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:0007611

GO learning or memory

GO:0050890

GO cognition

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

WikiUser_28

Vertebrates

WikiUser_29

Invertebrates

WCS_9606

common toxicological species human

10116

NCBI rat

10090

NCBI mouse

Binding to voltage-gated sodium channel

Binding to VGSC

Molecular

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 with their concentration gradient across the membrane. Those 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 are essential for chemical communication between cells, or synaptic transmission. Ion channels also function to maintain membrane potential and initiate and propagate electrical impulses. Voltage-gated sodium channels are therefore responsible for action potential initiation and propagation in excitable cells, including nerve, muscle and neuroendocrine cell types. They are also expressed at low levels in non-excitable cells. It is important to note is that functional VGSC are present in both grey and white matter in the brain and approximately 50% of white matter oligodendrocyte precursor cells producing trains of action potentials and receiving synaptic input (Fields, 2008). VGSC are also present on microglia cells and contribute to 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 a tissue, region and time specific manner. 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, and their sensitivity and their functional role, may all contribute to the manifestation of toxicity and age dependent sensitivity, including the effects caused by pyrethroids. <img alt="" src="https://aopwiki.org/system/dragonfly/production/2022/03/15/9bkwiiz0mg_Picture1.jpg" /> At resting membrane potentials the channel is closed. During the rising phase of an action potential the channel activates or opens. Channel inactivation contributes to the falling phase. During the undershoot phase the channel deactivates before returning to the closed phase once resting membrane resting potential has been restored. Source: adapted from Motifolio Biomedical PowerPoint Toolkit Suite.

The sodium channel protein has been discovered and characterised in biochemical and molecular detail, even to atomic resolution. The initial works performed to measure and detect the electrical signals in nerves were initiated by Hodgkin and Huxley in 1952, showing a voltage‐dependent activation of sodium current that carries Na+ inward. The structure of VGSCs is nowadays known in detail and some seminal papers are available (Catterall, 2012). Intracellular microelectrode recording using voltage or patch clamp are the common methods used for electrophysiological studies of VGSC. Channels and locations can also be measured using immunohistochemical methods, transcriptomics and at protein levels. Expression of different sodium channel isoforms can be measured using a panel of sodium channel subunit-specific antibodies. Quantification of immunocytochemical staining is difficult due to differences in equipment, tissue preparation, inter-assay variability and analysis methods. However, using a quantitative approach, it is possible to determine the localisation and relative levels of sodium channel subunit protein expression (Westenbroek et al., 2013). PCR amplification and competitive PCR approach, real-time PCR, are used to isolate the mRNA levels of VGSC isoforms (Haufe et al., 2005).

Every cell within living organisms actively maintains an intracellular Na+ concentration that is 10–12 times lower than the extracellular concentration. The cells then utilise this transmembrane Na+ concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising VGSC (Navs) is essential for such signalling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another. VGSC were first predicted in squid and were later identified through molecular biology in the electric eel. Since then, these proteins have been discovered in organisms ranging from bacteria to humans (Chaihne, 2018). Sodium channels consist of a highly processed α subunit, which is approximately 260 kDa, associated with auxiliary β subunits of 33–39 kDa. Sodium channels in the adult central nervous system (CNS) and heart contain a mixture of β1–β4 subunits, while sodium channels in adult skeletal muscle have only the β1 subunit. Nine different sodium channels have been identified using electrophysiological recording, biochemical purification, and cloning (Catterall, 2012). Nomenclature of the different sodium channels utilises 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). Nine mammalian sodium channel isoforms have been identified and functionally expressed with all greater than 50% identical in amino acid sequence in the transmembrane and extracellular domains, where the amino acid sequence is similar enough for clear alignment (Catterall, 2012). In addition to these nine sodium channels that have been functionally expressed, closely related sodium channel-like proteins (Nax) have been cloned from mouse, rat and human. They are approximately 50% identical to the Nav 1 subfamily of channels but more than 80% identical to each other (Catterall, 2012). In mammals, 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 impair nervous system structure and function, including muscle function, pain reception and cardia arrythmias (Chahine, 2018). VGSC show complex regional and temporal ontogeny in mammals (see Table 1, from Shafer et al., 2005). In general, embryonically expressed forms of VGSCs are replaced by expression of adult forms as neurodevelopment proceeds. <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" /> This complex ontogeny of VGSCs confounds any simple linkage of VGSCs to adverse outcomes and is an uncertainty in the development of this AOP. Since brain development in both humans and rodents extends from early gestation through lactation, it is not currently possible to state which VGSC subtype, or subtypes, may be responsible for the AOs. Ion channels, including VGSCs, are also expressed in oligodendrocytes, Schwann cells (Baker, 2002) and microglia (Hossain et al., 2017). The expression and function of VGSS in cells of the oligodendrocyte lineage follow a time and regional ontogeny. While present and active in the early stages of oligodendrocyte maturation, VGSC function decreases over developmental time and is absent in mature oligodendrocytes (Paez et al., 2009; Berret et al., 2017). Knockdown of VGSC in rat oligodendrocyte precursor cells (OPCs) leads to reduced myelination suggesting a function of VGSC for axon myelination (Berret et al., 2017). The physiological and anatomical ontogeny of Schwann cells is well known (Jessen and Mirsky, 2005). VGSCs are present in Schwann cells including the tetrodotoxin sensitive and Nav 1.7 types (Ritche, 1992; Chiu, 1991; Baker, 2002) less is known about their developmental profile. Microglia cells express several ion channels, including Cl-, K+, H+ and Ca2+ and VGSC that are involved in several cellular functions such as maintaining the membrane potential, cellular volume and intracellular ion concentrations. VGSCs are demonstrated, to be present both in rodents and human microglia. Different isoforms are present in primary microglia (Nav 1.1, 1.2, 1.3, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.1 isoforms) compared to immortalised BV2 cells (Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 isoforms) (Jung et al., 2013; Black and Waxman, 2012; reviewed by Hossain et al., 2017). Presence of sodium channel isoforms in immortalised BV2 cells and primary microglia were detected by mRNA expression with standard PCR. BV2 cells express some sodium channel isoforms including Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 whereas primary microglia from 1–2-day-old mice express channel isoforms Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 1.8, 1.9, and 2.1. Primary microglia expressed higher levels of Nav 1.1. 1.2, 1.3, 1.6, 1.9, and 2.1 compared with BV2 cells.

Not Specified Male Not Specified Female

Not Specified

All life stages

Not Specified Not Specified Baker MD, 2002. Electrophysiology of mammalian Schwann cells. Progress in Biophysics and Molecular Biology, 78(2–3), 83–103. <a href="https://doi.org/10.1016/S0079-6107(02)00007-X" style="color:blue; text-decoration:underline">https://doi.org/10.1016/S0079–6107(02)00007-X</a> 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. <a href="https://doi.org/10.1038/s41467-017-00688-0" style="color:blue; text-decoration:underline">https://doi.org/10.1038/s41467–017–00688–0</a> Black JA and Waxman SG, 2012. Sodium channels and microglial function. Experimental Neurology, 234(2), 302–315. <a href="https://doi.org/10.1016/j.expneurol.2011.09.030" style="color:blue; text-decoration:underline">https://doi.org/10.1016/j.expneurol.2011.09.030</a> Cao Z, Shafer TJ and Murray TF, 2011. Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons, Journal of Pharmacology and Experimental Therapeutics, 336 (1), 197–205. American Society for Pharmacology and Experimental Therapeutics. doi: <a href="https://doi.org/10.1124/jpet.110.171850" style="color:blue; text-decoration:underline">https://doi.org/10.1124/jpet.110.171850</a> Catterall WA, 2012. Voltage‐gated sodium channels at 60: structure, function and pathophysiology. Journal of Physiology, 590(11), 2577–2589. <a href="https://doi.org/10.1113/jphysiol.2011.224204" style="color:blue; text-decoration:underline">https://doi.org/10.1113/jphysiol.2011.224204</a> 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. Vol. 246. Springer. Chiu SY, 1991. Functions and distribution of voltage‐gated sodium and potassium channels in mammalian Schwann cells. Glia, 4(6), 541–558. <a href="https://doi.org/10.1002/glia.440040602" style="color:blue; text-decoration:underline">https://doi.org/10.1002/glia.440040602</a> Fields RD, 2008. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. The Neuroscientist, 14(6), 540–543. Haufe V, Camacho JA, Dumaine R, Günther B, Bollensdorff C, Von Banchet GS, … and Zimmer, T, 2005. Expression pattern of neuronal and skeletal muscle voltage‐gated Na+ channels in the developing mouse heart. Journal of Physiology, 564(3), 683–696. https://doi.org/10.1113/jphysiol.2004.079681 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, <a href="https://doi.org/10.1093/toxsci/kfw187" style="color:blue; text-decoration:underline">https://doi.org/10.1093/toxsci/kfw187</a> Isom LL, 2002. β subunits: Players in neuronal hyperexcitability? Sodium Channels and Neuronal Hyperexcitability, 124, 124–138. Jessen KR and Mirsky R, 2005. The origin and development of glial cells in peripheral nerves. Nature Reviews in Neuroscience, 6, 671–682. <a href="https://doi.org/10.1038/nrn1746" style="color:blue; text-decoration:underline">https://doi.org/10.1038/nrn1746</a> 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. <a href="https://doi.org/10.1002/glia.22559" style="color:blue; text-decoration:underline">https://doi.org/10.1002/glia.22559</a> Káradóttir R, Hamilton NB, Bakiri Y and Attwell D, 2008. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neuroscience, 11(4), 450–456. <a href="https://doi.org/10.1038/nn2060" style="color:blue; text-decoration:underline">https://doi.org/10.1038/nn2060</a> Lee SH and Soderlund DM, 2001. The V410M mutation associated with pyrethroid resistance in Heliothis virescens reduces the pyrethroid sensitivity of house fly sodium channels expressed in Xenopus oocytes. Insect Biochemistry and Molecular Biology, 31(1), 19–29. <a href="https://doi.org/10.1016/S0965-1748(00)00089-8" style="color:blue; text-decoration:underline">https://doi.org/10.1016/S0965–1748(00)00089-8</a> Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14. <a href="https://doi.org/10.1111/j.1600-0773.1996.tb00234.x" style="color:blue; text-decoration:underline">https://doi.org/10.1111/j.1600–0773.1996.tb00234.x</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. <a href="https://doi.org/10.1254/jjp.88.365" style="color:blue; text-decoration:underline">https://doi.org/10.1254/jjp.88.365</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" style="color:blue; text-decoration:underline">https://doi.org/10.1002/jnr.21938</a> Ray DE, 2001. Pyrethroid insecticides: mechanisms of toxicity, systemic poisoning syndromes, paresthesia, and therapy. In: Krieger RI and Krieger WC. Handbook of Pesticide Toxicology. Academic Press, pp. 1289–1303. Ritchie JM, 1992. Voltage-gated ion channels in Schwann cells and glia. Trends in Neurosciences, 15(9), 345–351. <a href="https://doi.org/10.1016/0166-2236(92)90052-A" style="color:blue; text-decoration:underline">https://doi.org/10.1016/0166–2236(92)90052-A</a> Shafer TJ, Meyer DA and Crofton KM, 2005. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environmental Health Perspectives, 113(2), 123–136. <a href="https://doi.org/10.1289/ehp.7254" style="color:blue; text-decoration:underline">https://doi.org/10.1289/ehp.7254</a> Smith TJ and Soderlund DM, 1998. Action of the pyrethroid insecticide cypermethrin on rat brain IIa sodium channels expressed in xenopus oocytes. Neurotoxicology, 19(6), 823–832. Smith TJ and Soderlund DM, 2001. Potent actions of the pyrethroid insecticides cismethrin and cypermethrin on rat tetrodotoxin-resistant peripheral nerve (SNS/PN3) sodium channels expressed in Xenopus oocytes. Pesticide Biochemistry and Physiology, 70(1), 52–61. <a href="https://doi.org/10.1006/pest.2001.2538" style="color:blue; text-decoration:underline">https://doi.org/10.1006/pest.2001.2538</a> Smith TJ, Lee SH, Ingles PJ, Knipple DC and Soderlund DM, 1997. The L1014F point mutation in the house fly Vssc1 sodium channel confers knockdown resistance to pyrethroids. Insect Biochemistry and Molecular Biology, 27(10), 807–812. <a href="https://doi.org/10.1016/S0965-1748(97)00065-9" style="color:blue; text-decoration:underline">https://doi.org/10.1016/S0965–1748(97)00065–9</a> Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, … and Weiner ML, 2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59. <a href="https://doi.org/10.1016/S0300-483X(01)00569-8" style="color:blue; text-decoration:underline">https://doi.org/10.1016/S0300–483X(01)00569–8</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: <a href="https://doi.org/10.1124/mol.51.4.651" style="color:blue; text-decoration:underline">https://doi.org/10.1124/mol.51.4.651</a> Vais H, Williamson MS, Devonshire AL and Usherwood PNR, 2001. The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels. Pest Management Science, 57(10), 877–888. <a href="https://doi.org/10.1002/ps.392" style="color:blue; text-decoration:underline">https://doi.org/10.1002/ps.392</a> Vais H, Williamson MS, Goodson SJ, Devonshire AL, Warmke JW, Usherwood PN and Cohen CJ, 2000. Activation of Drosophila sodium channels promotes modification by deltamethrin: reductions in affinity caused by knock-down resistance mutations. Journal of General Physiology, 115(3), 305–318. doi: <a href="https://doi.org/10.1085/jgp.115.3.305" style="color:blue; text-decoration:underline">https://doi.org/10.1085/jgp.115.3.305</a> Volpe JJ, Kinney HC, Jensen FE and Rosenberg PA, 2011. Reprint of ‘The developing oligodendrocyte: key cellular target in brain injury in the premature infant’. International Journal of Developmental Neuroscience, 29(6), 565–582. <a href="https://doi.org/10.1016/j.ijdevneu.2011.07.008" style="color:blue; text-decoration:underline">https://doi.org/10.1016/j.ijdevneu.2011.07.008</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, 39–66. <a href="http://dx.doi.org/10.5772/5033" style="color:blue; text-decoration:underline">http://dx.doi.org/10.5772/5033</a> Wang SY, Barile M and Wang GK, 2001. A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na+ channels is critical for pyrethroid action. Molecular Pharmacology, 60(3), 620–628. Westenbroek RE, Bischoff S, Fu Y, Maier SK, Catterall WA and Scheuer T, 2013. Localization of sodium channel subtypes in mouse ventricular myocytes using quantitative immunocytochemistry. Journal of Molecular and Cellular Cardiology, 64, 69–78. doi: 10.1016/j.yjmcc.2013.08.004 AOPWiki 2017-04-14T15:25:30

2023-11-10T03:36:24

Disruption of sodium channel gating kinetics

Altered kinetics of sodium channel

Cellular

Action potentials 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, all the gated sodium and potassium channels are 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. VGSC 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 starts to get more positive. Gate h (the deactivation gate) is normally open, and swings shut when the cells gets too positive. Gate n is normally closed, but slowly opens when the cell is depolarised (very positive). VGSC exist in one of three states: Deactivated (closed) – at rest, channels are deactivated. The m gate is closed and does not let sodium ions through. Activated (open) – when a current pass through and changes the voltage difference across a membrane, the channel will activate and the m gate will open. Inactivated (closed) – as the neuron depolarises, the h gate swings shut and blocks sodium ions from entering the cell. Voltage-gated potassium channels are either open or closed. Typically, activation and inactivation of VGSC occur quite rapidly. However, some compounds can bind to the VGSC and disrupt the kinetics of activation and inactivation. This typically slows the kinetics of those processes. Slowed VGSC activation leads to a decrease in peak Na+ current measured throughout the cell as well as a delay in the time for the current to reach its peak. By slowing VGSC inactivation and deactivation leads to a prolonged VGSC open time. The longer channel open time results in more Na+ entering the cell and this leads to hyperexcitability, membrane depolarisation, increase in firing rate and conduction block. A short prolongation of the channel inactivation kinetics causes repetitive firing of action potentials (repetitive discharge) as a small percentage of modified channels in the membrane can cause unmodified channels to activate, or open again. However, if the channel inactivation is sufficiently period, the membrane potential eventually becomes depolarised to the point at which generation of action potentials is not possible (depolarisation-dependent block). A small percentage of modified VGSCs can increase Na+ current substantially (Narahashi, 1996), driving repetitive firing and depolarization-dependent conduction block.

The modifications of the sodium channel gating have been studied using voltage- and patch-clamp experiments in models from many different invertebrate and vertebrate species, including mammals and even human cells (Ruigt et al., 1987; Soderlund et al., 2002), showing that the prolongation of the sodium current is mainly due to the reduced rate of closure of a fraction of sodium channels affected by pyrethroids. In neuroblastoma cell preparations, deltamethrin and other type II pyrethroids induced slow tail currents with a relatively rapid 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 time of exposure, temperature and membrane potential (Ruigt et al., 1987). The voltage-clamp technique typically uses two microelectrodes, allowing control of the membrane potential and recording transmembrane currents flowing across the membrane of the entire cell that result from ion channel opening and closing (Guan et al., 2013). Patch clamp is a highly sensitive version of the voltage-clamp technique in which currents flowing through a single ion channel, or across the entire cell membrane ("whole cell" current) of an individual can be measured, depending on the configuration of the recording. Further, pharmacological interventions can be used such that the current flowing through only a single type of channel in the memberane can be measured. For example, by blocking potassium, calcium and chloride channels, the current flowing through voltage-gated sodium channels can be isolated. A single electrode serves both to measures voltage and pass current (Molleman, 2003). This technique allows measurement of the altered kinetics of a single channel, which can then be manifested by changes in the kinetics of the whole-cell current.

Ion channels are essential for the initiation and propagation of action potential in excitable cells from 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 therefore a target of natural and synthetic chemicals and disruption of the gate kinetics has been characterised in insects and mammalian cells (Soderlund et al., 2002).

Not Specified Male Not Specified Female

Not Specified

All life stages

Not Specified Not Specified 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 Molleman A, 2003. Patch Clamping: An Introductory Guide to Patch Clamp Electrophysiology. John Wiley and Sons. Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14. https://doi.org/10.1111/j.1600–0773.1996.tb00234.x Ruigt GF, 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. Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargen D, … 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

2022-09-13T20:44:31

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 of, 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). 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). Test of novelty 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. A brief description of these tasks follows. 1) RAM, Barnes, 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). 2) Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. 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., I have seen one of these objects before, but not this one. Cohen and Stackman, 2015). 3) 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. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009). 4) Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock 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). Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. 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 developmental neurotoxicity 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 WAIS and the Wechsler. Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include: 1) Rey Osterieth Complex Figure (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006). 2) 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 1995; Talley, 1986).  3) 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). 4) Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986). 5) 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, 2015). 6) Staged Autobiographical Memory 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, buy 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).

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

During brain development

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. 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]. 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. 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

2018-08-09T11:55:05

Inhibition of voltage-gated sodium channels leading to decreased cognition

Voltage-gated sodium channels and DNT

Brendan Ferreri-Hanberry

Eliska Kuchovska, Jördis Klose, 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 expsoures on cognitive function, often including spatially-mediated behaviors, is an intergral part of both EPA and OECD developmental neurotoxicity guidelines (USEPA, 1998; OECD, 2007).

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During brain development

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<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>

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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

2024-05-26T20:39:59