Mephedrone Impact on Matrix Metalloproteinases Activity - Do they Influence the Memory Processes?

Author(s): Anna Boguszewska-Czubara*, Jacek Kurzepa, Grażyna Biała, Katarzyna Kaszubska, Karolina Grot, Piotr Tarkowski, Joanna Kowalczyk, Serena Silvestro, Caterina Faggio, Barbara Budzyńska

Journal Name: Current Molecular Pharmacology

Volume 12 , Issue 2 , 2019

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Graphical Abstract:


Background: The use of drugs of addiction, as mephedrone, is associated with functional neuronal disorders due to remodeling of the nervous tissue. Key enzymes in remodeling are extracellular matrix (ECM) proteases like matrix metalloproteases (MMPs). Recently, MMPs have been of great interest as some studies point to a fact that the alterations in structural remodeling of synaptic connections modify learning-dependent changes, which remain active even after a prolonged period of abstinence. This entails a continuous development of dependence.

Objectives: The aim of the study was to determine the influence of subchronic exposure to three different doses of mephedrone on the activity of MMP-2 and 9 in hippocampus and prefrontal cortex and how this was correlated with memory processes in mice.

Methods: The homogenates of hippocampus and cortex were assayed for MMP-2 and MMP-9 activity by gelatin zymography. Memory consolidation processes were evaluated in the passive avoidance (PA) test.

Results: The study confirmed the dose-dependent increase in activity of MMP-2 and -9 exerted by subchronic administration of mephedrone. Moreover, the highest dose of mephedrone attenuated consolidation of memory and learning processes.

Conclusions: We could hypothesize that inhibition of MMPs can be considered as a therapeutic option for the treatment of addictive behaviors associated with cognitive processes. Moreover, further studies are required to find out if elevated activities of MMPs contribute to brain damage or recovery from brain damage caused directly by mephedrone.

Keywords: Mephedrone, mice, matrix metalloproteinases, memory, hippocampus, prefrontal cortex, cognitive processes.

U.S Drug Enforcement Administration. Drugs of Abuse 2017 Edition: A DEA Resource Guide; U.S. Dep. Justice, 2017, p. 94.
European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2017: Trends and Developments; Publications Office of the European Union, 2017.
The ESPAD Group. ESPAD Report 2015: Results from the European School Survey Project on Alcohol and Other Drugs; Publications Office of the European Union, 2016.
Baumann, M.H.; Solis, E.; Watterson, L.R.; Marusich, J.A.; Fantegrossi, W.E.; Wiley, J.L. Baths Salts, Spice, and Related Designer Drugs: The Science Behind the Headlines. J. Neurosci., 2014, 34(46), 15150-15158.
Schifano, F.; Corkery, J.; Ghodse, A.H. Suspected and Confirmed Fatalities Associated with Mephedrone (4-Methylmethcathinone, “Meow Meow”) in the United Kingdom. J. Clin. Psychopharmacol., 2012, 32(5), 710-714.
Schifano, F.; Albanese, A.; Fergus, S.; Stair, J.L.; Deluca, P.; Corazza, O.; Davey, Z.; Corkery, J.; Siemann, H.; Scherbaum, N.; Farre, M.; Torrens, M.; Demetrovics, Z.; Ghodse, H. Psychonaut Web Mapping; ReDNet Research Groups. Mephedrone (4-Methylmethcathinone; ‘Meow Meow’): Chemical, Pharmacological and Clinical Issues. Psychopharmacology (Berl.), 2011, 214(3), 593-602.
Lõpez-Arnau, R.; Martínez-Clemente, J.; Pubill, D.; Escubedo, E.; Camarasa, J. Comparative Neuropharmacology of Three Psychostimulant Cathinone Derivatives: Butylone, Mephedrone and Methylone. Br. J. Pharmacol., 2012, 167(2), 407-420.
Ramoz, L.; Lodi, S.; Bhatt, P.; Reitz, A.B.; Tallarida, C.; Tallarida, R.J.; Raffa, R.B.; Rawls, S.M. Mephedrone (“bath Salt”) Pharmacology: Insights from Invertebrates. Neuroscience, 2012, 208, 79-84.
Wood, D.M.; Davies, S.; Puchnarewicz, M.; Button, J.; Archer, R.; Ovaska, H.; Ramsey, J.; Lee, T.; Holt, D.W.; Dargan, P.I. Recreational Use of Mephedrone (4-Methylmethcathinone, 4-MMC) with Associated Sympathomimetic Toxicity. J. Med. Toxicol., 2010, 6(3), 327-330.
Kehr, J.; Ichinose, F.; Yoshitake, S.; Goiny, M.; Sievertsson, T.; Nyberg, F.; Yoshitake, T. Mephedrone, Compared with MDMA (Ecstasy) and Amphetamine, Rapidly Increases Both Dopamine and 5-HT Levels in Nucleus Accumbens of Awake Rats. Br. J. Pharmacol., 2011, 164(8), 1949-1958.
Angoa-Pérez, M.; Kane, M.J.; Francescutti, D.M.; Sykes, K.E.; Shah, M.M.; Mohammed, A.M.; Thomas, D.M.; Kuhn, D.M. Mephedrone, an Abused Psychoactive Component of “bath Salts” and Methamphetamine Congener, Does Not Cause Neurotoxicity to Dopamine Nerve Endings of the Striatum. J. Neurochem., 2012, 120(6), 1097-1107.
Pantano, F.; Tittarelli, R.; Mannocchi, G.; Pacifici, R.; di Luca, A.; Busardò, F.P.; Marinelli, E. Neurotoxicity Induced by Mephedrone: An up-to-Date Review. Curr. Neuropharmacol., 2017, 15(5), 738-749.
German, C.L.; Fleckenstein, A.E.; Hanson, G.R. Bath Salts and Synthetic Cathinones: An Emerging Designer Drug Phenomenon. Life Sci., 2014, 97(1), 2-8.
Establishment of Drug Codes for 26 Substances. Final Rule. Fed. Regist., 2013, 78(3), 664-666.
Den Hollander, B.; Rozov, S.; Linden, A.M.; Uusi-Oukari, M.; Ojanperä, I.; Korpi, E.R. Long-Term Cognitive and Neurochemical Effects of “Bath Salt” Designer Drugs Methylone and Mephedrone. Pharmacol. Biochem. Behav., 2013, 103(3), 501-509.
Baumann, M.H.; Drug, D.; Institutes, N.; Abuse, D.; Drive, C.; Bath, K. Awash in a Sea of “Bath Salts”: Implications for Biomedical Research and Public Health. Addiction, 2014, 109(10), 1577-1579.
Wood, D.M.; Dargan, P.I. Mephedrone (4-Methylmethcathinone): What Is New in Our Understanding of Its Use and Toxicity. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2012, 39(2), 227-233.
Lisek, R.; Xu, W.; Yuvasheva, E.; Chiu, Y.T.; Reitz, A.B.; Liu-Chen, L.Y.; Rawls, S.M. Mephedrone (‘bath Salt’) Elicits Conditioned Place Preference and Dopamine-Sensitive Motor Activation. Drug Alcohol Depend., 2012, 126(1-2), 257-262.
Baumann, M.H.; Ayestas, M.A.; Partilla, J.S.; Sink, J.R.; Shulgin, A.T.; Daley, P.F.; Brandt, S.D.; Rothman, R.B.; Ruoho, A.E.; Cozzi, N.V. The Designer Methcathinone Analogs, Mephedrone and Methylone, Are Substrates for Monoamine Transporters in Brain Tissue. Neuropsychopharmacology, 2012, 37(5), 1192-1203.
Martínez-Clemente, J.; López-Arnau, R.; Abad, S.; Pubill, D.; Escubedo, E.; Camarasa, J. Dose and Time-Dependent Selective Neurotoxicity Induced by Mephedrone in Mice. PLoS One, 2014, 9(6), e99002.
Di Chiara, G.; Bassareo, V. Reward System and Addiction: What Dopamine Does and Doesn’t Do. Curr. Opin. Pharmacol., 2007, 7(1), 69-76.
Meighan, P.C.; Meighan, S.E.; Davis, C.J.; Wright, J.W.; Harding, J.W. Effects of Matrix Metalloproteinase Inhibition on Short- and Long-Term Plasticity of Schaffer Collateral/CA1 Synapses. J. Neurochem., 2007, 102(6), 2085-2096.
Mizoguchi, H.; Yamada, K.; Niwa, M.; Mouri, A.; Mizuno, T.; Noda, Y.; Nitta, A.; Itohara, S.; Banno, Y.; Nabeshima, T. Reduction of Methamphetamine-Induced Sensitization and Reward in Matrix Metalloproteinase-2 and -9-Deficient Mice. J. Neurochem., 2007, 100(6), 1579-1588.
Boguszewska-Czubara, A.; Budzynska, B.; Skalicka-Wozniak, K.; Kurzepa, J. Perspectives and New Aspects of Metalloproteinases’ Inhibitors in Therapy of CNS Disorders: From Chemistry to Medicine. Curr. Med. Chem., 2018, 25.
Tsilibary, E.; Tzinia, A.; Radenovic, L.; Stamenkovic, V.; Lebitko, T.; Mucha, M.; Pawlak, R.; Frischknecht, R.; Kaczmarek, L. Neural ECM Proteases in Learning and Synaptic Plasticity. Prog. Brain Res., 2014, 214, 135-157.
Vandenbroucke, R.E.; Libert, C. Is There New Hope for Therapeutic Matrix Metalloproteinase Inhibition? Nat. Rev. Drug Discov., 2014, 13(12), 904-927.
Meyer, M.B.; Benkusky, N.A.; Onal, M.; Pike, J.W. Selective Regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through Distal Enhancers. J. Steroid Biochem. Mol. Biol., 2016, 164, 258-264.
Prystupa, A.; Boguszewska-Czubara, A.; Bojarska-Junak, A.; Toruń-Jurkowska, A.; Roliński, J.; Załuska, W. Activity of MMP-2, MMP-8 and MMP-9 in Serum as a Marker of Progression of Alcoholic Liver Disease in People from Lublin Region, Eastern Poland. Ann. Agric. Environ. Med., 2015, 22(2), 325-328.
Gołąb, P.; Boguszewska-Czubara, A.; Kiełbus, M.; Kurzepa, J. The RtPA Increases MMP-9 Activity in Serum during Ischaemic Stroke. Neurol. Neurochir. Pol., 2015, 48(5), 309-314.
Seong-Ryong Lee, Kiyoshi Tsuji, Sun-Ryung Lee, and E. H. Lo. Role of Matrix Metalloproteinases in Delayed Neuronal Damage after Transient Global Cerebral Ischemia. J. Neurosci., 2004, 24(3), 671-678.
Xu, T.; Liu, S.; Ma, T.; Jia, Z.; Zhang, Z.; Wang, A. Aldehyde Dehydrogenase 2 Protects against Oxidative Stress Associated with Pulmonary Arterial Hypertension. Redox Biol., 2017, 11, 286-296.
Lubbers, B.R.; Smit, A.B.; Spijker, S.; van den Oever, M.C. Neural ECM in Addiction, Schizophrenia, and Mood Disorder. Prog. Brain Res., 2014, 214, 263-284.
Zimmermann, D.R.; Dours-Zimmermann, M.T. Extracellular Matrix of the Central Nervous System: From Neglect to Challenge. Histochem. Cell Biol., 2008, 130(4), 635-653.
Frischknecht, R.; Chang, K-J.J.; Rasband, M.N.; Seidenbecher, C.I. Neural ECM Molecules in Axonal and Synaptic Homeostatic Plasticity. Prog. Brain Res., 2014, 214, 81-100.
Song, I.; Dityatev, A. Crosstalk between Glia, Extracellular Matrix and Neurons. Brain Res. Bull., 2018, 136, 101-108.
Brown, T.E.; Forquer, M.R.; Cocking, D.L.; Jansen, H.T.; Harding, J.W.; Sorg, B.A. Role of Matrix Metalloproteinases in the Acquisition and Reconsolidation of Cocaine-Induced Conditioned Place Preference. Learn. Mem., 2007, 14(3), 214-223.
Mizoguchi, H.; Yamada, K.; Mouri, A.; Niwa, M.; Mizuno, T.; Noda, Y.; Nitta, A.; Itohara, S.; Banno, Y.; Nabeshima, T. Role of Matrix Metalloproteinase and Tissue Inhibitor of MMP in Methamphetamine-Induced Behavioral Sensitization and Reward: Implications for Dopamine Receptor down-Regulation and Dopamine Release. J. Neurochem., 2007, 102(5), 1548-1560.
Nagy, V.; Bozdagi, O.; Huntley, G.W. The Extracellular Protease Matrix Metalloproteinase-9 Is Activated by Inhibitory Avoidance Learning and Required for Long-Term Memory. Learn. Mem., 2007, 14(10), 655-664.
Knapska, E.; Lioudyno, V.; Kiryk, A.; Mikosz, M.; Gorkiewicz, T.; Michaluk, P.; Gawlak, M.; Chaturvedi, M.; Mochol, G.; Balcerzyk, M.; Wojcik, D.; Wilczynski, F.; Kaczmarek, L. Reward Learning Requires Activity of Matrix Metalloproteinase-9 in the Central Amygdala. J. Neurosci., 2013, 33(36), 14591-14600.
Gorkiewicz, T.; Balcerzyk, M.; Kaczmarek, L.; Knapska, E. Matrix Metalloproteinase 9 (MMP-9) Is Indispensable for Long Term Potentiation in the Central and Basal but Not in the Lateral Nucleus of the Amygdala. Front. Cell. Neurosci., 2015, 9, 1-5.
Nagy, V.; Bozdagi, O.; Matynia, A.; Balcerzyk, M.; Okulski, P.; Dzwonek, J.; Costa, R.M.; Silva, A.J.; Kaczmarek, L.; Huntley, G.W. Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory. J. Neurosci., 2006, 26(7), 1923-1934.
Haorah, J.; Ramirez, S.H.; Schall, K.; Smith, D.; Pandya, R.; Persidsky, Y. Oxidative Stress Activates Protein Tyrosine Kinase and Matrix Metalloproteinases Leading to Blood-Brain Barrier Dysfunction. J. Neurochem., 2007, 101(2), 566-576.
Batra, A.; Latour, L.L.; Ruetzler, C.A.; Hallenbeck, J.M.; Spatz, M.; Warach, S.; Henning, E.C. Increased Plasma and Tissue MMP Levels Are Associated with BCSFB and BBB Disruption Evident on Post-Contrast FLAIR after Experimental Stroke. J. Cereb. Blood Flow Metab., 2010, 30(6), 1188-1199.
DeLarge, A.F.; Erwin, L.L.; Winsauer, P.J. Atypical Binding at Dopamine and Serotonin Transporters Contribute to the Discriminative Stimulus Effects of Mephedrone. Neuropharmacology, 2017, 119, 62-75.
Budzynska, B.; Boguszewska-Czubara, A.; Kruk-Slomka, M.; Kurzepa, J.; Biala, G. Mephedrone and Nicotine: Oxidative Stress and Behavioral Interactions in Animal Models. Neurochem. Res., 2015, 40(5), 1083-1093.
Tarkowski, P.; Jankowski, K.; Budzyńska, B.; Biała, G.; Boguszewska-Czubara, A. Potential Pro-Oxidative Effects of Single Dose of Mephedrone in Vital Organs of Mice. Pharmacol. Rep., 2018, 70, 1097-1104.
Samochowiec, A.; Grzywacz, A.; Kaczmarek, L.; Bienkowski, P.; Samochowiec, J.; Mierzejewski, P.; Preuss, U.W.; Grochans, E.; Ciechanowicz, A. Functional Polymorphism of Matrix Metalloproteinase-9 (MMP-9) Gene in Alcohol Dependence: Family and Case Control Study. Brain Res., 2010, 1327, 103-106.
Baumann, M.H.; Partilla, J.S.; Lehner, K.R. Psychoactive “Bath Salts”: Not so Soothing. Eur. J. Pharmacol., 2013, 698(1-3), 1-5.
Green, A.R.; King, M.V.; Shortall, S.E.; Fone, K.C.F. The Preclinical Pharmacology of Mephedrone; Not Just MDMA by Another Name. Br. J. Pharmacol., 2014, 171(9), 2251-2268.

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Article Details

Year: 2019
Published on: 14 January, 2019
Page: [115 - 121]
Pages: 7
DOI: 10.2174/1874467212666190114154307
Price: $65

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