Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.
Acetyl-L-carnitine
Danio rerio
Epilepsy
N-Acetylcysteine
Pentylenetetrazole
Seizure
Journal
Pharmacological reports : PR
ISSN: 2299-5684
Titre abrégé: Pharmacol Rep
Pays: Switzerland
ID NLM: 101234999
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
27
07
2023
accepted:
26
09
2023
revised:
25
09
2023
medline:
27
11
2023
pubmed:
10
10
2023
entrez:
9
10
2023
Statut:
ppublish
Résumé
Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission. This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances. Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures. Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.
Sections du résumé
BACKGROUND
BACKGROUND
Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission.
METHODS
METHODS
This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances.
RESULTS
RESULTS
Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures.
CONCLUSION
CONCLUSIONS
Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.
Identifiants
pubmed: 37814098
doi: 10.1007/s43440-023-00536-7
pii: 10.1007/s43440-023-00536-7
doi:
Substances chimiques
Acetylcysteine
WYQ7N0BPYC
Acetylcarnitine
6DH1W9VH8Q
Pentylenetetrazole
WM5Z385K7T
Anticonvulsants
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1544-1555Informations de copyright
© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.
Références
Falco-Walter J. Epilepsy-definition, classification, pathophysiology, and epidemiology. Semin Neurol. 2020;40:617–23. https://doi.org/10.1055/s-0040-1718719 .
doi: 10.1055/s-0040-1718719
pubmed: 33155183
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475–82. https://doi.org/10.1111/epi.12550 .
doi: 10.1111/epi.12550
pubmed: 24730690
Fisher RS, Boas WE, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470–2. https://doi.org/10.1111/j.0013-9580.2005.66104.x .
doi: 10.1111/j.0013-9580.2005.66104.x
pubmed: 15816939
Beghi E. The epidemiology of epilepsy. Neuroepidemiology. 2019;54:185–91. https://doi.org/10.1159/000503831 .
doi: 10.1159/000503831
pubmed: 31852003
Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev Dis Primer. 2018;4:18024. https://doi.org/10.1038/nrdp.2018.24 .
doi: 10.1038/nrdp.2018.24
Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015;5: a022426. https://doi.org/10.1101/cshperspect.a022426 .
doi: 10.1101/cshperspect.a022426
pubmed: 26033084
pmcid: 4448698
Sultana B, Panzini M-A, Veilleux Carpentier A, Comtois J, Rioux B, Gore G, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96:805–17. https://doi.org/10.1212/WNL.0000000000011839 .
doi: 10.1212/WNL.0000000000011839
pubmed: 33722992
Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov. 2010;9:68–82. https://doi.org/10.1038/nrd2997 .
doi: 10.1038/nrd2997
pubmed: 20043029
Skvarc DR, Dean OM, Byrne LK, Gray L, Lane S, Lewis M, et al. The effect of N-acetylcysteine (NAC) on human cognition—a systematic review. Neurosci Biobehav Rev. 2017;78:44–56. https://doi.org/10.1016/j.neubiorev.2017.04.013 .
doi: 10.1016/j.neubiorev.2017.04.013
pubmed: 28438466
Zheng W, Zhang Q-E, Cai D-B, Yang X-H, Qiu Y, Ungvari GS, et al. N-Acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2018;137:391–400. https://doi.org/10.1111/acps.12862 .
doi: 10.1111/acps.12862
pubmed: 29457216
Mocelin R, Herrmann AP, Marcon M, Rambo CL, Rohden A, Bevilaqua F, et al. N-Acetylcysteine prevents stress-induced anxiety behavior in zebrafish. Pharmacol Biochem Behav. 2015;139:121–6. https://doi.org/10.1016/j.pbb.2015.08.006 .
doi: 10.1016/j.pbb.2015.08.006
pubmed: 26261019
Santos P, Herrmann AP, Benvenutti R, Noetzold G, Giongo F, Gama CS, et al. Anxiolytic properties of N-acetylcysteine in mice. Behav Brain Res. 2017;317:461–9. https://doi.org/10.1016/j.bbr.2016.10.010 .
doi: 10.1016/j.bbr.2016.10.010
pubmed: 27725170
Mocelin R, Marcon M, D’ambros S, Herrmann AP, da Rosa Araujo AS, Piato A. Behavioral and biochemical effects of N-acetylcysteine in Zebrafish acutely exposed to ethanol. Neurochem Res. 2018;43:458–64. https://doi.org/10.1007/s11064-017-2442-2 .
doi: 10.1007/s11064-017-2442-2
pubmed: 29196951
Bilister Egilmez C, Azak Pazarlar B, Erdogan MA, Erbas O. N-Acetyl cysteine: a new look at its effect on PTZ-induced convulsions. Epilepsy Res. 2023;193: 107144. https://doi.org/10.1016/j.eplepsyres.2023.107144 .
doi: 10.1016/j.eplepsyres.2023.107144
pubmed: 37116249
Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, et al. L-Acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci. 2013;110:4804–9. https://doi.org/10.1073/pnas.1216100110 .
doi: 10.1073/pnas.1216100110
pubmed: 23382250
pmcid: 3607061
Hussein AM, Adel M, El-Mesery M, Abbas KM, Ali AN, Abulseoud OA. L-Carnitine modulates epileptic seizures in pentylenetetrazole-kindled rats via suppression of apoptosis and autophagy and upregulation of Hsp70. Brain Sci. 2018;8:45. https://doi.org/10.3390/brainsci8030045 .
doi: 10.3390/brainsci8030045
pubmed: 29538301
pmcid: 5870363
Baker DA, Xi Z-X, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci Off J Soc Neurosci. 2002;22:9134–41. https://doi.org/10.1523/JNEUROSCI.22-20-09134.2002 .
doi: 10.1523/JNEUROSCI.22-20-09134.2002
Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci. 2005;25:6389–93. https://doi.org/10.1523/JNEUROSCI.1007-05.2005 .
doi: 10.1523/JNEUROSCI.1007-05.2005
pubmed: 16000629
pmcid: 1413952
Baraban SC, Taylor MR, Castro PA, Baier H. Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression. Neuroscience. 2005;131:759–68. https://doi.org/10.1016/j.neuroscience.2004.11.031 .
doi: 10.1016/j.neuroscience.2004.11.031
pubmed: 15730879
Siebel AM, Menezes FP, da Costa SI, Petersen BD, Bonan CD. Rapamycin suppresses PTZ-induced seizures at different developmental stages of zebrafish. Pharmacol Biochem Behav. 2015;139 Pt B:163–8. https://doi.org/10.1016/j.pbb.2015.05.022 .
doi: 10.1016/j.pbb.2015.05.022
pubmed: 26051026
Bertoncello KT, Aguiar GPS, Oliveira JV, Siebel AM. Micronization potentiates curcumin’s antiseizure effect and brings an important advance in epilepsy treatment. Sci Rep. 2018;8:2645. https://doi.org/10.1038/s41598-018-20897-x .
doi: 10.1038/s41598-018-20897-x
pubmed: 29422541
pmcid: 5805781
Mussulini BHM, Leite CE, Zenki KC, Moro L, Baggio S, Rico EP, et al. Seizures induced by pentylenetetrazole in the adult zebrafish: a detailed behavioral characterization. PLoS One. 2013;8: e54515. https://doi.org/10.1371/journal.pone.0054515 .
doi: 10.1371/journal.pone.0054515
pubmed: 23349914
pmcid: 3549980
Berghmans S, Hunt J, Roach A, Goldsmith P. Zebrafish offer the potential for a primary screen to identify a wide variety of potential anticonvulsants. Epilepsy Res. 2007;75:18–28. https://doi.org/10.1016/j.eplepsyres.2007.03.015 .
doi: 10.1016/j.eplepsyres.2007.03.015
pubmed: 17485198
Lawrence C, James A, Mobley S. Successful replacement of Artemia salina nauplii with Marine rotifers (Brachionus plicatilis) in the diet of preadult Zebrafish (Danio rerio). Zebrafish. 2015;12:366–71. https://doi.org/10.1089/zeb.2015.1118 .
doi: 10.1089/zeb.2015.1118
pubmed: 26107114
pmcid: 7366268
Hernandez RE, Galitan L, Cameron J, Goodwin N, Ramakrishnan L. Delay of initial feeding of zebrafish larvae until 8 days postfertilization has no impact on survival or growth through the juvenile stage. Zebrafish. 2018;15:515–8. https://doi.org/10.1089/zeb.2018.1579 .
doi: 10.1089/zeb.2018.1579
pubmed: 30089231
pmcid: 6198760
Leary S, Pharmaceuticals F, Underwood W, Anthony R, Cartner S, Johnson CL, et al. AVMA Guidelines for the Euthanasia of Animals: 2020 Edition 2020.
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. Br J Pharmacol. 2020;177:3617–24. https://doi.org/10.1111/bph.15193 .
doi: 10.1111/bph.15193
pubmed: 32662519
pmcid: 7393194
Pancotto L, Mocelin R, Marcon M, Herrmann AP, Piato A. Anxiolytic and anti-stress effects of acute administration of acetyl-L-carnitine in zebrafish. PeerJ. 2018;6: e5309. https://doi.org/10.7717/peerj.5309 .
doi: 10.7717/peerj.5309
pubmed: 30083453
pmcid: 6074796
Marcon M, Mocelin R, de Oliveira DL, da Rosa Araujo AS, Herrmann AP, Piato A. Acetyl-L-carnitine as a putative candidate for the treatment of stress-related psychiatric disorders: novel evidence from a zebrafish model. Neuropharmacology. 2019;150:145–52. https://doi.org/10.1016/j.neuropharm.2019.03.024 .
doi: 10.1016/j.neuropharm.2019.03.024
pubmed: 30917915
Fontana BD, Ziani PR, Canzian J, Mezzomo NJ, Müller TE, Dos Santos MM, et al. Taurine protects from pentylenetetrazole-induced behavioral and neurochemical changes in zebrafish. Mol Neurobiol. 2019;56:583–94. https://doi.org/10.1007/s12035-018-1107-8 .
doi: 10.1007/s12035-018-1107-8
pubmed: 29748917
Afrikanova T, Serruys A-SK, Buenafe OEM, Clinckers R, Smolders I, de Witte PAM, et al. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PloS One. 2013;8:e54166. https://doi.org/10.1371/journal.pone.0054166 .
doi: 10.1371/journal.pone.0054166
pubmed: 23342097
pmcid: 3544809
Friard O, Gamba M. BORIS: a free, versatile open-source event-logging software for video/audio coding and live observations. Methods Ecol Evol. 2016;7:1325–30. https://doi.org/10.1111/2041-210X.12584 .
doi: 10.1111/2041-210X.12584
Canzian J, Müller TE, Franscescon F, Michelotti P, Fontana BD, Costa FV, et al. Modeling psychiatric comorbid symptoms of epileptic seizures in zebrafish. J Psychiatr Res. 2019;119:14–22. https://doi.org/10.1016/j.jpsychires.2019.09.007 .
doi: 10.1016/j.jpsychires.2019.09.007
pubmed: 31542703
Kim Y, Lee Y, Lee H, Jung MW, Lee C. Impaired avoidance learning and increased hsp70 mRNA expression in pentylenetetrazol-treated zebrafish. Anim Cells Syst. 2009;13:275–81. https://doi.org/10.1080/19768354.2009.9647219 .
doi: 10.1080/19768354.2009.9647219
Kim Y-H, Lee Y, Lee K, Lee T, Kim Y-J, Lee C-J. Reduced neuronal proliferation by proconvulsant drugs in the developing zebrafish brain. Neurotoxicol Teratol. 2010;32:551–7. https://doi.org/10.1016/j.ntt.2010.04.054 .
doi: 10.1016/j.ntt.2010.04.054
pubmed: 20420900
Hong S, Lee P, Baraban SC, Lee LP. A novel long-term, multi-channel and non-invasive electrophysiology platform for zebrafish. Sci Rep. 2016;6:28248. https://doi.org/10.1038/srep28248 .
doi: 10.1038/srep28248
pubmed: 27305978
pmcid: 4910293
Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacology. 2020;168: 107966. https://doi.org/10.1016/j.neuropharm.2020.107966 .
doi: 10.1016/j.neuropharm.2020.107966
pubmed: 32120063
Pieróg M, Socała K, Doboszewska U, Wyska E, Guz L, Szopa A, et al. Effects of new antiseizure drugs on seizure activity and anxiety-like behavior in adult zebrafish. Toxicol Appl Pharmacol. 2021;427: 115655. https://doi.org/10.1016/j.taap.2021.115655 .
doi: 10.1016/j.taap.2021.115655
pubmed: 34329640
Uma Devi P, Pillai KK, Vohora D. Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine. Fundam Clin Pharmacol. 2006;20:247–53. https://doi.org/10.1111/j.1472-8206.2006.00401.x .
doi: 10.1111/j.1472-8206.2006.00401.x
pubmed: 16671959
Zaeri S, Emamghoreishi M. Acute and chronic effects of n-acetylcysteine on pentylenetetrazole-induced seizure and neuromuscular coordination in mice. Iran J Med Sci. 2015;40:118–24.
pubmed: 25821291
pmcid: 4359931
Tallarico M, Leo A, Guarnieri L, Zito MC, De Caro C, Nicoletti F, et al. N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy. Mol Neurobiol. 2022;59:2702–14. https://doi.org/10.1007/s12035-021-02720-3 .
doi: 10.1007/s12035-021-02720-3
pubmed: 35167014
Mason CR, Cooper RM. A permanent change in convulsive threshold in normal and brain-damaged rats with repeated small doses of Pentylenetetrazol*. Epilepsia. 1972;13:663–74. https://doi.org/10.1111/j.1528-1157.1972.tb04401.x .
doi: 10.1111/j.1528-1157.1972.tb04401.x
pubmed: 4563784
Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci. 2012;58:9371–93712. https://doi.org/10.1002/0471142301.ns0937s58 .
doi: 10.1002/0471142301.ns0937s58
Davoudi M, Shojaei A, Palizvan MR, Javan M, Mirnajafi-Zadeh J. Comparison between standard protocol and a novel window protocol for induction of pentylenetetrazol kindled seizures in the rat. Epilepsy Res. 2013;106:54–63. https://doi.org/10.1016/j.eplepsyres.2013.03.016 .
doi: 10.1016/j.eplepsyres.2013.03.016
pubmed: 23619005
Essawy AE, El-Sayed SA, Tousson E, Abd El-Gawad HS, Alhasani RH, Abd Elkader H-TAE. Anti-kindling effect of Ginkgo biloba leaf extract and L-carnitine in the pentylenetetrazol model of epilepsy. Environ Sci Pollut Res Int. 2022;29:48573–87. https://doi.org/10.1007/s11356-022-19251-6 .
doi: 10.1007/s11356-022-19251-6
pubmed: 35194715
pmcid: 9252962
Tashakori-Miyanroudi M, Ramazi S, Hashemi P, Nazari-Serenjeh M, Baluchnejadmojarad T, Roghani M. Acetyl-L-carnitine exerts neuroprotective and anticonvulsant effect in kainate murine model of temporal lobe epilepsy. J Mol Neurosci. 2022;72:1224–33. https://doi.org/10.1007/s12031-022-01999-8 .
doi: 10.1007/s12031-022-01999-8
pubmed: 35320462
Dhaliwal JS, Rosani A, Saadabadi A. Diazepam. Treasure Island: StatPearls Publishing; 2023.
Choo BKM, Kundap UP, Kumari Y, Hue S-M, Othman I, Shaikh MF. Orthosiphon stamineus leaf extract affects TNF-α and seizures in a zebrafish model. Front Pharmacol. 2018;9:139. https://doi.org/10.3389/fphar.2018.00139 .
doi: 10.3389/fphar.2018.00139
pubmed: 29527169
pmcid: 5829632
da Silva AW, Ferreira MKA, Rebouças EL, Mendes FRS, Dos S Moura AL, de Menezes JESA, et al. Anxiolytic-like effect of natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus in adult zebrafish via serotonergic neuromodulation involvement of the 5-HT system. Naunyn Schmiedebergs Arch Pharmacol. 2021;394:2023–32. https://doi.org/10.1007/s00210-021-02116-z .
doi: 10.1007/s00210-021-02116-z
pubmed: 34251503
Kumari S, Sharma P, Mazumder AG, Rana AK, Sharma S, Singh D. Development and validation of chemical kindling in adult zebrafish: a simple and improved chronic model for screening of antiepileptic agents. J Neurosci Methods. 2020;346: 108916. https://doi.org/10.1016/j.jneumeth.2020.108916 .
doi: 10.1016/j.jneumeth.2020.108916
pubmed: 32818549
Kundap UP, Kumari Y, Othman I, Shaikh MF. Zebrafish as a model for epilepsy-induced cognitive dysfunction: a pharmacological. Biochem Behav Approach Front Pharmacol. 2017;8:515. https://doi.org/10.3389/fphar.2017.00515 .
doi: 10.3389/fphar.2017.00515