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Relationship: 1889
Title
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Acetylcholinesterase Inhibition Leading to Neurodegeneration | adjacent | Moderate | Low | Karen Watanabe (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
Muscarinic receptors are metabotropic, affecting a target enzyme which typically sends secondary messenger signals (Kandel et al., 2013). Pharmacological evidence indicates the mAChR M1 subtype modulates the M current in sympathetic ganglion neurons. In mice, M1 agonists suppress the M current and results in membrane depolarization that leads to focal seizures (Hamilton et al., 1997). Seizures occurring through the M1 muscarinic receptor have been observed to start at 5-15 minutes after exposure in rats and guinea pigs (Miller, 2015, Sparenborg et al., 1992).
Evidence Collection Strategy
Evidence was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts. Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources. The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.
Evidence Supporting this KER
Biological Plausibility
M1 Muscarinic receptors are modulators of M-current potassium channel activity (Marrion, 1997). Blocking the M-current through the M1 receptor contributes to cell depolarization, which then leads to the start of epileptiform activity (Greget et al., 2016). The use of muscarinic agonists is well established and often used in animal models of epilepsy and include compounds such as pilocarpine and carbachol (Curia et al., 2008, Turski et al., 1983). It has been suggested that seizures initiated through M1 receptor activation occur when the ratio between glutamatergic and GABAergic activity reaches a threshold (Miller, 2015).
Empirical Evidence
- Investigations into receptors involved in cholinergic seizures have found that pre-treatment with the selective M1 antagonist pirenzepine abolished seizures in 91% of the rats tested. The drugs mecamylamine, a nicotinic antagonist, and methoctramine, a M1 receptor antagonist, did not significantly affect seizure activity (Cruickshank et al., 1994).
- Muscarinic antagonists were effective in lessening the seizure activity in guinea pig hippocampal slices (Harrison et al., 2004).
- M1- deficient mice neurons lacked the modulation of M-current caused by muscarinic agonists that is shown in wild-type mice. The mice lacking M1 receptors are also resistant to pilocarpine-induced seizures (Hamilton et al., 1997).
- In a rat study, pretreatment with atropine, a mAChR antagonist, was able to prevent cholinergic symptoms such as convulsions and acute mortality following an injection of physostigmine, a reversible AChE inhibitor (Davis and Hatoum, 1980).
Uncertainties and Inconsistencies
Experiments blocking the M2 subtype have not led to a decrease in seizures from acetylcholinesterase inhibitors, only the antagonist for M1 subtype decreased seizure activity (Cruickshank et al., 1994). This demonstrates that the M1 subtype is vital for muscarinic receptor caused seizures. Many studies have noted that delaying administration of M1 antagonist, even for just a short amount of time after exposure, does not halt status epilepticus development (Miller, 2015). This indicates that M1 receptors are not responsible for maintaining seizure activity, they are only responsible for the initial phase (Hamilton et al., 1997). The secondary generalization of the focal seizure is continued by some other mechanism.
Known modulating factors
Quantitative Understanding of the Linkage
The papers in the table below present EEG data from timepoint 0 onwards through injection of seizure-inducing compounds. Focal seizures can be seen to occur in EEG where there is activity localized between a set or sets of electrodes while normal activity continues in the remaining electrodes (Britton et al., 2016). Additionally, the full spectrum of the EEG is not published, and one would need to contact the author.
Table 1. Summary of available quantitative data describing responses of focal seizure to mAChR activation. CHO = Chinese hamster ovary, DFP = diisopropylfluorophosphate, EEG = electroencephalogram; GABA = gamma-aminobutyric acid; Glu = glutamate.
Upstream Muscarinic Receptor Activation |
Downstream Focal Seizure |
Brief Summary |
Species / Model |
Reference |
|
|
Pilocarpine (10 mM) through microdialysis cannula in the hippocampus |
EEG activity (ECoG). Seizure severity score over time. |
Induced seizure activity through intrahippocampal administration of pilocarpine and monitored EEG activity. Additionally measured various neurotransmitter concentrations including Glu and GABA. |
Male albino Wistar rats (270-320g) |
Meurs et al. (2008) |
||
Pilocarpine (240 mg/kg; 280mg/kg; 320 mg/kg) IP |
EEG activity (surface electrodes on skull) |
Induced seizure activity through pilocarpine (ip) and measured EEG activity. An additional experiment performed involving injection of methylscopolamine (1 mg/kg) before injection of 320 mg/kg pilocarpine. |
Adult male Sprague-Dawley rats (225-250g) |
Tetz et al. (2006) |
||
Pilocarpine (2 doses of 20 mg/kg, i.p., per 30 min) |
EEG (intracranial). Seizure stages over time. |
Induced seizure activity through pilocarpine injection. Monitored EEG activity for 24 hrs from injection time and onwards. Additionally compared activity to DFP and soman injection models. |
Young adult male Sprague-Dawley rats (250-300g) |
Reddy et al. (2021) |
||
Pilocarpine (for M3 mAchR) (k_on = 4.47 ± 0.53 × 10^5 M^-1 min^-1 k_off = 15.3 ± 2.3 min^-1 t_1/2 = 3.0 ± 0.4 s) |
NA |
Activity and binding data for pilocarpine through a competitive binding assay with l-[N-methyl]-[3H]scopolamine methyl chloride, for M3 mAChRs. |
CHO cells transfected with human M3 mAChR |
Sykes et al. (2009) |
||
Acetylcholine |
Electrophysiological response of CA1 neuron to mAChR activation |
Computational model of a CA1 pyramidal neuron that incorporates mAChR activation through acetylcholine application, intracellular calcium dynamics, and its electrophysiological response. They provide the kinetics in response to acetylcholine application and provide the associated kinetic rate constants. |
Computational model |
Mergenthal et al. (2020) |
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
M1 activation leading to focal seizure activity appears in many different species, both genders, and at various life stages. Specific experiments are listed under the empirical evidence above.
References
Britton, J. W., Frey, L. C., Hopp, J. L., Korb, P., Koubeissi, M. Z., Lievens, W. E., Pestana-Knight, E. M. & St. Louis, E. K. 2016. In: ST. LOUIS, E. K. & FREY, L. C. (eds.) Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. Chicago: American Epilepsy Society Copyright ©2016 by American Epilepsy Society.
Cruickshank, J. W., Brudzynski, S. M. & McLachlan, R. S. 1994. Involvement of M1 muscarinic receptors in the initiation of cholinergically induced epileptic seizures in the rat brain. Brain Research, 643, 125-129. DOI: 10.1016/0006-8993(94)90017-5.
Curia, G., Longo, D., Biagini, G., Jones, R. S. & Avoli, M. 2008. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods, 172, 143-57. DOI: 10.1016/j.jneumeth.2008.04.019.
Davis, W. M. & Hatoum, N. S. 1980. Synergism of the toxicity of physostigmine and neostigmine by lithium or by a reserpine-like agent (Ro4-1284). Toxicology, 17, 1-7. DOI: 10.1016/0300-483x(80)90021-9.
Greget, R., Dadak, S., Barbier, L., Lauga, F., Linossier-Pierre, S., Pernot, F., Legendre, A., Ambert, N., Bouteiller, J. M., Dorandeu, F., Bischoff, S., Baudry, M., Fagni, L. & Moussaoui, S. 2016. Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies. NeuroToxicology, 54, 140-152. DOI: 10.1016/j.neuro.2016.04.013.
Hamilton, S. E., Loose, M. D., Qi, M., Levey, A. I., Hille, B., McKnight, G. S., Idzerda, R. L. & Nathanson, N. M. 1997. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proceedings of the National Academy of Sciences, 94, 13311-13316. DOI: 10.1073/pnas.94.24.13311.
Harrison, P. K., Sheridan, R. D., Green, A. C., Scott, I. R. & Tattersall, J. E. H. 2004. A guinea pig hippocampal slice model of organophosphate-induced seizure activity. Journal of Pharmacology and Experimental Therapeutics, 310, 678-686. DOI: 10.1124/jpet.104.065433.
Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. 2013. Modulation of Synaptic Transmission: Second Messengers. Principles of Neural Science, Fifth Edition. Blacklick, United States: McGraw-Hill Publishing.
Marrion, N. V. 1997. Control of M-current. Annu Rev Physiol, 59, 483-504. DOI: 10.1146/annurev.physiol.59.1.483.
Mergenthal, A., Bouteiller, J.-M. C., Yu, G. J. & Berger, T. W. 2020. A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity. Frontiers in Computational Neuroscience, 14. DOI: 10.3389/fncom.2020.00075.
Meurs, A., Clinckers, R., Ebinger, G., Michotte, Y. & Smolders, I. 2008. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin. Epilepsy Res, 78, 50-9. DOI: 10.1016/j.eplepsyres.2007.10.007.
Miller, S. L. 2015. The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures. Doctor of philosophy in the neuroscience graduate program Doctoral dissertation, Uniformed Services University.
Reddy, D. S., Zaayman, M., Kuruba, R. & Wu, X. 2021. Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman. Neuropharmacology, 191, 108571. DOI: 10.1016/j.neuropharm.2021.108571.
Sparenborg, S., Brennecke, L. H., Jaax, N. K. & Braitman, D. J. 1992. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology, 31, 357-68. DOI: 10.1016/0028-3908(92)90068-z.
Sykes, D. A., Dowling, M. R. & Charlton, S. J. 2009. Exploring the mechanism of agonist efficacy: A relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor. Molecular Pharmacology, 76, 543-551. DOI: 10.1124/mol.108.054452.
Tetz, L. M., Rezk, P. E., Ratcliffe, R. H., Gordon, R. K., Steele, K. E. & Nambiar, M. P. 2006. Development of a rat pilocarpine model of seizure/status epilepticus that mimics chemical warfare nerve agent exposure. Toxicol Ind Health, 22, 255-66. DOI: 10.1191/0748233706th268oa.
Turski, W. A., Czuczwar, S. J., Kleinrok, Z. & Turski, L. 1983. Cholinomimetics produce seizures and brain damage in rats. Experientia, 39, 1408-11. DOI: 10.1007/bf01990130.