Write your message
Volume 15, Issue 2 (May 2021)                   IJT 2021, 15(2): 83-90 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Sakhaie M H, Mohammad-Hosseini A, Sadegh M, Khansari-nejad B, Babaei S. Pentoxifylline Protects Against Hippocampal Damage and Memory Impairment Induced by Trimethyltin. IJT 2021; 15 (2) :83-90
URL: http://ijt.arakmu.ac.ir/article-1-897-en.html
1- Department of Anatomy, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
2- Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
3- Department of Immunology and Microbiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
4- Department of Anatomy, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran. , babaei@arakmu.ac.ir
Full-Text [PDF 1030 kb]   (627 Downloads)     |   Abstract (HTML)  (1691 Views)
Full-Text:   (678 Views)

Introduction

Neurodegenerative diseases are disabling disorders of the Central Nervous System (CNS). The molecular mechanisms of the disorders may include mitochondrial dysfunction, cell membrane peroxidation, glutamate excitation, calcium overload, and activation of pro-apoptotic proteins [1]. Hippocampus is one of the vital constituents of the brain. It is also believed that some deleterious conditions of the brain, such as trauma, seizure, hypoxia, ischemia, among others, may induce injury to the hippocampus [2-4]. 
Trimethyltin (TMT) is a fungicidal agent and stabilizer of plastic materials. This agent is used as a convenient compound to induce experimental degenerative model of hippocampus injury in rodents, manifested by cognitive deficits, inflammation, neuronal death and apoptosis [5]. The clinical signs of hippocampal injury in rodent are tremor, convulsion, hyperactivity, tail mutilation, raring and aggressive behaviors [6]. It has been shown that treating mice with TMT causes neuronal loss in the dentate gyrus of the hippocampus [7]. Although the mechanisms of TMT action in the hippocampus are not completely elucidated, experimental findings suggest that this agent affects mitochondria and membrane proteins, leading to the release of cytochrome C [8]. Other studies have suggested that the mechanisms of neurotoxicity of TMT may be related to impairment of neurotransmitters, glutamate excitotoxicity, formation of Reactive Oxygen Species (ROS), and the elevated expression of Necrotizing Factor (NF-kB) [9, 10]. Moreover, the administration of TMT can activate the microglia and induce neuronal cell death [11]. It may upregulate the expression of inducible Nitric Oxide Synthase (iNOS), which augments the Reactive Nitrogen Species (RNS) and apoptosis in the hippocampus [12]. Exposure to TMT also damages pyramidal cells in dorsal hippocampus and the hillus through astrogliosis and toxicity to the microglia [13]. Further, it has been shown that TMT organotin compound induces spatial learning deficit, based on water maze and radial arm maze tests in rats [14].
Pentoxifylline (PTX) is an alkylxanthine phosphodiesterase inhibitor that reduces the plasma viscosity and is used to treat some vascular disorders. Noyan, et al. reported that PTX has the potential to be used as an immunomodulatory and ROS scavenging agent [15]. The anti-inflammatory effect of PTX is thought to be due to the inhibition of glial cell activities, which are the primary sources of releasing inflammatory cytokines [16]. This agent plays a protective role against experimental neurotoxicity and neuropathic pain [16, 17]. It down-regulates the pro-inflammatory Tumor Necrosis Factor-α (TNF-α) and interleukin-1β in neurons, and enhances the anti-inflammatory effects of cytokines [18]. The study by Banfi et al. revealed that PTX reduced brain damage dose dependently by inhibiting the inflammatory events [19]. Another study showed that using PTX in an experimental model of status epilepticus improved behavioral learning, cognition, alleviated seizures, and reduced neuronal death by inhibiting the oxidative stress, and augmented monoamines in the hippocampus [20]. Another in vitro study has revealed that PTX plays a major anti-inflammatory and anti-apoptotic role by inhibiting TNF-α and the caspase-dependent pathways [21]. 
The aim of this study was to investigate the neuroprotective effects of PTX on neuronal injuries, and deficits in the behavior, learning and memory that are induced by TMT in rat hippocampus. 

Materials and Methods

Animals: Sixty male Wistar rats, weighing 190-220 g, were randomly divided into five groups of 12 each. They were housed under controlled conditions of temperature (21-23°C), humidity (50%-60%), lighting (12 h light–dark cycle), and free access to food and water. The established animal care procedures were observed to reduce stress in rats, as approved by the Review Board and Ethics Committee of Arak University of Medical Sciences (Registration #: IR.ARAKMU.REC 1394.318). The five experimental groups (n=12 each) were as follows: 
● Control Group was injected with normal saline intraperitoneally (IP).
● TMT Group received a single dose of TMT at 8 mg/kg (Sigma, St. Louis, USA), which was dissolved in normal saline and injected IP on the first day of the study.
● TMT+PTX60 Group received 60 mg/kg PTX.
● TMT+PTX100 Group received 100 mg/kg PTX.
● TMT+PTX120 Group received 120 mg/kg PTX. 
PTX: The PTX compound was obtained from Abcam Co. (Cambridge, UK), dissolved in normal saline and administrated IP twice daily, starting 24 hours after the TMT injection over six consecutive days for a total of 12 PTX injections during the study.
Radial Arm Maze (RAM): The RAM apparatus consisted of eight arms (50×15×15cm), marked as number 1 to 8, were made of black plexiglass and were radiating outward from a central point. The arms were separated from each other by a sliding gate.
During the trials, additional visual cues were placed at similar points in the experimental space. Twenty-four hours after the last PTX administration, the RAM tasks were performed for eight consecutive days (9 a.m. to 12 noon). One day before starting the RAM tasks, the rats were placed in the apparatus to become familiar with the experimental environment. To provoke their exploring behavior, the food was removed from the animal cage 2 hr before each trail. 
Throughout the training period and for adaptation to the experimental environment, each animal was placed on the octagonal central platform of the maze for 30 seconds. Then all gates were opened and rats were allowed to freely explore the maze for five minutes. During the RAM tasks, four out of the eight arms contained the same bait for the daily training. The baiting was arranged in the same order throughout the experiment and all rats were trained on this arrangement. The rats had access to all baited arms to explore and eat the foods within the five minutes. The foods were removed from the maze after that period and the arms were cleaned with 40% ethanol between trials. The following variables were used for the analysis according to the established procedures [22]: 
1. Latency: total time taken to finish with the baited arms
2. Working Memory Error (WME): re-entry to a previous baited arm where the food was taken 
3. Reference Memory Error (RME): entering into an unbaited arm. 
Histological study: Prior to the histological analysis, the rats were anesthetized IP with ketamine and xylazine at 60 mg/kg and 10 mg/kg of each drug, respectively. Transcardiac perfusion was performed with 0.9% normal saline, followed by 4% buffered paraformaldehyde fixative in 0.1 M phosphate buffered saline at pH 7.4. The brains were carefully removed from the rat skulls and immersed in the fixative solution overnight. After the tissues were dehydrated in ethanol and cleared with xylene, they were embeded in paraffin and coronal sections were made of hippocampus at 5μm thickness (2.28 to 3.82 mm post bregma) [23]. Sections were then dehydrated serially in increasing alcohol concentrations, stained with cresyl violet, and mounted. The slides were examined under light microscopy at x40 magnification. The microscopic examinations focused on pyknotic neurons, cells with dark nuclei, loss or unusual clumping of heterochromatin, and images were photographed by an Olympus microscope (BX51, Japan). To determine the number of Cornu Ammonis 1 (CA1) pyknotic neurons, five sections from each sample were randomly selected and the cells in four fields were counted in each optic field.
Statistical analyses: All data were presented as Means±SEM. Total time to finish the baited arms were analyzed by two-way ANOVA repeated measures followed by Bonferroni post-test. Numbers of working and reference memory errors were analyzed by the Kruskal-Wallis test followed by the Dunn multiple comparison tests. One-way ANOVA with Tukey’s post-hoc test was used to evaluate the mean number of necrotic neurons in the CA1 area of hippocampus samples. 

Results

Spatial memory study: As shown in Figure 1A, TMT significantly increased the delay time taken by the rats to finish with 4 baited arms (P<0.001). The PTX administration at the three given doses significantly reduced the effect of TMT (P<0.001). As demonstrated in Figures 1B and 1C, TMT significantly increased the working and reference memory errors (P<0.001) while PTX significantly decreased the effects of TMT on memory errors at the three administered doses of 60, 100, and 120 mg/kg (P<0.001). 



Histological study: As seen in Figure 2, the administration of TMT significantly increased the numbers of pyknotic neurons in the nissl stained CA1 region of the hippocampus (P<0.001) compared to the group treated with normal saline. Further, PTX at 60 and 100 mg/kg significantly decreased the numbers of pyknotic neurons in the CA1 area of the hippocampus (P<0.05) compared to the group treated with TMT alone. However, there were no significant differences noted for the PTX treatment at 120 mg/kg compared to that in the TMT group.


 

Discussion

This study was conducted to investigate the neuroprotective effects of PTX on the induced neuronal injury by TMT in the rat hippocampus. The results indicated that the chronic administration of PTX significantly reduced histological damages in the CA1 area of the hippocampus and improved the spatial memory impairment caused by TMT. This toxin has been used previously in animal studies to induce neuronal damage in the hippocampus and produce impairment in spatial learning and memory [5, 6, 24]. The findings of the current study confirmed the neuronal damage based on the histological examinations following TMT administration to the rats. These histological findings were also associated with spatial memory impairment detected on the radial maze tasks. It is believed that TMT induces oxidative stress, inflammation, and neuronal death in the hippocampus through the stimulation of microglia and astrocytes. These events are associated with the release of pro-inflammatory cytokines and stress related factors, which promote inflammation in neurons [5, 6, 9]. 
Neuro-inflammatory conditions are known as the major contributors to the development of neurodegenerative and cognitive disorders [25]. Initially, the inflammation leads to neuronal death mediated by cytokines, such as interleukins 1α, β and 6, TNF-α and the activation of iNOS [26, 27]. Earlier findings have also shown TMT-induced apoptosis in an immortalized hippocampal cell line (HT-22). This is believed to be due to the excessive ROS/RNS generation secondary to the up-regulation of NF-κB, iNOS and Bax expression [12]. Studies have demonstrated that the number of TUNEL-positive pyramidal neurons in the CA1 and CA3 regions of hippocampus increased to a maximal level after 5 days of exposure to TMT while the number of Nissl-positive mature neurons decreased 21 days after the TMT treatment [27, 28]. The findings from these studies are consistent with the histological results of the current study regarding the neuronal damages found in the CA1 region of the rats’ hippocampus.
With respect to the important role of hippocampus in learning and memory, the impaired learning documented in the rats following TMT treatments, could be linked to neuronal damages in the CA1 region of the hippocampus. As mentioned earlier, the TMT toxicity might have increased the oxidative stress and mitochondrial dysfunction in the hippocampus, likely to be associated with gliosis and spatial learning impairment in rats [29]. The mechanisms by which oxidative stress can impair cognitive behavior may be related to alteration in the Brain-Derived Neurotrophic Factor (BDNF). This factor is produced by hippocampus neurons and has a critical role in synaptic plasticity, neuronal excitability, and learning and memory tasks. The rise in the oxidative stressors in the CNS can decrease the BDNF expression while increasing the lipid peroxidation, both of which can lead to impairment in cognitive functions, learning memory and neuroplasticity [30, 31]. 
The findings of the current study suggest that PTX at all of the three doses (60, 100, and 120 mg/kg) might have protected the hippocampus against the adverse effects of TMT on the spatial learning and memory functions. Also, our histological results were consistent with the findings of previous studies that have shown PTX treatment to have a discernible attenuation of cell loss in the CA1, CA3 and hilus areas of hippocampus [20]. Further, PTX may modulate the inflammatory response by down-regulating the production of various pro- and anti-inflammatory cytokines. In previous in vivo studies, PTX at 200 mg/kg diminished the spatial memory deficit, which was probably mediated by the inhibition of TNFα synthesis [32, 33]. Also, in a rat model of neuropathic pain, it was reported that PTX dose-dependently reduced the activity of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, and enhanced the IL-10 activity [16]. It has also been reported that PTX alleviates the memory impairment secondary to hypoxia or ischemia by reducing the ratio of BAX/Bcl-2 protein levels [17, 24]. Previous studies have also shown that the suppression of apoptosis via controlling the Bax/Bcl-2 ratio in the hippocampus has improved the learning and memory performance in animal models [32, 33]. Finally, Tariq et al. have reported that PTX alleviated the neuronal cell loss and sprouting of mossy fibers in the hippocampal tissue damage induced by lithium-pilocarpine. These findings suggest the oxidative stress reduction, and reversal of the depletion of dopamine and 5-hydroxytryptamine in the hippocampus by PTX treatment [20]. 

Conclusions

The current study findings justify the neuroprotective effects of PTX against the spatial memory deficit and histological damage in the hippocampus induced by TMT neurotoxicity. These PTX effects, as supported by histological findings, suggest a decline in the neuronal necrosis through modulation of the anti-inflammatory processes and improved neuro-protective mechanisms.
Limitations of the study: This study had limited laboratory resources to assess a variety of anti-inflammatory mediators at molecular levels.
Recommendations for future research: The role of anti-inflammatory cytokines should be considered in the future studies.

Ethical Considerations

Compliance with ethical guidelines

All ethical principles were observed in conducting this research, including the principles governing the use of animals in experimental studies as approved by the Ethics Committee of Scientific Research at Arak University of Medical

Funding

This paper was extracted from the Master’s thesis materials of A. Mohammad-Hosseini, conducted at ARAK University of Medical Sciences. This study was financially supported by the Office of Vice Chancellor for Research, Arak University of medical science. 

Author's contributions

Conceptualization and Methodology: Sakhaie MH, Mohammad-Hosseini, and Sadegh M; Data Analyses and Experiments: Sadegh M and Sakhaie MH; Writing – original draft and Writing, review, and editing: Babaei S, Sakhaie MH and Sadegh M. 

Conflict of interest

The authors declared no conflict of interests.

Acknowledgments

The authors acknowledge the support of the office of Vice Chancellor for Research, Arak University of Medical Sciences, Arak, Iran. Sciences. 

References

  1. Pivovarova NB, Nguyen HV, Winters CA, Brantner CA, Smith CL, Andrews SB. Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons. J Neurosci. 2004; 24(24):5611-22. [DOI:10.1523/JNEUROSCI.0531-04.2004] [PMID] [PMCID]
  2. Taft WC, Yang K, Dixon CE, Hayes RL. Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury. J Neurotrauma. 1992; 9(3):281-90. [DOI:10.1089/neu.1992.9.281] [PMID]
  3. Hartman RE, Lee JM, Zipfel GJ, Wozniak DF. Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats. Brain Res. 2005; 1043(1-2):48-56. [DOI:10.1016/j.brainres.2005.02.030] [PMID]
  4. Vespa PM, McArthur DL, Xu Y, Eliseo M, Etchepare M, Dinov I, et al. Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy. Neurology. 2010; 75(9):792-8. [DOI:10.1212/WNL.0b013e3181f07334] [PMID] [PMCID]
  5. Lee S, Yang M, Kim J, Kang S, Kim J, Kim JC, et al. Trimethyltin-induced hippocampal neurodegeneration: A mechanism-based review. Brain Res Bull. 2016; 125:187-99. [DOI:10.1016/j.brainresbull.2016.07.010] [PMID]
  6. Geloso MC, Corvino V, Michetti F. Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int. 2011; 58(7):729-38. [DOI:10.1016/j.neuint.2011.03.009] [PMID]
  7. Ogita K, Nishiyama N, Sugiyama C, Higuchi K, Yoneyama M, Yoneda Y. Regeneration of granule neurons after lesioning of hippocampal dentate gyrus: Evaluation using adult mice treated with trimethyltin chloride as a model. J Neurosci Res. 2005; 82(5):609-21. [DOI:10.1002/jnr.20678] [PMID]
  8. Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, Michetti F. Mitochondrial oxygen consumption inhibition importance for TMT-dependent cell death in undifferentiated PC12 cells. Neurochem Int. 2008; 52(6):1092-99. [DOI:10.1016/j.neuint.2007.11.008] [PMID]
  9. Jenkins SM, Barone S. The neurotoxicant trimethyltin induces apoptosis via caspase activation, p38 protein kinase, and oxidative stress in PC12 cells. Toxicol Lett. 2004; 147(1):63-72. [DOI:10.1016/j.toxlet.2003.10.023] [PMID]
  10. Florea AM, Splettstoesser F, Dopp E, Rettenmeier AW, Büsselberg D. Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: Neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3. Toxicology. 2005; 216(1):1-8. [DOI:10.1016/j.tox.2005.05.029] [PMID]
  11. Eskes C, Juillerat-Jeanneret L, Leuba G, Honegger P, Monnet-Tschudi F. Involvement of microglia-neuron interactions in the tumor necrosis factor‐α release, microglial activation, and neurodegeneration induced by trimethyltin. J Neurosci Res. 2003; 71(4):583-90. [DOI:10.1002/jnr.10508] [PMID]
  12. Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE. Trimethyltin-induced apoptosis is associated with upregulation of inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol. 2006; 216(1):34-43. [DOI:10.1016/j.taap.2006.05.004] [PMID]
  13. Yuliani S, Mustofa, Partadiredja G. Turmeric (Curcuma longa L.) extract may prevent the deterioration of spatial memory and the deficit of estimated total number of hippocampal pyramidal cells of trimethyltin-exposed rats. Drug Chem Toxicol. 2018; 41(1):62-71. [DOI:10.1080/01480545.2017.1293087] [PMID]
  14. Park HJ, Shim HS, Choi WK, Kim KS, Bae H, Shim I. Neuroprotective effect of lucium Chinese fruit on Trimethyltin-Induced learning and memory deficits in the rats. Exp neurobiol. 2011; 20(3):137-43. [DOI:10.5607/en.2011.20.3.137] [PMID] [PMCID]
  15. Noyan T, Onem O, Ramazan Sekeroğlu M, Köseoğlu B, Dülger H, Bayram I, et al. Effects of erythropoietin and pentoxifylline on the oxidant and antioxidant systems in the experimental short bowel syndrome. Cell biochem funct. 2003; 21(1):49-54. [DOI:10.1002/cbf.991] [PMID]
  16. Liu J, Feng X, Yu M, Xie W, Zhao X, Li W, et al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain. Neurosci Lett. 2007; 412(3):268-72. [DOI:10.1016/j.neulet.2009.01.073] [PMID]
  17. 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. [DOI:10.1016/j.brainres.2008.12.064] [PMID]
  18. Fernandes JL, de Oliveira RTD, Mamoni RL, Coelho OR, Nicolau JC, Blotta MHSL, et al. Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease: A randomized placebo-controlled study. Atherosclerosis. 2008; 196(1):434-42. [DOI:10.1016/j.atherosclerosis.2006.11.032] [PMID]
  19. Banfi C, Sironi L, De Simoni G, Gelosa P, Barcella S, Perego C, et al. Pentoxifylline prevents spontaneous brain ischemia in stroke-prone rats. J Pharmacol Exp Ther. 2004; 310(3):890-5. [DOI:10.1124/jpet.104.067090] [PMID]
  20. Tariq M, Ahmad M, Moutaery KA, Deeb SA. Pentoxifylline ameliorates lithium-Pilocarpine induced status epilepticus in young rats. Epilepsy Behav. 2008; 12(3):354-65. [DOI:10.1016/j.yebeh.2007.12.004] [PMID]
  21. Dong J, Yuan X, Xie W. Pentoxifylline exerts anti-Inflammatory effects on cerebral ischemia reperfusion-induced injury in a rat model via the p38 mitogen-Activated protein kinase signaling pathway. Mol Med Rep. 2018; 17(1):1141-7. [DOI:10.3892/mmr.2017.7953]
  22. Zareie P, Gholami M, Amirpour-Najafabadi B, Hosseini S, Sadegh M. Sodium valproate ameliorates memory impairment and reduces the elevated levels of apoptotic caspases in the hippocampus of diabetic mice. Naunyn Schmiedebergs Arch Pharmacol. 2018; 391(10):1085-92. [DOI:10.1007/s00210-018-1531-3] [PMID]
  23. Patanella AK, Zinno M, Quaranta D, Nociti V, Frisullo G, Gainotti G, et al. Correlations between peripheral blood mononuclear cell production of BDNF, TNF‐alpha, IL‐6, IL‐10 and cognitive performances in multiple sclerosis patients. J Neurosci Res. 2010; 88(5):1106-12. [DOI:10.1002/jnr.22276] [PMID]
  24. More SV, Kumar H, Cho DY, Yun YS, Choi DK. Toxin-Induced experimental models of learning and memory impairment. Int J Mol Sci. 2016; 17(9):1447. [DOI:10.3390/ijms17091447] [PMID] [PMCID]
  25. Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003; 304(3):437-44. [DOI:10.1016/S0006-291X(03)00615-6]
  26. McPherson CA, Merrick BA, Harry GJ. In vivo molecular markers for pro-inflammatory cytokine M1 stage and resident microglia in trimethyltin-induced hippocampal injury. Neurotox Res. 2014; 25(1):45-56. [DOI:10.1007/s12640-013-9422-3] [PMID] [PMCID]
  27. Morita M, Imai H, Liu Y, Xu X, Sadamatsu M, Nakagami R, et al. FK506-protective effects against trimethyltin neurotoxicity in rats: Hippocampal expression analyses reveal the involvement of periarterial osteopontin. Neuroscience. 2008; 153(4):1135-45. [DOI:10.1016/j.neuroscience.2008.01.078] [PMID]
  28. Kurkowska-Jastrzebska I, Joniec I, Zaremba M, Fiedorowicz A, Czlonkowska A, Oderfeld-Nowak B. Anti-Myelin basic protein T cells protect hippocampal neurons against trimethyltin-Induced damage. Neuroreport. 2007; 18(5):425-9. [DOI:10.1097/WNR.0b013e3280586777] [PMID]
  29. Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med. 2003; 167(11):1548-53. [DOI:10.1164/rccm.200209-1050OC] [PMID]
  30. Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain‐derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004; 19(7):1699-707. [DOI:10.1111/j.1460-9568.2004.03246.x] [PMID]
  31. Fukui K, Onodera K, Shinkai T, Suzuki S, Urano S. Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Ann N Y Acad Sci. 2001; 928:168-75. [DOI:10.1111/j.1749-6632.2001.tb05646.x] [PMID]
  32. Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, et al. Treadmill exercise prevents aging-Induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Exp Gerontol. 2010; 45(5):357-65. [DOI:10.1016/j.exger.2010.02.005] [PMID]
  33. Wang T, Liu CZ, Yu JC, Jiang W, Han JX. Acupuncture protected cerebral multi-Infarction rats from memory impairment by regulating the expression of apoptosis related genes Bcl-2 and Bax in hippocampus. Physiol Behav. 2009; 96(1):155-61. [DOI:10.1016/j.physbeh.2008.09.024] [PMID]
Type of Study: Research | Subject: General

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Iranian Journal of Toxicology

Designed & Developed by : Yektaweb