Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Evaluation of the anticonvulsant effect of tropinone derivatives

Tropinone 유도체의 항경련성 효과 평가

  • 김익수 (동아대학교 의과대학 생리학교실) ;
  • 서덕준 (동아대학교 의과대학 생리학교실)
  • Published : 2002.10.01
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of this study was to evaluate the anticonvulsant activity of four agents derived from tropinone (T-1: 2,4-dipyrrolylmethenylnortropinone, T-2: 2,4-diphenylmethenylnortropinone, T-3 : 2,4-difurfurylmethenylnortropinone, T-4 : 2,4-dimethoxyphenylmethenylnortropinone) in NIH Swiss mouse. Pentylenetetrazole (nZ) was injected via intraperi-toniurn in mouse and Maximal Electroshock (MES) stimulation was through both conjunctivas by electrodes. Tropinone derivatives were treated at 15 minutes before PTZ or MES procedure. PIZ of 25 mg/kg induced generalized seizure in mouse, effects of tropinone derivatives on PTZ-induced seizure were monitored. Compared with control group, T-4 decreased seizure grade most effectively. Also T-4 increased onset time of PTZ-induced seizure. This result showed that T-4 is most effective on PTZ-induced seizure. In MES-induced seizure, T-1 decreased seizure grade and recovery time. nNOS expression in hippocampus and cortex were increased in nZ- and MES-induced seizure animals compared with control. Pretreatment of tropinone derivatives in PTZ-induced seizure did not affected nNOS expression in brain tissues, but T-1 and T-4 decreased nNOS expression in cortex of MES-induced seizure animals. These findings suggest that tropinone derivatives have specific anticonvulsant activities according to PTZ- and MES-induced seizure. 2,4- dimethoxyphenylmethenylnoroopinone is most effective in PTZ-induced seizure and 2,4-di methoxyphenylmethenylnortropinone is most effective in MES-induced seizure.

생쥐에서 최근 합성된 4가지 종류의 tropinone유도체들의 항경련 효과를 조사하기 위하여 pentylenetetrazole (PTZ) 및 Maximal Electroshock (MES)로 유발된 경련에 tropinone 유도체들이 경련상태에 미치는 효과를 관찰하였다. Troponine 유도체로는 화학구조가 다른 4가지 종류를 사용하였다(T-1:2,4-dipywolylmethenylnortropinone, T-2:2,L di phenylme thenylnortropinone, T-3 : 2,Ldifurfurylmetheny- Inortropinone, 74 : 2,4-dimetho xyphenylmethenylnortro- pinone). nZ 25 mg/kg을 복강 내로 투여 후 전신성 경련을 유발하였으며 tropinone 유도체를 전처치한 후 PTZ에 의한 경련의 변화를 관찰하였다. 대조군에 비하여 T-1과 T-2는 경련정도에 변화가 없었으나 T-3과 T-4는 유의하게 경련정도를 약화시켰다. PTZ에 의한 경련의 시작 시간은 T-4에서 유의하게 지연되어 T-4가 PTZ에 의한 경련에 항경련 효과가 있음을 나타내었다. MES로 경련을 유발한 경우에 있어서는 T-1이 경련정도를 유의하게 약화시켰으며 경련 후 회복시간도 T-1에서 가장 빨리 회복되는 특성을 보였다. 따라서 T-1이 MES에 의한 경련유발에 항경련 효과가 있음을 나타내었다. Troponine 유도체에 의한 경련 억제 효과와 경련과 동반되어 증가한다고 알려진 neuronal nitric oxide synthase (nNOS) 발현과의 관계를 알아보기 위하여 조직 단백질에서 Western blot을 하였다. 대조군에 비하여 PTZ 및 MES에 의해 경련을 유발한 생쥐에서 모두 해마부 및 전뇌피질부에서 nNOS가 증가하였다. Tropinone 유도체를 투여하지 않고 경련을 유발시킨 대조군에 비하여 tropinone 유도체를 투여한 군에서도 모두 nNOS의 발현이 해마부 및 전뇌피질부에서 증가되었다. MES로 경련을 유발한 생쥐에서 대조군에 비하여 T-1 및 T-4는 피질부에서 nNOS가 감소했으나 나머지군에서는 감소가 없었다. 이 상의 결과를 토대로 tropinone 유도체들은 경련유발의 자극 조건에 따라 항경련 효과가 다르게 나타났으며, PTZ유 발경련에서 2,4-dimethoxyphenylmethenylnortropinone의 항경련 효과가 가장 크고, MES 유발경련에서는 2,4-dipyrrolylmethenylnortropinone의 항경련 효과가 가장 크게 나타났다.

Keywords

References

  1. Epilepsia v.21 Development of a new pharmacological seizure model: effects of anticonvulsants on cortical- and amygdala-kindled seizures in the rat Albright, P. S.;W. M. Burnhan https://doi.org/10.1111/j.1528-1157.1980.tb04321.x
  2. Anal Biochem v.72 A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding Bradford, M. https://doi.org/10.1016/0003-2697(76)90527-3
  3. Lancet v.336 Established anticonvulsants and the treatment of refractory epilepsy Brodie, M. J. https://doi.org/10.1016/0140-6736(90)91886-F
  4. NINCD Monography no.12 Costsworth, J. J.
  5. Brain Res Bull v.43 Anticonvulsant activity of new and potent inhibitors of nitric oxide synthase Dzoljic, E.;De Vries R.;M. R. Dzoljic https://doi.org/10.1016/S0361-9230(96)00437-6
  6. Neuroreport v.7 Regulation of neuronal nitric oxide synthase mRNA levels in rat brain by seizure activity Elmer E.;P. Alm;M. Kokaia;B. Larsson;M. Keep;K. E, Andersson;O. Lindvall https://doi.org/10.1097/00001756-199605170-00024
  7. J Pharm Sci v.72 Synthesis and structural study of N-substituted nortropane spirohydantoins Galvez E.;M., Martine;J., Gonzalez;G. G., Trigo;P., Smith-Verdier;F. Florencio;S. Garcia-Blanco https://doi.org/10.1002/jps.2600720811
  8. Experimental and Clinical Aspects Epidemiology of intractable epilepsy Juul-Jenson, P.;Schmidt, D.(ed.);P. L. Morselli(ed.)
  9. Drugs v.46 Place of newer anticonvulsant drugs in the treatment of epilepsy Kalviainen, R.;T. Keranen;P. J. Riekkinen https://doi.org/10.2165/00003495-199346060-00006
  10. J Med Chem. v.36 Synthesis and Anticonvulsant activity of α-acetamido-N-bezoyl acetamide derivatives Kohn, H.;K. N., Sawhley;P., Bardel;D. W. Robertson;J. D. Leander https://doi.org/10.1021/jm00074a016
  11. J Pharm Exp Ther v.288 Finasteride, a 5 α- reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice Kokate, T. G.;M. K., Banks;T., Magee;S. Yamaguchi;M. A. Rogawski
  12. Epilepsia v.19 Antiepileptic Drug Development Ⅱ. Anticonvulsant Drug Screening Krall, R. L.;J. K., Penry;B. G., White;H. J. Kupfererg;E. A. Swinyyard https://doi.org/10.1111/j.1528-1157.1978.tb04506.x
  13. Neurosci Biobehav Rev v.9 Anxiety anxiolytics and brain stimulation reinforcement Liebman, J. M. https://doi.org/10.1016/0149-7634(85)90033-8
  14. Epilepsy, Diagnosis Management Quality of Life Penry, J. K.
  15. Eur J Pharmacol v.274 Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats Rundfeldt, C.;R., Koch;A., Richter;M., Mevissen;U. Gerecke;W. Loscher https://doi.org/10.1016/0014-2999(94)00711-F
  16. Bull. World Health Organization v.71 Epidemiology of epilepsy in developing countries Senanayake, N.;G. C. Roman
  17. Lancet v.336 Epidemiology, classification, natural history, and genetics of epilepsy Shorvon, S. D. https://doi.org/10.1016/0140-6736(90)91603-8
  18. J Pharmacol Exp Ther v.51 Anticonvulsant properties of some benzodiazepines Swinyard, E. A.;A. W. Castellion
  19. Antiepileptic Drugs(3rd) General principles, experimental selection, quantification, and evaluation of anticonvulsants Swinyard, E. A.;J. H, Woodhead;H. S. White;M. R. Franklin;Levy, R.(ed.);R., Mattso (ed.);B., Meldrum(ed.);J. K. Penry(ed.);R. E. Dreifuss(ed.)
  20. J Pharm Sci v.70 PMR and 13C-NMR spectroscopy of tropane and N-substituted nortropane spirohydantoins Trigo, G. G.;M. Martinez;E. Galvez https://doi.org/10.1002/jps.2600700118
  21. Trends Pharmacol Sci v.15 Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings Upton, N. https://doi.org/10.1016/0165-6147(94)90059-0
  22. Anticonvulsant in principle of Medicinal Chemistry(4th eds.) Vida, J. A.;W. O., Foye;T. L. Lemke;D. A. Williams
  23. Brain Res v.654 Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after focal cerebral ischemia in rat Zhang, Z. G.;M., Chopp;S. Gautam;C., Zaloga;R. L.,Zhang;H. H., Schmidt;J. S. Pollock;Forstermann. U. https://doi.org/10.1016/0006-8993(94)91574-1