Analysis of the effectiveness and risk benefit of N acetyl cysteine compared to ceftriaxone in the expression of GLT1 transporters.
DOI:
https://doi.org/10.19136/mh5ganthff096cdKeywords:
Ceftriaxone, GLT-1, N-Acetylcysteine, ExpressionAbstract
The concentration of glutamate in the synaptic cleft is regulated primarily by glutamate transporters, especially by the glial glutamate-specific transporter type 1 (GLT-1). Ceftriaxone (CTX), a β-lactam antibiotic, has been reported to significantly increase GLT-1 expression. N-acetylcysteine as a derivative of cysteine, is oxidized into cystine within the brain, increasing the availability of cystine for the glial cystine-glutamate exchanger, this action increases the amount of glutamate exchanged by glial cells, raising the concentration of glutamate within the extra-synaptic space and effectively promoting GLT-1 transcription. It is suspected that the β-lactam antibiotic ceftriaxone is more effective than N-acetylcysteine in upregulating GLT-1 expression. We conducted a systematic review to investigate the effectiveness of the drugs N-acetylcysteine and ceftriaxone with respect to their effect on increasing the expression of GLT-1 transporters in experimental studies. This systematic review was carried out with methodology in accordance with the Cochrane Handbook and reporting consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The main objective of this work is to determine the difference in effectiveness of N-acetylcysteine compared to Ceftriaxone in the expression of the GLT-1 transporter. A clear superiority is shown by ceftriaxone, because by itself it can induce an increase in the levels of these proteins either in circumstances where the glutamatergic flux is affected or in control groups, in contrast to N-acetylcysteine. which improves the expression of these transporters only when there is a deficit in the levels of GLT-1.
References
Duailibi, M. S., Cordeiro, Q., Brietzke, E., Ribeiro, M., LaRowe, S., Berk, M., & Trevizol, A. P. (2017). N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis. The American Journal on Addictions, 26(7), 660–666. https://doi.org/10.1111/AJAD.12620
Fan, S., Xian, X., Li, L., Yao, X., Hu, Y., Zhang, M., & Li, W. (2018). Ceftriaxone Improves Cognitive Function and Upregulates GLT-1-Related Glutamate-Glutamine Cycle in APP/PS1 Mice. Journal of Alzheimer’s Disease, 66(4), 1731–1743. https://doi.org/10.3233/JAD-180708
Gao, J., Liu, L., Liu, C., Fan, S., Liu, L., Liu, S., Xian, X.-H., & Li, W.-B. (2020a). GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice. Frontiers in Aging Neuroscience, 0, 318. https://doi.org/10.3389/FNAGI.2020.580772
Gao, J., Liu, L., Liu, C., Fan, S., Liu, L., Liu, S., Xian, X.-H., & Li, W.-B. (2020b). GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice. Frontiers in Aging Neuroscience, 12. https://doi.org/10.3389/FNAGI.2020.580772
Hajhashemi, V., Hosseinzadeh, H., & Amin, B. (2013). Antiallodynia and antihyperalgesia effects of ceftriaxone in treatment of chronic neuropathic pain in rats. Acta Neuropsychiatrica, 25(1), 27–32. https://doi.org/10.1111/J.1601-5215.2012.00656.X
Israel, Y., Quintanilla, M. E., Ezquer, F., Morales, P., Santapau, D., Berríos-Cárcamo, P., Ezquer, M., Olivares, B., & Herrera-Marschitz, M. (2019). Aspirin and N-acetylcysteine co-administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation-oxidative stress self-perpetuation. Addiction Biology, 26(1). https://doi.org/10.1111/ADB.12853
Israel, Y., Quintanilla, M. E., Ezquer, F., Morales, P., Santapau, D., Berríos-Cárcamo, P., Ezquer, M., Olivares, B., & Herrera-Marschitz, M. (2021). Aspirin and N-acetylcysteine co-administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation-oxidative stress self-perpetuation. Addiction Biology, 26(1). https://doi.org/10.1111/ADB.12853
Knackstedt, L. A., Melendez, R. I., & Kalivas, P. W. (2010a). Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking. Biological Psychiatry, 67(1), 81–84. https://doi.org/10.1016/J.BIOPSYCH.2009.07.018
Knackstedt, L. A., Melendez, R. I., & Kalivas, P. W. (2010b). Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking. Biological Psychiatry, 67(1), 81–84. https://doi.org/10.1016/J.BIOPSYCH.2009.07.018
Krzyzanowska, W., Pomierny, B., Budziszewska, B., Filip, M., & Pera, J. (2016a). N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression. Neurotoxicity Research 2016 29:4, 29(4), 539–550. https://doi.org/10.1007/S12640-016-9602-Z
Krzyzanowska, W., Pomierny, B., Budziszewska, B., Filip, M., & Pera, J. (2016b). N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression. Neurotoxicity Research, 29(4), 539. https://doi.org/10.1007/S12640-016-9602-Z
Krzyżanowska, W., Pomierny, B., Bystrowska, B., Pomierny-Chamioło, L., Filip, M., Budziszewska, B., & Pera, J. (2017a). Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia. PLOS ONE, 12(10), e0186243. https://doi.org/10.1371/JOURNAL.PONE.0186243
Krzyżanowska, W., Pomierny, B., Bystrowska, B., Pomierny-Chamioło, L., Filip, M., Budziszewska, B., & Pera, J. (2017b). Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia. PLOS ONE, 12(10), e0186243. https://doi.org/10.1371/JOURNAL.PONE.0186243
Lebourgeois, S., González-Marín, M. C., Antol, J., Naassila, M., & Vilpoux, C. (2019). Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats. Neuropharmacology, 150, 112–120. https://doi.org/10.1016/J.NEUROPHARM.2019.03.010
Lee, S.-G., Su, Z.-Z., Emdad, L., Gupta, P., Sarkar, D., Borjabad, A., Volsky, D. J., & Fisher, P. B. (2008). Mechanism of Ceftriaxone Induction of Excitatory Amino Acid Transporter-2 Expression and Glutamate Uptake in Primary Human Astrocytes. The Journal of Biological Chemistry, 283(19), 13116. https://doi.org/10.1074/JBC.M707697200
Logan, C. N., Bechard, A. R., Hamor, P. U., Wu, L., Schwendt, M., & Knackstedt, L. A. (2020). Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats. Psychopharmacology 2020 237:7, 237(7), 2007–2018. https://doi.org/10.1007/S00213-020-05514-Y
Luo, X., He, T., Wang, Y., Wang, J.-L., Yan, X.-B., Zhou, H.-C., Wang, R.-R., Du, R., Wang, X.-L., Chen, J., & Huang, D. (2020a). Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn. Frontiers in Cellular Neuroscience, 0, 199. https://doi.org/10.3389/FNCEL.2020.00199
Luo, X., He, T., Wang, Y., Wang, J.-L., Yan, X.-B., Zhou, H.-C., Wang, R.-R., Du, R., Wang, X.-L., Chen, J., & Huang, D. (2020b). Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn. Frontiers in Cellular Neuroscience, 14. https://doi.org/10.3389/FNCEL.2020.00199
MA, N. E., T, A. R., G, R. C., V, S. S., DX, da S., & TM, F. (2017). N-acetylcysteine for treating cocaine addiction - A systematic review. Psychiatry Research, 251, 197–203. https://doi.org/10.1016/J.PSYCHRES.2017.02.024
Matos-Ocasio, F., Hernández-López, A., & Thompson, K. J. (2014). Ceftriaxone, a GLT-1 transporter activator, disrupts hippocampal learning in rats. Pharmacology Biochemistry and Behavior, 122, 118–121. https://doi.org/10.1016/J.PBB.2014.03.011
Namba, M. D., Kupchik, Y. M., Spencer, S. M., Garcia-Keller, C., Goenaga, J. G., Powell, G. L., Vicino, I. A., Hogue, I. B., & Gipson, C. D. (2020). Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine-seeking behavior. Addiction Biology, 25(5), e12797. https://doi.org/10.1111/ADB.12797
Nicholson, K. J., Gilliland, T. M., & Winkelstein, B. A. (2014). Upregulation of GLT-1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability. Journal of Neuroscience Research, 92(1), 116–129. https://doi.org/10.1002/JNR.23295
Notartomaso, S., Scarselli, P., Mascio, G., Liberatore, F., Mazzon, E., Mammana, S., Gugliandolo, A., Cruccu, G., Bruno, V., Nicoletti, F., & Battaglia, G. (2020). N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy: Https://Doi.Org/10.1177/1744806920904292, 16. https://doi.org/10.1177/1744806920904292
Quintanilla, E., Rivera-Meza, M., Berr Ios-C Arcamo, P., Salinas-Luypaert, C., Herrera-Marschitz, M., & Israel, Y. (2016). Beyond the “First Hit”: Marked Inhibition by N-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation. https://doi.org/10.1111/acer.13031
Quintanilla, M. E., Morales, P., Ezquer, F., Ezquer, M., Herrera-Marschitz, M., & Israel, Y. (2021). Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats. Frontiers in Behavioral Neuroscience, 0, 284. https://doi.org/10.3389/FNBEH.2020.617418
Quintanilla, M. E., Rivera-Meza, M., Berríos-Cárcamo, P., Salinas-Luypaert, C., Herrera-Marschitz, M., & Israel, Y. (2016). Beyond the “First Hit”: Marked Inhibition by N-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation. Alcoholism: Clinical and Experimental Research, 40(5), 1044–1051. https://doi.org/10.1111/ACER.13031
Ramandi, D., Salmani, M. E., Moghimi, A., Lashkarbolouki, T., & Fereidoni, M. (2021). Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy. PLOS ONE, 16(1), e0246068. https://doi.org/10.1371/JOURNAL.PONE.0246068
Ramos, K. M., Lewis, M. T., Morgan, K. N., Crysdale, N. Y., Kroll, J. L., Taylor, F. R., Harrison, J. A., Sloane, E. M., Maier, S. F., & Watkins, L. R. (2010). Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. Neuroscience, 169(4), 1888. https://doi.org/10.1016/J.NEUROSCIENCE.2010.06.014
Roberts-Wolfe, D. J., & Kalivas, P. W. (n.d.). Glutamate transporter GLT-1 as a therapeutic target for substance use disorders.
Roberts-Wolfe, D. J., & Kalivas, P. W. (2015). Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS & Neurological Disorders Drug Targets, 14(6), 745. /pmc/articles/PMC4730383/
Saeedi, N., Darvishmolla, M., Tavassoli, Z., Davoudi, S., Heysieattalab, S., Hosseinmardi, N., Janahmadi, M., & Behzadi, G. (2021). The role of hippocampal glial glutamate transporter (GLT-1) in morphine-induced behavioral responses. Brain and Behavior. https://doi.org/10.1002/BRB3.2323
Sari, Y., Prieto, A. L., Barton, S. J., Miller, B. R., & Rebec, G. V. (2010). Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington’s disease. Journal of Biomedical Science 2010 17:1, 17(1), 1–5. https://doi.org/10.1186/1423-0127-17-62
Sci-Hub | Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats. Neuropharmacology | 10.1016/j.neuropharm.2019.03.010. (n.d.). Retrieved August 29, 2021, from https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0028390819300875?via%3Dihub
Siemsen, B. M., Reichel, C. M., Leong, K. C., Garcia-Keller, C., Gipson, C. D., Spencer, S., McFaddin, J. A., Hooker, K. N., Kalivas, P. W., & Scofield, M. D. (2019). Effects of Methamphetamine Self-Administration and Extinction on Astrocyte Structure and Function in the Nucleus Accumbens Core. Neuroscience, 406, 528–541. https://doi.org/10.1016/J.NEUROSCIENCE.2019.03.040
Smaga, I., Fierro, D., Mesa, J., Filip, M., & Knackstedt, L. A. (2020). Molecular changes evoked by the beta-lactam antibiotic ceftriaxone across rodent models of substance use disorder and neurological disease. Neuroscience & Biobehavioral Reviews, 115, 116–130. https://doi.org/10.1016/J.NEUBIOREV.2020.05.016
Soni, N., Reddy, B. V. K., & Kumar, P. (2014). GLT-1 transporter: An effective pharmacological target for various neurological disorders. Pharmacology Biochemistry and Behavior, 127, 70–81. https://doi.org/10.1016/J.PBB.2014.10.001
Tai, C. H., Bellesi, M., Chen, A. C., Lin, C. L., Li, H. H., Lin, P. J., Liao, W. C., Hung, C. S., Schwarting, R. K., & Ho, Y. J. (2019). A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects. Behavioural Brain Research, 364, 149–156. https://doi.org/10.1016/J.BBR.2019.02.020
Trantham-Davidson, H., LaLumiere, R. T., Reissner, K. J., Kalivas, P. W., & Knackstedt, L. A. (2012). Ceftriaxone Normalizes Nucleus Accumbens Synaptic Transmission, Glutamate Transport, and Export following Cocaine Self-Administration and Extinction Training. Journal of Neuroscience, 32(36), 12406–12410. https://doi.org/10.1523/JNEUROSCI.1976-12.2012
Wilkie, C. M., Barron, J. C., Brymer, K. J., Barnes, J. R., Nafar, F., & Parsons, M. P. (2021a). The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics. Frontiers in Cellular Neuroscience, 15, 661412. https://doi.org/10.3389/FNCEL.2021.661412
Wilkie, C. M., Barron, J. C., Brymer, K. J., Barnes, J. R., Nafar, F., & Parsons, M. P. (2021b). The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics. Frontiers in Cellular Neuroscience, 15, 661412. https://doi.org/10.3389/FNCEL.2021.661412
Wilkie, C. M., Barron, J. C., Brymer, K. J., Barnes, J. R., Nafar, F., & Parsons, M. P. (2021c). The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics. Frontiers in Cellular Neuroscience, 15, 661412. https://doi.org/10.3389/FNCEL.2021.661412
Wright, D J, Renoir, T., Smith, Z. M., Frazier, A. E., Francis, P. S., Thorburn, D. R., McGee, S. L., Hannan, A. J., & Gray, L. J. (2015). N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington’s disease. Translational Psychiatry, 5(1), e492. https://doi.org/10.1038/TP.2014.131
Wright, Dean J., Gray, L. J., Finkelstein, D. I., Crouch, P. J., Pow, D., Pang, T. Y., Li, S., Smith, Z. M., Francis, P. S., Renoir, T., & Hannan, A. J. (2016). N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington’s disease. Human Molecular Genetics, 25(14), 2923–2933. https://doi.org/10.1093/HMG/DDW144
X, L., T, H., Y, W., JL, W., XB, Y., HC, Z., RR, W., R, D., XL, W., J, C., & D, H. (2020). Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn. Frontiers in Cellular Neuroscience, 14. https://doi.org/10.3389/FNCEL.2020.00199
Zhao, Z., Hiraoka, Y., Ogawa, H., & Tanaka, K. (2018). Region-specific deletions of the glutamate transporter GLT1 differentially affect nerve injury-induced neuropathic pain in mice. Glia, 66(9), 1988–1998. https://doi.org/10.1002/GLIA.23452
Zumkehr, J., Rodriguez-Ortiz, C. J., Cheng, D., Kieu, Z., Wai, T., Hawkins, C., Kilian, J., Lim, S. L., Medeiros, R., & Kitazawa, M. (2015). Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiology of Aging, 36(7), 2260–2271. https://doi.org/10.1016/J.NEUROBIOLAGING.2015.04.005
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