|摘要(英)||2C-T-2 (2,5–dimethoxy–4–ethylthio- phenethylamine), a psychoactive drug, is a ring-substituted phenethylamine derivative that exerts psychological effects including changes in mood, cognition, and behavior. It had been reported that psychoactive drugs caused the health problems if there were abused intake. The previously studies indicated that oral intake 2C-T-2 suppressed the nitric oxide production of mitogen-stiumated splenocytes in mice. However, little information is available concerning its bioactivity and immunomodulatory activity. In this study, the metabolic kinetic and immunomodulatory effects of 2C-T2 after single or repeated oral intake are examined and characterized used the mice animal model. In addition, the neuroendocrine-mediated mechanism(s) of 2C-T-2-induced immunosuppression was also examined. Results indicated that the level of 2C-T-2 in the peripheral blood was firstly detected at 30 minutes after intake, and 6 hours later, the level of 2C-T-2 was metabolic clear and less than detectable amount. In parallel, 2C-T-2 oral intake also increased the level of corticosterone in blood plasma. The results of single intake 2C-T-2 on immune activities indicated that 2C-T-2 induced the decrease the distribution of T, B, and NK cell populations in peripheral blood. And the ability of phagocytosis in leukocytes was suppressed significantly after 2C-T-2 oral intake 6 hours. 2C-T-2 also induced the suppression of mitogen-stimulated proliferation and nitric oxide in spleen and thymus. In addition, the production of IL-1β, IL-6, TNF-α, IFN-γ, IL-4, and IL-10 cytokines from LPS or Con A-stimulated splenocytes were significantly decreased after 2C-T-2 oral intake. However, 2C-T-2 intake significantly increased the IL-2 and TGF-β1 production. Repeated 2C-T-2 intake induced the immunosuppression on production of nitric oxide, IL-1β, IL-6, TNF-α, IL-4, IL-10, and TGF-β1, but no change on leukocytes subpopulation number, proliferation and production of IL-2 and IFN-γ. Furthermore, in this study, we observed that in vitro exposure to 2C-T-2 did not alter LPS-stimulated nitric oxide production. This data indicate that the ability of 2C-T-2 to suppress the production of nitric oxide and cytokine production is not due to a direct action on immune cells. Interestingly, administrated nodolol, a β-adrenoceptor blockade, or epinephrine attenuated the decrease in nitric oxide production induced by 2C-T-2 oral intake. In summary, these data demonstrate that 2C-T-2 intake induce the suppression effect on immune activities of mice. However, further studies are needed to elucidate the exact mechanisms that underlie 2C-T-2 induced suppression of nitric oxide and cytokine production.|
Ashok BK, Tamizchelvi T, Letterio JJ. Function of cytokine within the TGF-β superfamily as determined from transgenic and gene knockout studies in mice. Curr Mol Med. 2002; 2(3): 303- 327
Ben-Sasson SZ, Kagan J. Antigen-induced proliferation of murine T-lymphocytes in vitro. II. The effect of different macrophage populations on the antigen-induced proliferative response. J Immunol Methods. 1981; 41(3):321-31.
Black MD, Simmonds J, Senyah Y, Wettstein JG. Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs. Neuropharmacology. 2002; 42: 414-420.
de Boer D, Bosman I. A new trend in drugs-of-abuse; the 2C-series of phenethylamine designer drugs. Pharm World Sci. 2004 Apr;26(2):110-3.
Bogdan C, Nathan C. Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10.
Ann N Y Acad Sci. 1993 Jun 23;685:713-39.
Braun U, Shulgin AT, Braun G. Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylene- dioxyamphetamine). J Pharm Sci. 1980; 69: 192-195.
Chiu YC, Chou SH, Liu JT, Lin CH. The bioactivity of 2,5-dimethoxy-4-ethylthiophenthylamine（2C-T-2）and its detection in rat urine by capillary electrophoresis combined with an online sample concentration technique. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 811: 127-133.
Chou SH, Kojic LD, Messingham KN, Cunnic JE. Characterization of the effect of 2-deoxy-D-glucose (2-DG) on the immune system.
Brain Behav Immun. 1996 Dec;10(4):399-416.
Chou SH, Kojic LD, Cunnick JE. Evidence for the involvement of catecholamines in the 2-DG-induced immunomodulatory deffects in spleen. Brain Behav Immun. 1997; 11: 79-93
Connor TJ, Dennedy MC, Harkin A, Kelly JP. Methylenedioxymethamphetamine- induced suppression of interleukin-1β and tumour necrosis factor-α is not mediated by serotonin. Eur J Pharmacol. 2001; 418: 147-152.
Connor TJ., Kelly JP., McGee M., Leonard BE., Methylenedioxymethamphetamine （MDMA；”Ecstasy”） suppresses IL-1β and TNF-α secretion following an in vivo lipopolysaccharide challenge. Life Sci. 2002; 67: 1601-1612.
Connor TJ, Harkin A, Kelly JP. Methylenedioxymethamphetamine（MDMA,‘Ecstasy’）increases LPS-induced IL-10 production via β-adrenoceptor activation. Eur Cytokine Netw. 2003; 4（Suppl.）: 47
Connor TJ. Methylenedioxymethamphetamine（MDMA,‘Ecstasy’）：a stressor on the immune system. Immunology. 2004; 111: 357-367.
Connor TJ, Harkin A, Kelly JP. Methylenedioxymethamphetamine suppresses production of the proinflammatory cytokine tumor necrosis factor-α independent of a β-adrenoceptor-mediated increase in interleukin-10. J Pharmacol Exp Ther. 2005; 312: 134-143.
Cunnick JE, Lysle DT, Kucinski BJ, Rabin BS. Evidence that shock-induced immune suppression is mediated by adrenal hormone and peripheral β-adrenergic receptor. Pharmacol Biochem Behav. 1990; 36: 645-651.
Dubovsky SL and Thomas M. Beyond specificity: effects of serotonin and serotonergic treatments on psychobiological dysfunction. J Psychosom Res. 1995; 39: 429-444.
Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulation effects of glucorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians. 1996; 108: 374-381.
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000 Dec;52(4):595-638.
Felipe A, Long-hai Z, Martin K, Richard L, Epinephrine promotes pulmonary angiitis：evidence for a β1-adrenoreceptor-mediated mechanism. J Physiol Lung Cell Mol Physiol. 2003; 285: L232-L239.
Gagnon L, Lacroix F, Chan J, Buttar HS. In vitro effect of “designer” amphetamines on human peripheral blood mononuclear leukocytes proliferation and on natural killer cell activity. Toxicol Lett. 1992; 63: 319-319.
Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJ, Knowles RG. 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J Biol Chem. 1997; 272(8): 4959-4963.
Gerlier D and Thomasset N. Use of MTT colorimetric assay to measure cell activation. J Immunol Methods. 1986; 94(1-2): 57-63.
Gibb J, Johnson M, Hanson G. Neurochemical basis of neurotoxicity. Neurotoxicology. 1990; 11: 317-321.
Glaser R, Lafuse WP, Bpnneau RH, Atkinson B, Kiecolt-Glaser JK. Stress-associated modulation pf proto-oncogen expression in human peripheral blood leukocytes. Behav Neurosci. 2003; 107: 525-529.
Glaser R, Pearson GR, Bonneau RH, Esterling BA, Atkinson C, Kiecolt-Glaser JK. Stress and the memory T-cell response to the Epstein-Barr virus in healthy medical students. Health Psychol. 1993; 12(6):435-442.
Gonzalo A, Carrasco, Louis D, Van de Kar. Neuroendocrine pharmacology of stress. Eur J Pharmacol. 2003; 463: 235-272.
Habrdova V, Peters FT, Theobald DS, Maurer HH. Screening for and validated quantification of phenethylamine-type designer drugs and mescaline in human blood plasma by gas chromatography/mass spectrometry. J Mass Spectrom. 2005 Jun;40(6):785-95.
House R, Thomas P, Bhargava H. Comparison of immune functional parameters following in vitro exposure to natural and synthetic amphetamines. Immunopharmacol Immunotoxicol. 1994; 16(1): 1-21.
House RV, Thomas PT, Bhargava HN. Selective modulation of immune function resulting from in vitro exposure to methylenedioxymethamphetamine (Ecstasy). Toxicology. 1995; 96: 59-69.
Kanamori T, Inoue H, Iwata Y, Ohmae Y, Kishi T. In vivo metabolism of 4-bromo-2,5-dimethoxyphenethylamine（2C-B）in the rat：identification of urinary metabolites. J Anal Toxicol. 2002; 26(2); 61-66.
Kubera M, Filip M, Basta-Kaim A, Nowak E, Budziszewska B, Tetich M, Holan V, Korzeniak B, Przegalinski E, The effect of amphetamine sensitization on mouse immunoreactivity. J Physiol Pharmacol. 2002; 53: 233-242.
Le Gros G, Ben-Sasson SZ, Sender R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4) -producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990; 172: 921-929.
Lin LC, Liu JT, Chou SH, Lin CH. Identification of 2,5-dimethoxy-4-ethylthioph-enethylamine and its metabolites in the urine of rats by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 12991: 1-7.
Lisbon. Report on the Risk Assessment of 2C-T-2 in the Framework of the Joint Action on New Synthetic Drugs, 2003; 1-7.
McCardle K, Luebbers S, Carter JD, Croft RJ and Stough C. Chronic MDMA (ecstasy) use, cognition and mood. Psychopharmacology (Berl). 2004; 173: 434-439.
Nash JF Jr, Meltzer HY, Gudelsky GA. Elevation of serum prolactin and corticosterone concentrations in the rat after the administration of 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther. 1988 Jun;245(3):873-9.
Nichols DE. Medicinal chemistry and structure-activity relationships, in Cho, AK., and Segal, DS.,(eds) amphetamine and its analogs, Academic Press, San Diego, 1994, 3-41
Nunez-Iglesias MJ, Castro-Bolano C, Pereiro-Raposo MD, Riveiro P, Sancheez-Sebio P, Mayan-Santos JM, Rey- Mendez M, Freire-Garabal M. Effects of amphetamine on cell mediated immune response in mice. Life Sci. 1996; 58: PL 29-33.
Pezzone MA, Rush KA, Kusnecov AW, Wood PG, Rabin BS. Corticosterone-independent alteration of lymphocyte mitogenic function by amphetamine. Brain Behav Immun. 1992; 6: 293-299.
Savino W, Dardenne M. Immune-neuroendocrine interactions. Immunol Today. 1995; 16(7): 318-322.
Scott P, Kaufmann SHE. The role of T-cell subsets and cytokines in the regulation of infection. Immunol Today. 1991; 12: 346-348.
Shulgin A. A Chemical Love Story, PiHKAL, Fifth Ed, 2000; 577.
Stuehr DJ, Nathan CF. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989; 169(5): 1543-1555.
Theobald DS, Staack RF, Puetz M, Maurer HH. New designer drug 2,5-dimethoxy-4-ethylthio-beta-phenethylamine (2C-T-2): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry. J Mass Spectrom. 2005 Sep; 40(9):1157-72.
Thomsen LL, Scott JM, Topley P, Knowles RG, Keerie AJ, Frend AJ. Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. Cancer Res. 1997; 57(15): 3300-3304.
Tsai CC, Liu JT, Shu YR, Chan PH, Lin CH. Optimization of the separation and on-line sample concentration of phenethylamine designer drugs with capillary electrophoresis-fluorescence detection. J Chromatogr A. 2006 Jan 6;1101(1-2):319-23.
Zhou JF, Zhou YH, Zhang L, Chen HH, Cai D. 3,4-methylenedioxymethamphetamine (MDMA) abuse markedly inhibits acetylcholinesterase activity and induces severe oxidative damage and liperoxidative damage. Biomed Environ Sci. 2003; 16(1): 53-61.