The Neuroprotective Effect of a Triazine Derivative in an Alzheimer's Rat Model

  • Fatemeh Alipour Shafa Neuroscience Research Center, Tehran, Iran. AND Department of Animal Physiology, Faculty of Biological Sciences, Tehran University of Medical Sciences, Tehran, Iran.
  • Shahrbanoo Oryan Department of Animal Physiology, Faculty of Biological Sciences, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Sharifzadeh Department of Pharmacology and Toxicology, School of Pharmacy, Tehran University of Medical Sciences, Tehran Iran.
  • Fariba Karimzadeh Shafa Neuroscience Research Center, Tehran, Iran. AND Department of Neuroscience,School of Advanced Medical Technology, Tehran University of Medical Sciences, Tehran, Iran.
  • Laya Kafami Shafa Neuroscience Research Center, Tehran, Iran. AND Department of Pathobiology, School of Medicine, Alborz University of Medical Sciences, Alborz, Iran.
  • Hamid Irannejad Department of Medicinal Chemistry, School of Pharmacy, Mazandaran University of Medical Sciences, Mazandaran, Iran.
  • Mohsen Amini Department of Medicinal Chemistry, Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Gholamreza Hassanzadeh Mail Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Triazine, Learning, Alzheimers disease


Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. It is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain, degeneration of the cholinergic neurons and neural cell death. This study was aimed to investigate the effect of a triazine derivative, C16H12Cl2N3S, on learning in an Alzheimer's rat model. Animals were divided into seven groups; each group contained seven animals.animals received no surgery and treatment; saline group: animals received normal saline after recovery; sham group: animals received 10% DMSO after recovery; STZ group (Alzheimer's model): animals received streptozotocin (STZ) in four and six days after recovery; T5, T10 and T15 groups: animals were treated with triazine derivative, C16H12Cl2N3S, at doses of 5, 10 and 15 µM, respectively. All drugs were injected intracerebroventricular. The spatial learning and histological assessment were performed in all groups. Animals in STZ group had more deficits in spatial learning than the control group in Morris water maze. C16H12Cl2N3S improved spatial learning significantly compared to STZ group. The CA1 pyramidal layer thicknesses in STZ group were reduced significantly compared to control group. C16H12Cl2N3S increased the CA1 pyramidal layer thickness in T15 group compared to STZ group. Current findings suggest C16H12Cl2N3S may have a protective effect on learning deficit and hippocampal structure in AD.


Cohen E, Bieschke J, Perciavalle RM, et al. Opposing activities protect against age-onset proteotoxicity. Science 2006;313(5793):1604-10.

Alzheimer's Association. 2009 Alzheimer's disease facts and figures. Alzheimer's Dement 2009:5(3):234-70.

Marcus DL, Thomas C, Rodriguez C, et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp Neurol 1998;150(1):40-4.

Zheng L, Kågedal K, Dehvari N, et al. Oxidative stress induces macroautophagy of amyloid β-protein and ensuing apoptosis. Free Radic Biol Med 2009;46(3):422-9.

Behl C, Holsboer F. Oxidative stress in the pathogenesis ofAlzheimer's disease and antioxidant neuroprotection. Fortschr Neurol Psychiatr 1998;66(3):113-21.

Peng QL, Buz’Zard AR, Lau BH. Pycnogenol protects neurons from amyloid-β peptide-induced apoptosis. Brain Res Mol Brain Res 2002;104(1):55-65.

Tamagno E, Parola M, Guglielmotto M, et al. Multiple signaling events in amyloid beta-induced, oxidative stressdependent neuronal apoptosis. Free Radic Biol Med 2003;35(1):45-58.

Xiao XQ, Zhang HY, Tang XC. Huperzine A attenuates amyloid β-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci Res 2002;67(1):30-6.

Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med 2004;10(Suppl):S18-25.

Butterfield DA, Perluigi M, Sultana R. Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics. Eur J Pharmacol 2006;545(1):39-50.

Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J NeuropatholExp Neurol 2001;60(8):759-67.

Aliev G, Obrenovich ME, Reddy VP, et al. Antioxidant therapy in Alzheimer’s disease: theory and practice. Mini Rev Med Chem 2008;8(13):1395-406.

Lin YH, Liu AH, Wu HL, et al. Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents Abeta(25-35)-induced reduction in BPRP in PC12 cells. Biochem Biophys Res Commun 2006;348(2):593-9.

Mukherjee PK, Kumar V, Mal M, et al. Acetylcholinesterase inhibitors from plants. Phytomedicine 2007;14(4):289-300.

Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994;271(13):985-91.

Schulz V. Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider. Phytomedicine 2003;10(Suppl 4):74-9.

Saxena S, Verma M, Saxena AK, et al. Triazines as antiinflammatory agents. Arzneimittelforschung 1994;44(6):766-9.

Irannejad H, Amini M, Khodagholi F, et al. Synthesis and in vitro evaluation of novel 1, 2, 4-triazine derivatives as neuroprotective agents. Bioorg Med Chem 2010;18(12):4224-30.

Shaykhalishahi H, Taghizadeh M, Yazdanparast R, et al. Anti-amyloidogenic effect of AA3E2 attenuates β-amyloid induced toxicity in SK-N-MC cells. Chem Biol Interact 2010;186(1):16-23.

Shaykhalishahi H, Yazdanparast R, Ha HH, et al. Inhibition of H2O2-induced neuroblastoma cell cytotoxicity by a triazine derivative, AA3E2. Eur J Pharmacol 2009;622(1-3):1-6.

Tusi SK, Ansari N, Amini M, et al. Attenuation of NF-κB and activation of Nrf2 signaling by 1, 2, 4-triazine derivatives, protect neuron-like PC12 cells against apoptosis. Apoptosis 2010;15(6):738-51.

Yazdanparast R, Shaykhalishahi H. Protective effect of a triazine-derivative (AA3E2) on β-amyloid-induced damages in SK-N-MC cells. Toxicol Vitro 2009;23(7):1277-83.

Bekircan O, Küxük M, Kahveci B, et al. Convenient Synthesis of Fused Heterocyclic 1, 3, 5-Triazines from Some N-Acyl Imidates and Heterocyclic Amines as Anticancer and Antioxidant Agents. Archiv Pharm 2005;338(8):365-72.

Brzozowski Z, Sączewski F. Synthesis and antitumor activity of novel 2-amino-4-(3, 5, 5-trimethyl-2- pyrazolino)-1, 3, 5-triazine derivatives. Eur J Med Chem 2002;37(9):709-20.

Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clin Exp Pharm Physiol 2003;30(5-6):336-42.

Grunblatt E, Salkovic-Petrisic M, Osmanovic J, et al. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 2007;101(3):757-70.

Paxinos G, Watson C, editors. The rat brain in stereotaxicncoordinates. 6th ed. San Diego: Academic Press; 2007.

Saffarzadeh F, Eslamizade MJ, Nemati Karimooy HA, et al. The effect of L-arginine on Morris water maze tasks of ovariectomized rats. Acta Physiol Hung 2010;97(2):216-23.

Sharifzadeh M, Naghdi N, Khosrovani S, et al. Posttraining intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats. Eur J Pharm 2005;511(2-3):159-66.

Tabrizian K, Najafi S, Belaran M, et al. Effects of Selective iNOS Inhibitor on Spatial Memory in Recovered and Non-recovered Ketamine Induced-anesthesia in Wistar Rats. Iran J Pharm Res 2010;9(3):313-20.

Sharma VK. Streptozotocin, An experimental tool in diabetes and alzhemir’s disease. Int J Pharm Res Deveopment 2010;2(1):1-7.

Salkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 2007;(72):217-33.

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001;81(2):741-66.

Maiese K, Chong ZZ. Insights into oxidative stress and potential novel therapeutic targets for Alzheimer disease. Restor Neurol Neurosci 2004;22(2):87-104.

Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 20045;430(7000):631-9.

Maiese K, editor. Organic brain disease. Encyclopedia of the human brain. 1st ed. Oxford: Elsevier Inc; 2002: p. 509-27.

Behl C, Davis J, Lesley R, et al. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 1994;77(6):817-27.

Varadarajan S, Yatin S, Kanski J, et al. Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 1999;50(2):133-41.

Behl C, Holsboer F. Oxidative stress in the pathogenesis of Alzheimer's disease and antioxidant neuroprotection. Fortschr Neurol Psychiatr 1998;66(3):113-21. 40. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid betaprotein (Abeta) in human neuroblastoma cells. Biochemistry 2000;39(23):6951-9.

Zheng L, Kagedal K, Dehvari N, et al. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis. Free Radic Biol Med 2009;46(3):422-9.

Subramaniam R, Koppal T, Green M, et al. The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide(25-35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer's disease. Neurochem Res 1998;23(11):1403-10.

Rasoolijazi H, Joghataie MT, Roghani M, et al. The beneficial effect of (-)-epigallocatechin-3-gallate in an experimental model of Alzheimer’s disease in rat: A behavioral analysis. Iran Biomed J 2007;11(4):237-43.

Gilgun-Sherki Y, Rosenbaum Z, Melamed E, et al. Antioxidant therapy in acute central nervous system injury: current state. Pharmacological reviews. 2002;54(2):271-84.

How to Cite
Alipour F, Oryan S, Sharifzadeh M, Karimzadeh F, Kafami L, Irannejad H, Amini M, Hassanzadeh G. The Neuroprotective Effect of a Triazine Derivative in an Alzheimer’s Rat Model. Acta Med Iran. 53(1):8-16.