bowers WJ, Hass U, Alleva E, Calamandrei G, Sheets L, Amcoff P, Delrue N, Crofton KM. A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect. 2009 Jan;117(1):17-25.  Morris RG, Frey U. Hippocampal synaptic plasticity: role in spatial learning or the automaticrecording of attended experience? Philos Trans R Soc Lond B Biol Sci. 1997 Oct 29;352(1360):1489-503. Review  O’Keefe, J. and Nadel, L. (1978). The Hippocampus as a Cognitive Map. Oxford: Oxford University Press.  OECD. 2007. OECD guidelines for the testing of chemicals/ section 4: Health effects. Test no. 426: Developmental neurotoxicity study.  www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed May 21, 2012].  OECD Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery; Series on Testing and Assessment No. 377. 2023. Available at: https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf Samuels BA, Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33:1152-1159.  Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical appliations fo the Rey-Osterrieth complex figure test. Nature Protocols, 1: 892-899.  Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376. Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82:171-177.  Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267.  Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver.  U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances.  Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332.  Vorhees, C and Williams M. Tests for Learning and Memory in Rodent Regulatory Studies. Current Research in Toxicology, 2024, Curr Res Toxicol. 2024; 6: 100151. doi: 10.1016/j.crtox.2024.100151 Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014. 9:1-11.  AOPWiki 2016-11-29T18:41:24

2024-07-25T17:23:57

Inhibition of voltage-gated sodium channels leading to decreased cognition

Voltage-gated sodium channels and DNT

Lidwina Gerner

Eliska Kuchovska, Jördis Klose, Lidwina Gerner, Lihini Nilma, Ellen Fritsche

BY-SA

2.5

Due to their importance in neurons, sodium channels are known molecular targets of neurotoxins and neurotoxicants (Wakeling et al., 2012). There is strong evidence implicating the voltage-sensitive sodium channel as the principal site of insecticidal action of pyrethroids, which has led to extensive studies of the action of pyrethroids on mammalian sodium channels. Binding studies using radioactive pyrethroid demonstrated specific binding of the pyrethroid to rat brain VGSC α subunits (Trainer et al., 1997).

A prime example of impairments in cognitive function as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). In addition, testing for the impact of chemical exposures on cognitive function, often including spatially-mediated behaviors, is an integral part of both EPA and OECD developmental neurotoxicity guidelines (USEPA, 1998; OECD, 2007).

Not Specified

During brain development

Not Specified

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Not Specified

Klose et al. 2022 DOI 10.1007/S10565-022-09730-4 https://link.springer.com/article/10.1007/s10565-022-09730-4 EFSA 2021 DOI https://doi.org/10.2903/j.efsa.2021.6599 AOPWiki 2023-02-22T08:31:03

2026-03-25T13:52:44