Comparison between a Phoneutria nigriventer toxin treatment and galantamine treatment in a memory deficit mouse model
Main Article Content
Abstract
Acetylcholine modulates circuits related to cognitive functions (attention, cognitive flexibility, memory, and social interaction). Consequences of low acetylcholine levels in cholinergic synaptic clefts include memory and sociability impairments. VAChT KDHET mice exhibit diminished vesicular acetylcholine transporter protein production, which could evoke low acetylcholine quantal release and memory and sociability issues. It has been demonstrated that the PhKv toxin, isolated from the Phoneutria nigriventer (Brazilian wandering spider) venom, inhibits the enzyme responsible for acetylcholine hydrolysis, acetylcholinesterase. This could result in acetylcholine remaining longer in the synaptic cleft, as well as alleviating cognitive problems caused by low levels of this neurotransmitter. Hence, here we intended to investigate VAChT KDHET mice cognitive deficits in a behavioral assay - the novel object recognition task - and examine the potential effect of the PhKv toxin in memory improvement of this mouse model. First, we noted that VAChT KDHET mice showed impaired object recognition memory. We also observed that these deficits, especially those related to short-term memory in the behavioral test, are sex-related. Subsequently, to assess the effects of PhKv toxin in object recognition memory, we injected PhKv or galantamine in VAChT KDHET mice and compared their performance in the novel object recognition task. We noted that mice treated with PhKv performed similarly to mice treated with galantamine or both vehicles in this behavioral assay. Finally, we observed that mice treated with both vehicles displayed memory improvements compared to non-treated (naive) mutant mice. Together, our results imply that PhKv may have an effect on memory improvement, which might be further explored to elucidate its mechanisms of action.
Keywords:
Phoneutria nigriventer, PhKv, spider toxin, object recognition memory, vesicular acetylcholine transporter
Article Details
How to Cite
NOGUEIRA-SOUZA, Ana Caroline et al.
Comparison between a Phoneutria nigriventer toxin treatment and galantamine treatment in a memory deficit mouse model.
Medical Research Archives, [S.l.], v. 11, n. 12, dec. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4693>. Date accessed: 16 may 2024.
doi: https://doi.org/10.18103/mra.v11i12.4693.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Parsons SM. Transport mechanisms in acetylcholine and monoamine storage. FASEB J. 2000; 14(15):2423–2434.
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7. Prado VF, Martins-Silva C, de Castro BM, Lima RF, Barros DM, Amaral E, Ramsey AJ, Sotnikova TD, Ramirez MR, Kim HG, Rossato JI, Koenen J, Quan H, Cota VR, Moraes MFD, Gomez MV, Guatimosim C, Wetsel WC, Kushmerick C, Pereira GS, Gainetdinov RR, Izquierdo I, Caron MG, Prado MAM. Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron. 2006;51(5):601–612.
8. de Castro BM, de Jaeger X, Martins-Silva C, Lima RDF, Amaral E, Menezes C, Lima P, Neves CML, Pires RG, Gould TW, Welch I, Kushmerick C, Guatimosim C, Izquierdo I, Cammarota M, Rylett RJ, Gomez MV, Caron MG, Oppenheim RW, Prado MAM, Prado VF. The vesicular acetylcholine transporter is required for neuromuscular development and function. Mol Cell Biol. 2009; 29(19):5238–5250.
9. de Castro, BM, Pereira GS, Magalhães V, Rossato JI, de Jaeger X, Martins-Silva C, Leles B, Lima P, Gomez MV, Gainetdinov RR, Caron MG, Izquierdo I, Cammarota M, Prado VF, Prado MAM. Reduced expression of the vesicular acetylcholine transporter causes learning deficits in mice. Genes Brain Behav. 2009; 8(1);23–35.
10. Capettini SB, Moraes MFD, Prado VF, Prado MAM, Pereira GS. Vesicular acetylcholine transporter knockdown mice show sexual dimorphism on memory. Brain Res Bull. 2011; 85(1–2):54–57.
11. de Jaeger X, Cammarota M, Prado MAM, Izquierdo I, Prado VF, Pereira GS. Decreased acetylcholine release delays the consolidation of object recognition memory. Behav Brain Res. 2013; 238(1): 62–68.
12. Magalhães-Gomes MPS, Motta-Santos D, Schetino, LPL, Andrade JN, Bastos CP, Guimarães DAS, Vaughan SK, Martinelli PM, Guatimosim S, Pereira GS, Coimbra CC, Prado VF, Prado MAM, Valdez G, Guatimosim C. Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia. Neurochem Int. 2018; 120:1–12.
13. Karantzoulis S, Galvin JE. Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother. 2011; 11(11):1579.
14. Tarawneh R, Holtzman DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med. 2012; 2(5).
15. Kolisnyk B, Al-Onaizi MA, Hirata PHF, Guzman MS, Nikolova S, Barbash S, Soreq H, Bartha R, Prado MAM, Prado V F. Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex. J Neurosci. 2013;33(37):14908–14920.
16. Carvajal FJ, Inestrosa NC. Interactions of AChE with Aβ Aggregates in Alzheimer’s Brain: Therapeutic Relevance of IDN 5706. Front Mol Neurosci. 2011;4.
17. Haass C, Selkoe DJ. Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell. 1993;75(6):1039–1042.
18. Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K,Xu HE. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38(9) :1205–1235.
19. Rees TM, Brimijoin S. The role of acetylcholinesterase in the pathogenesis of Alzheimer’s disease. Drugs Today (Barc). 2003; 39(1):75–83.
20. Rees, T, Hammond PI, Soreq H, Younkin S, Brimijoin S. Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging. 2003; 24(6):777–787.
21. Garcia-Ayllon MS, Small DH, Avila J, Sáez-Valero J. Revisiting the role of acetylcholinesterase in Alzheimer's disease: Cross-talk with β-tau and p-amyloid. Front Mol Neurosci. 2011; 4(SEP):22.
22. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 2013; 11(3):315.
23. Almeida AP, Andrade AB, Ferreira AJ, Pires ACG, Damasceno DD, Alves MNM, Gomes ERM, Kushmerick C, Lima RF, Prado MAM, Prado VF, Richardson M, Cordeiro MN, Guatimosim S, Gomez MV. Antiarrhythmogenic effects of a neurotoxin from the spider Phoneutria nigriventer. Toxicon. 2011; 57(2): 217–224.
24. Rigo FK, Rossato MF, Trevisan G, de Prá SDT, Ineu RP, Duarte MB, de Castro Junior CJ, Ferreira J, Gomez MV. PhKv a toxin isolated from the spider venom induces antinociception by inhibition of cholinesterase activating cholinergic system. Scand J Pain. 2017; 17:203–210.
25. Gomez MV, Kalapothakis E, Guatimosim C, Prado MAM. Phoneutria nigriventer venom: a cocktail of toxins that affect ion channels. Cell Mol Neurobiol. 2002; 22(5–6):579–588.
26. de Lima ME, Figueiredo SG, Matavel A, Nunes KP, da Silva CN, de Marco Almeida F, Diniz MRV, Cordeiro MN, Stankiewicz M, Beirão PSL. Phoneutria nigriventer Venom and Toxins: A Review. In: Spider Venoms, Diego-García, E., Ed.; Springer Science+Business Media Dordrecht. 2015; 71–99.
27. Peigneur S, de Lima ME, Tytgat J. Phoneutria nigriventer venom: A pharmacological treasure. Toxicon. 2008;151: 96–110.
28. Kushmerick C, Kalapothakis E, Beirão PSL, Penaforte CL, Prado VF, Cruz JS, Diniz CR, Cordeiro MN, Gomez MV, Romano-Silva MA, Prado MAM. Phoneutria nigriventer toxin Tx3-1 blocks A-type K+ currents controlling Ca2+ oscillation frequency in GH3 cells. J Neurochem. 1999;72(4):1472–1481.
29. Gomes GM, Dalmolin GD Cordeiro MN, Gomez MV, Ferreira J, Rubin MA. The selective A-type K+ current blocker Tx3-1 isolated from the Phoneutria nigriventer venom enhances memory of naïve and Aβ(25-35)-treated mice. Toxicon. 2013;76:23–27.
30. Cordeiro MN, de Figueiredo SG, Valentim AC, Diniz CR, von Eickstedt VRD, Gilroy J, Richardson M. Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian “armed” spider Phoneutria nigriventer (Keys). Toxicon. 1993; 31(1):35–42.
31. Magno LAV, Tenza-Ferrer H, Collodetti M, Aguiar MFG, Rodrigues APC, da Silva RS, do Prado Silva J, Nicolau NF, Rosa DVF, Birbrair A, Miranda DM, Romano-Silva MA. Optogenetic Stimulation of the M2 Cortex Reverts Motor Dysfunction in a Mouse Model of Parkinson’s Disease. J Neurosci. 2019. 39(17):3234–3248.
32. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988; 31(1):47–59.
33. Squire LR, Wixted JT, Clark RE. Recognition memory and the medial temporal lobe: a new perspective. Nat Rev Neurosci. 2007; 8(11):872.
34. Leger M, Quiedevill A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, Freret T. Object recognition test in mice. Nat Protoc. 2013; 8(12):2531–2537.
35. Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp. 2017;(126):55718.
36. Beery A. Inclusion of females does not increase variability in rodent research studies. Curr Opin Behav Sci. 2018;23:143.
37. Fric KM, Fernandez SM, Bulinski SC. Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience. 2002;115(2):547–558.
38. Yan Y, Cheng L, Chen X, Wang Q, Duan M, Ma J, Zhao L, Jiang X, Ai J, Yan Y, Cheng L, Chen X, Wang Q, Duan M, Ma J, Zhao L, Jiang X, Ai J. Estrogen deficiency is associated with hippocampal morphological remodeling of early postmenopausal mice. Oncotarget. 2017;8(13):21892–21902.
39. Renczes E, Borbelyova V, Steinhardt M, Hopfner T, Stehle T, Ostatníková D, Celec P. The role of estrogen in anxiety-like behavior and memory of middle-aged female rats. Front Endocrinol (Lausanne). 2020;11:734.
40. Tao X, Yan M, Wang L, Zhou Y, Wang Z, Xia T, Liu X, Pan R, Chang Q. Effects of estrogen deprivation on memory and expression of related proteins in ovariectomized mice. Ann Transl Med. 2020; 8(6):356–356.
41. Luo M, Zeng Q, Jiang K, Zhao Y, Long Z, Du Y, Wang K, He G. Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice. Genes Dis. 2021;9(5):1315-1331.
42. Micheau J, Marighetto A. Acetylcholine and memory: a long, complex and chaotic but still living relationship. Behav Brain Res. 2011; 221(2):424–429.
43. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: From 3D Structure to Function. Chem Biol Interact. 2010; 187(1–3):10.
44. Adams S, Pacharinsak C. Mouse anesthesia and analgesia. Curr Protoc Mouse Biol. 2015; 5(1):51–63.
45. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EFR, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621. https://doi.org/10.1124/PR.117.015198
46. Yang Y, Ju W, Zhang H, Sun L. Effect of ketamine on LTP and NMDAR EPSC in hippocampus of the chronic social defeat stress mice model of depression. Front Behav Neurosci. 2018;12:229.
47. Pitsikas N. The role of ketamine in object recognition memory in rodents. Handb Behav Neurosci. 2018;27:553–560.
48. Warburton EC, Barker GRI, Brown MW. Investigations into the involvement of NMDA mechanisms in recognition memory. Neuropharmacology. 2013;74:41–47.
49. Iwamura E, Yamada K, Ichitani Y. Involvement of hippocampal NMDA receptors in retrieval of spontaneous object recognition memory in rats. Behav Brain Res. 2016;307:92–99.
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