Neuroprotective Effect of Pentoxifylline on 3,4-Methylenedioxymethamphetamine-Induced Apoptosis in CA1 Cells of Wistar Rat Hippocampus

Authors

  • Zahra Nadia Sharifi Department of Anatomical Sciences and Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Shabnam Movassaghi Department of Anatomical Sciences and Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Zeinab Khazaei Koohpar Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
  • Mehrdad Hashemi Department of Genetics, Faculty of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran
  • Sourena Jafari Semnani Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

DOI:

https://doi.org/10.31661/gmj.v8i.963

Keywords:

Pentoxifylline, 3, 4-Methylenedioxymethamphetamine, Apoptosis, Hippocampus

Abstract

Background: 3,4-Methylenedioxymethamphetamine is psychoactive and hallucinogenic and has been shown to produce neurotoxicity both in animals and in humans. Recently, vasodilator drugs such as pentoxifylline (PTX) have been introduced as an alternative with neuroprotective effects. There is no study about the protective effect of PTX on hippocampal apoptosis due to high-dose administration of 3,4-Methylenedioxymethamphetamine (MDMA), so in this study, the protective effect of PTX on the hippocampus of male Wistar rats following high-dose of the drug has been investigated. Materials and Methods: Twenty-four male Wistar rats weighing 250-300 g were randomly divided into four groups: control, sham (MDMA injection), experimental (MDMA+PTX injection), and vehicle (MDMA+saline) groups. Two weeks later, the brains were removed and prepared for TUNEL and western blot techniques. Concomitantly the hippocampus was removed to study the change in Bcl-2 and BAX mRNA expression with quantitative real-time polymerase chain reaction. Results: Data showed that the number of apoptotic bodies significantly decreased in the experimental group compared to the other groups, except for in control. Also, further investigation revealed that BAX reduced considerably, while Bcl-2 mRNA expression increased dramatically after PTX treatment. Conclusions: Our results suggest that PTX may be a neuroprotective agent, and its neuroprotective potential may contribute to reducing the severity of lesions in the hippocampus following a high dose administration of MDMA. [GMJ.2019;8:e963] 

References

Capela JP, Carmo H, Remiao F, Bastos ML, Meisel A, Carvalho F. Molecular and cellular mechanisms of ecstasy- induced neurotoxicity: an overview. Mol Neurobiol. 2009; 39: 210-71. https://doi.org/10.1007/s12035-009-8064-1PMid:19373443 Stumm G, Schlegel J, Schafer T, Wurz C, Mennel HD, Krieg JC. Amphetamines induce apoptosis and regulation of bclX splice variants in neocortical neurons. FASEB J. 1999; 13: 1065-72. https://doi.org/10.1096/fasebj.13.9.1065PMid:10336889 Lyles J, Cadet JL. Methylenedioxymethamphetamine (MDMA) neurotoxicity: cellular and molecular mechanisms. Brain Res Rev. 2003; 42: 155-68. https://doi.org/10.1016/S0165-0173(03)00173-5 Green AR, Mechan AO, Ellio JM, O'Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA). Pharmacol Rev. 2003; 55:463-508. https://doi.org/10.1124/pr.55.3.3PMid:12869661 Jimenez A, Jorda EG, Verdaguer E, Pubill D, Sureda FX, Canudas AM, et al. Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Toxicol Appl Pharmacol. 2004; 196:223-34. https://doi.org/10.1016/j.taap.2003.12.017PMid:15081269 Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, et al. Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience .2006; 139(3):1069-81. https://doi.org/10.1016/j.neuroscience.2006.01.007PMid:16504407 Cunha-Oliveira T, Rego AC, Oliveira CR. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev .2008; 58: 192-208. https://doi.org/10.1016/j.brainresrev.2008.03.002PMid:18440072 Scott CW, Sobotka-Briner C, Wilkins DE, Jacobs RT, Folmer JJ, Frazee WJ, et al. Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. J Pharmacol Exp Ther. 2003; 304(1):433-40. https://doi.org/10.1124/jpet.102.039651PMid:12490620 Seiffge D. Pentoxifylline: its influence on interaction of blood cells with the vessel wall. Atherosclerosis. 1997; 131: 27-8. https://doi.org/10.1016/S0021-9150(97)06121-2 Windmeier C, Gressner AM. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Gen. Pharmacol 1997; 29: 181-96. https://doi.org/10.1016/S0306-3623(96)00314-X Teixeira MM, Gristwood RW, Cooper N, Hellewell PG. Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs for the future? Trends Pharmacol Sci. 1997; 18: 164-70. https://doi.org/10.1016/S0165-6147(97)01049-3 Laurat E, Poirier B, Tupin E, Caligiuri G, Hansson GK, Bariety J, et al. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation . 2001; 194(2):197-202. https://doi.org/10.1161/01.CIR.104.2.197PMid:11447086 Haddad JJ, Land SC, Tarnow-Mordi WO, Zembala M, Kowalczyk D, Lauterbach R. Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated pro-inflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells. J. Pharmacol. Exp. Ther.2002; 300: 559-66. https://doi.org/10.1124/jpet.300.2.559PMid:11805217 Movassaghi S, Sharifi Z. N., Soleimani M, Joghatai M. T, Hashemi M, Shafaroodi H, et al. Effect of Pentoxifylline on Ischemia-induced Brain Damage and Spatial Memory Impairment in Rat. Iran J Basic Med Sci. 2012; 15 (5): 1083-90. Yamamoto BK, Bankson MG. Amphetamine neurotoxicity: cause and consequence of oxidative stress. Crit Rev Neurobiol. 2005; 17(2):87-117. https://doi.org/10.1615/CritRevNeurobiol.v17.i2.30 Cadet JL, Jayanthi S, Deng X. Methamphetamine-induced neuronal apoptosis involves the activation of multiple death pathways. Rev. Neurotoxicity Res. 2005; 8: 199-206. https://doi.org/10.1007/BF03033973 Jayanthi S, Deng X, Bordelon M, Mccoy MT, Cadet JL. Methamphetamine causes differential regulation of pro-death and anti-death Bcl2 - genes in the mouse neocortex. FASEB. 2001; 15: 1745-52. https://doi.org/10.1096/fj.01-0025comPMid:11481222 Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, et al. Human ICE/CED-3 protease nomenclature. Cell 1996; 87(2):171. https://doi.org/10.1016/S0092-8674(00)81334-3 Capela JP, Meisel A, Abreu AR, Branco PS, Ferreira LM, Lobo AM, et al. Neurotoxicity of MDMA metabolites in rat cortical neurons, and influence of hyperthermia. J Pharmacol Exp Ther .2006; 316:53-61. https://doi.org/10.1124/jpet.105.092577PMid:16183702 Khazaei koohpar Z, Hashemi M, Mahdian R, Parivar k.The Effect of pentoxifylline on bcl-2 Gene Expression changes in Hippocampus after Long-term use of Ecstasy in wistear Rats. Iranian Journal of Pharmaceutical Research. 2013; 12(3):521-27 He J, Xu H, Yang Y, Zhang X, Li X-M. Neuroprotective effects of olanzapine on methamphetamine induced neurotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl2 decrease in rats. Brain Res. 2004; 1018: 186-92. https://doi.org/10.1016/j.brainres.2004.05.060PMid:15276877 Duman DG, Ozdemir F, Birben E, Keskin O, Eksioglu-Demiralp E, Celikel C, et al. Effects of pentoxifylline on TNF-alpha production by peripheral blood mononuclear cells in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2007; 52:2520-24. https://doi.org/10.1007/s10620-006-9723-yPMid:17436095 Klotz K.N. Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch. Pharmacol. 2000; 362:382-91. https://doi.org/10.1007/s002100000315PMid:11111832 Zou JY, Crews FT. TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res. 2005; 1034(1-2):11-24. https://doi.org/10.1016/j.brainres.2004.11.014PMid:15713255 Bruno Rde B, Marques TF, Batista TM, Lima JC, de Arruda KG, Lima PF, et al. Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia. Brain Res. 2009; 1260:55-64. https://doi.org/10.1016/j.brainres.2008.12.064PMid:19161991 Zhu DJ, Xia B, Bi Q, Zhang SJ, Qiu BS, Zhao C. Functional protection of pentoxifylline against spinal cord ischemia/reperfusion injury in rabbits: necrosis and apoptosis effects. Chin Med J (Engl). 2008; 121(23):2444-49. https://doi.org/10.1097/00029330-200812010-00016 He Jue, Xu H, Yang Y, Zhang X, Li X- M. Neuroprotective effects of olanzapine on methamphetamine-induced neurotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl-2 decrease in rats. Brain Research. 2004; 1018: 186-92. https://doi.org/10.1016/j.brainres.2004.05.060PMid:15276877

Downloads

Additional Files

Published

2019-08-07

How to Cite

Sharifi, Z. N., Movassaghi, S., Khazaei Koohpar, Z., Hashemi, M., & Jafari Semnani, S. (2019). Neuroprotective Effect of Pentoxifylline on 3,4-Methylenedioxymethamphetamine-Induced Apoptosis in CA1 Cells of Wistar Rat Hippocampus: . Galen Medical Journal, 8, e963. https://doi.org/10.31661/gmj.v8i.963

Issue

Vol. 8 (2019): 2019

Section

Original Article

License

https://creativecommons.org/licenses/by/4.0/