Document Type : Original Research


1 Neurophysiology Research Center, Shahed University, Tehran, Iran

2 Dept. of Chemistry, Faculty of Science, Islamic Azad University, Karaj Branch, Iran

3 Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran


Background and Objective: N-Methyl-D-aspartate (NMDA) antagonists such as piperidines are the most important antiepileptic drugs. Considering the fact that piperidine derivatives such as phencyclidine (PCP) and its new derivative, 1-[1-(3-methoxyphenyl) (tetralyl)] piperidine (PCP1), have different potencies, the antiepileptic effects of mentioned drugs were investigated in the present study.
Methods: Fifty male mice weighing 25-30 g were randomly selected and divided into five experimental groups: 1- Control 2- Pentylentetrazole-kindled mice, 3- Positive control group which received valproate, and groups 4 and 5, which received PCP and PCP1, respectively. Kindling was down by 11 periods injection of PTZ every second day for 22 days. At the 12th injection, all kindled group were tested for PTZ challenge dose. The exhibited phases of seizure (0-6) were observed and noted till 30 minutes after PTZ injection. Finally, the malondialdehyde, superoxide dismutase and nitric oxide levels of the animal’s brain tissues were determined and compared with others.
Results: PCP1 could have a prominent anti-convulsion effect compared to PCP, especially in the reduction of phase 2 duration time and seizure score in challenge dose. Our additional experiments showed that there was a significant reduction in NO level in PCP1 treated animals.
Conclusion: Administration of the new piperidine derivate, PCP1 could have yielded a prominent anti-convulsion effect in grand epilepsy. Regarding to the changes in conformation of PCP1 as a non-competitive antagonist of NMDA receptor, it may block the NMDA receptors potentially more effectively than phencyclidine.


  1. Snow RW, Williams RE, Rogers JE, Mung'ala VO, Peshu N. The prevalence of epilepsy among a rural Kenyan population. Its association with premature mortality. Trop Geogr Med 1994 46(3)175-9.
  2. Chawla, S, Aneja S, Kashyap R, Mallika V. Etiology and clinical predictors of intractable epilepsy. Pediatr Neurol 2002;27:186-91.
  3. Ilhan A, Gurel A, Armutcu F, Kamilsi S, Iraz M. Antiepileptogenic and antioxidant effects of Nigella sativa oil against pentylentetrazole-induced kindling in mice. Neuropharm 2005;49:456-64.
  4. Bernard S, Chang MD, Daniel H, Lowenstien MD. Mechanisms of disease epilepsy. N Engl J Med 2003;349:1257-66.
  5. Krivoshein, AV, Hess GP. The mechanism of alleviation by phenobarbital of the malfunction of an epilepsy-linked GABA (A) receptor. Biochem 2006;45:11632-41.
  6. Honey CR, Miljkovic Z, McDonald JF. Ketamine and phencyclidine cause a voltage-dependent block of responses to L-aspartic acid. Neurosci Lett 1985;61:135-9.
  7. Chen G, Ensor CR, Russell D, Bohner B. The pharmacology of 1-(1-phenylcyclohexyl) piperidine.HCl. J Pharmacol Exp Ther 1959;127:241-50.
  8. Darvich MR, Zonoozi A. Preparation of the phencyclidine analogues (part II). Iran J Chem & Chem Eng 1993;2(1):17-20.
  9. Ahmadi A, Mahmoudi A. Synthesis with improved yield and study on analgesic effect of 2-methoxyphencyclidine. Arzneim-Forsch-Drug Res 2006;56(5):346-50.
  10. Al-deeb OA. New analgesic derived from the phencyclidine analogue thiencyclidine. Arzneim-Forsch-Drug Res 1996;46:505-8.
  11. Ogunbadeniyi AM, Adejare A. Syntheses of fluorinated phencyclidine analogs. J Fluo Chem 2002;114:39-42.
  12. Kamenka JM, Herrmann P. Determination conformationnelle de derives de la phencyclidine en vue d'une correlation acture-active. Eur J Med Chem-Therapeutica 1979; 14:301-8.
  13. Oliver CN, Starke-Reed PE, Stadtman ER, Lin GJ. Correy JM. Oxidative damage to brain proteins, loss of glutamine synthetase activity and production of free radicals during ischemia/reperfusion induced injury to gerbil brain. Proc Natl Acad Sci 1990;87:5144–7.
  14. Rauca C, Zerbe R, Janze H. Formation of free hydroxyl radicals after pentylentetrazol-induced seizure and kindling. Brain Res 1999;847:347-51.
  15. Buisson A, Lakhmeche N, Verrecchia C, Plotkine M, Boulu RG. Nitric oxide: an endogenous anticonvulsant substance. Neuroreport 1993;4:444–6.
  16. Theard MA, Baughman VL, Wang Q, Pelligrino DA, Albrecht RF. The role of nitric oxide in modulating brain activity and blood flow during seizure. Neuroreport 1995;6:921–4.
  17. Osonoe K, Mori N, Suzuki K, Osonoe M. Antiepileptic effects of inhibitors of nitric oxide synthase examined in pentylenetetrazol-induced seizures in rats. Brain Res 1994;663: 338–40.
  18. Nidhi G, Balakrishnan S, Pandhi P. Role of nitric oxide in electroshock and pentylenetetrazole seizure threshold in rats. Clin Pharmacol 1999;21:609–12.
  19. Ilhan A, Iraz M, Kamisli S, Yigitoglu R. Pentylenetetrazol-induced kindling seizure attenuated by Ginkgo biloba extract (EGb 761) in mice. Progress in Neuro-Psychopharm 2006;30:1504–10.
  20. Akbas SH, Yegin, A, Ozben T. Effect of pentylenetetrazol-induced epileptic seizure on the antioxidant enzyme activities, glutathione and lipid peroxidation levels in rat erythrocytes and liver tissues. Clin Biochem 2005;38:1009-14.
  21. Kim  HY, Yokozawa T, Cho EJ, Cheigh HS, Choi JS, Chung HY. In vitro and in vivo antioxidant effects of mustard leaf (Brassica juncea). Phytother Res 2003;17:465-71.
  22. Geneste P, Kamenka JM, Dessapt P. Method for Stereoselective Production of Substituted Cyclohexylcyanhydrines. Bull Soc Chim Fr 1980;2:187-91.
  23. Fernandez J, Perez-Alvarez JA, Fernandez-lopez JA. Thiobarbituric acid test for monitoring lipid oxidation in meat. Food Chem 1998;99:345–53.
  24. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 1990;36:1440-3.
  25. SunY, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clinic Chem 1988;34:497-500.
  26. Salat K, Moniczewski, A, Salat R, Janaszek M, Filipek B, Malawska B, Wieckowski K. Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice. Pharmacol Biochem Behav 2012;101(1):138-47.
  27. Luszczki JJ, Wojda E, Raszewski G, Głowniak K, Czuczwar SJ. Influence of imperatorin on the anticonvulsant activity and acute adverse-effect profile of lamotrigine in maximal electroshock-induced seizures and chimney test in mice. Pharmacol Rep 2008;60: 566-73.
  28. Boissier JR, Tardy J, Diverres JC. A new simple method to explore the tranquilizing action: a chimney test. Med Exp Basel 1960;3:81–4.
  29. Roth JE, Zhang G, Murray TF, Franklin, PH. Dextrorotatory opioids and phencyclidine exert anticonvulsant action in prepiriform cortex. Eur J Pharmacol 1992;14: 293-6.
  30. Ghasemi M, Shafaroodi H, Nazarbeiki S, Meskar H, Ghasemi A, Bahremand A, et al. Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice. Epilepsy Res 2010;91:39-48.
  31. Pullan LM. Receptor specific inhibition of N-methyl-d-aspartate stimulated Na flux from rat hippocampal slices by phencyclidine and other drugs. Neuropharm 1988;27(5):493-7.
  32. Loo PS, Braunwalder AF, Lehmann J, Williams M, Sills MA. Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. Mol Pharmacol 187;32(6):820-30.
  33. Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Ann Rev Physiol 1995;57:683-706.
  34. Vincent SR, Hope BT. Neurons that say NO. Trends Neuroscience 1992;15:108-12.
  35. Gaweł S, Wardas M, Niedworok E, Wardas P. Malondialdehyde (MDA) as a lipid peroxidation marker. Wiad Lek 2004;57:453-5.
  36. Jain S, Bharal N, Khurana S, Mediratta PK, Sharma KK. Anticonvulsant and antioxidant actions of trimetazidine in pentylenetetrazole-induced kindling model in mice. Naunyn Schmiedebergs Arch Pharmacol 2011;383(4):385-92.
  37. Tanaka DH, Toriumi K, Kubo K, Nabeshima T, Nakajima K. GABAergic precursor transplantation into the prefrontal cortex prevents phencyclidine-induced cognitive deficits. J Neurosci 2011;31(40):14116-25.
  38. Erakovic V, Zupan, G, Varljen, J, Simonic A. Pentylenetetrazol-induced seizures and kindling: changes in free fatty acids, superoxide dismutase, and glutathione peroxidase activity. Neurochem Int 2003;42(2):173-8.
  39. Obay BD, Taşdemir E, Tümer C, Bilgin HM, Atmaca M. Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model. Peptides 2008; 29(3):448-55.
  40. Khalili M, Kiasalari Z, Roghani M, Azizi Y. Anticonvulsant and antioxidant effect of hydroalcoholic extract of Cyperus rotundus rhizome on pentylentetrazole-induced kindling model in male mice. J Med Plants Res 2011;5(7):1140-6.