Volume 10, Issue 1 (January & February 2019)                   BCN 2019, 10(1): 23-36 | Back to browse issues page

XML Print

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

Jahanmahin A, Abbasnejad Z, Haghparast A, Ahmadiani A, Ghasemi R. The Effect of Intrahippocampal Insulin Injection on Scopolamine-induced Spatial Memory Impairment and Extracellular Signal-regulated Kinases Alteration. BCN. 2019; 10 (1) :23-36
URL: http://bcn.iums.ac.ir/article-1-1096-en.html
1- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Introduction: It is well documented that insulin has neuroprotective and neuromodulator effects and can protect against different models of memory loss. Furthermore, cholinergic activity plays a significant role in memory, and scopolamine-induced memory loss is widely used as an experimental model of dementia. The current study aimed at investigating the possible effects of insulin against scopolamine-induced memory impairment in Wistar rat and its underlying molecular mechanisms.
Methods: Accordingly, animals were bilaterally cannulated in CA1, hippocampus. Intrahippocampal administration of insulin 6 MU and 12 MU in CA1 per day was performed during first 6 days after surgery. During next four days, the animal’s spatial learning and memory were assessed in Morris water maze test (three days of learning and one day of retention test). The animals received scopolamine (1 mg/kg) Intraperitoneally (IP) 30 minutes before the onset of behavioral tests in each day. In the last day, the hippocampi were dissected and the levels of MAPK (mitogen-activated protein kinases) and caspase-3 activation were analyzed by Western blot technique. 
Results: The behavioral results showed that scopolamine impaired spatial learning and memory without activating casapase-3, P38, and JNK, but chronic pretreatment by both doses of insulin was unable to restore this spatial memory impairment. In addition, scopolamine significantly reduced Extracellular signal-Regulated Kinases (ERKs) activity and insulin was unable to restore this reduction. Results revealed that scopolamine-mediated memory loss was not associated with hippocampal damage.
Conclusion: Insulin as a neuroprotective agent cannot restore memory when there is no hippocampal damage. In addition, the neuromodulator effect of insulin is not potent enough to overwhelm scopolamine-mediated disruptions of synaptic neurotransmission.
Type of Study: Original | Subject: Behavioral Neuroscience
Received: 2017/12/19 | Accepted: 2018/03/6 | Published: 2019/01/1

1. Anagnostaras, S. G., Maren, S., Sage, J. R., Goodrich, S., & Fanselow, M. S. (1999). Scopolamine and Pavlovian fear conditioning in rats: Dose-effect analysis. Neuropsychopharmacology, 21(6), 731-44. [DOI:10.1016/S0893-133X(99)00083-4] [DOI:10.1016/S0893-133X(99)00083-4]
2. Aredia, F., Malatesta, M., Veneroni, P., & Bottone, M. G. (2015). Analysis of ERK3 intracellular localization: dynamic distribution during mitosis and apoptosis. European Journal of Histochemistry, 59(4), 2571-4. [DOI:10.4081/ejh.2015.2571] [DOI:10.4081/ejh.2015.2571]
3. Balaban, H., Naziroglu, M., Demirci, K., & Ovey, I. S. (2016). The protective role of selenium on scopolamine-induced memory impairment, oxidative stress, and apoptosis in aged rats: The involvement of TRPM2 and TRPV1 channels. Molecular Neurobiology, 54(4), 2852-68. [DOI:10.1007/s12035-016-9835-0] [DOI:10.1007/s12035-016-9835-0]
4. Bartus, R. T., Dean, R. L., Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217(4558), 408-14. [DOI:10.1126/science.7046051] [PMID] [DOI:10.1126/science.7046051]
5. Blum, S., Moore, A. N., Adams, F., & Dash, P. K. (1999). A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. Journal of Neuroscience, 19(9), 3535-44. [DOI:10.1523/JNEUROSCI.19-09-03535.1999] [PMID] [DOI:10.1523/JNEUROSCI.19-09-03535.1999]
6. Christie, J. M., Wenthold, R. J., & Monaghan, D. T. (1999). Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. Journal of Neurochemistry, 72(4), 1523-8. [DOI:10.1046/j.1471-4159.1999.721523.x] [PMID] [DOI:10.1046/j.1471-4159.1999.721523.x]
7. Contestabile, A. (2011). The history of the cholinergic hypothesis. Behavioural Brain Research, 221(2), 334-40. [DOI:10.1016/j.bbr.2009.12.044] [DOI:10.1016/j.bbr.2009.12.044]
8. Day, J., Damsma, G., & Fibiger, H. C. (1991). Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity: an in vivo microdialysis study. Pharmacology, Biochemistry, and Behavior, 38(4), 723-29. [DOI:10.1016/0091-3057(91)90233-R] [DOI:10.1016/0091-3057(91)90233-R]
9. Deiana, S., Platt, B., & Riedel, G. (2011). The cholinergic system and spatial learning. Behavioural Brain Research, 221(2), 389-411. [DOI:10.1016/j.bbr.2010.11.036] [DOI:10.1016/j.bbr.2010.11.036]
10. Gehring, T. V., Luksys, G., Sandi, C., & Vasilaki, E. (2015). Detailed classification of swimming paths in the Morris Water Maze: Multiple strategies within one trial. Science Report, 5(1), 14562. [DOI:10.1038/srep14562] [DOI:10.1038/srep14562]
11. Ghasemi, R., Dargahi, L., Haeri, A., Moosavi, M., Mohamed, Z., & Ahmadiani, A. (2013). Brain insulin dysregulation: Implication for neurological and neuropsychiatric disorders. Molecular Neurobiology, 47(3), 1045-65. [DOI:10.1007/s12035-013-8404-z] [DOI:10.1007/s12035-013-8404-z]
12. Ghasemi, R., Haeri, A., Dargahi, L., Mohamed, Z., & Ahmadiani, A. (2013). Insulin in the brain: Sources, localization and functions. Molecular Neurobiology, 47(1), 145-71. [DOI:10.1007/s12035-012-8339-9] [DOI:10.1007/s12035-012-8339-9]
13. Ghasemi, R., Moosavi, M., Zarifkar, A., Rastegar, K., & Maghsoudi, N. (2015). The interplay of Akt and ERK in Abeta toxicity and insulin-mediated protection in primary hippocampal cell culture. Journal of Molecular Neuroscience, 57(3), 325-34. [DOI:10.1007/s12031-015-0622-6] [DOI:10.1007/s12031-015-0622-6]
14. Ghasemi, R., Zarifkar, A., Rastegar, K., maghsoudi, N., & Moosavi, M. (2014a). Insulin protects against Abeta-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology, 85(1), 113-20. [DOI:10.1016/j.neuropharm.2014.01.036] [DOI:10.1016/j.neuropharm.2014.01.036]
15. Ghasemi, R., Zarifkar, A., Rastegar, K., Maghsoudi, N., & Moosavi, M. (2014b). Repeated intra-hippocampal injection of beta-amyloid 25-35 induces a reproducible impairment of learning and memory: Considering caspase-3 and MAPKs activity. European Journal of Pharmacology, 726, 33-40. [DOI:10.1016/j.ejphar.2013.11.034] [DOI:10.1016/j.ejphar.2013.11.034]
16. Havrankova, J., Roth, J., & Brownstein, M. (1978). Insulin receptors are widely distributed in the central nervous system of the rat. Nature, 272(5656), 827-9. [DOI:10.1038/272827a0] [PMID] [DOI:10.1038/272827a0]
17. Havrankova, J., Schmechel, D., Roth, J., & Brownstein, M. (1978). Identification of insulin in rat brain. Proceedings of the National Academy of Sciences of the United States of America, 75(11), 5737-41. [DOI:10.1073/pnas.75.11.5737] [PMID] [PMCID] [DOI:10.1073/pnas.75.11.5737]
18. Hill, J. M., Lesniak, M. A., Pert, C. B., & Roth, J. (1986). Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience, 17(4), 1127-38. [DOI:10.1016/0306-4522(86)90082-5] [DOI:10.1016/0306-4522(86)90082-5]
19. Jahanshahi, M., Nickmahzar, E. G., & Babakordi, F. (2013). Effect of Gingko biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anatomical Science International, 88(4), 217-22. [DOI:10.1007/s12565-013-0188-8] [DOI:10.1007/s12565-013-0188-8]
20. Jiang, L. H., Zhang, Y. N., Wu, X. W., Song, F. F., & Guo, D. Y. (2008). Effect of insulin on the cognizing function and expression of hippocampal Abeta1-40 of rat with Alzheimer disease. Chinese Medical Journal, 121(9), 827-31. [DOI:10.1097/00029330-200805010-00014] [PMID]
21. Jin, C. H., Shin, E. J., Park, J. B., Jang, C. G., Li, Z., Kim, M. S. et al. (2009). Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment. Journal of Neuroscience Research, 87(16), 3658-70. [DOI:10.1002/jnr.22159] [DOI:10.1002/jnr.22159]
22. Jin, Y., Fan, Y., Yan, E. Z., Liu, Z., Zong, Z. H., & Qi, Z. M. (2006). Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus. Acta Pharmacologica Sinica, 27(10), 1309-16. [DOI:10.1111/j.1745-7254.2006.00414.x] [DOI:10.1111/j.1745-7254.2006.00414.x]
23. Kapgal, V., Prem, N., Hegde, P., Laxmi, T. R., & Kutty, B. M. (2016). Long term exposure to combination paradigm of environmental enrichment, physical exercise and diet reverses the spatial memory deficits and restores hippocampal neurogenesis in ventral subicular lesioned rats. Neurobiology of Learning and Memory, 130(1), 61-70. [DOI:10.1016/j.nlm.2016.01.013] [DOI:10.1016/j.nlm.2016.01.013]
24. Karthick, C., Periyasamy, S., Jayachandran, K. S., & Anusuyadevi, M. (2016). Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology. Frontiers in Molecular Neuroscience, 9(1), 28-32. [DOI:10.3389/fnmol.2016.00028] [DOI:10.3389/fnmol.2016.00028]
25. Khakpai, F., Nasehi, M., Haeri-Rohani, A., Eidi, A., & Zarrindast, M. R. (2012). Scopolamine induced memory impairment; possible involvement of NMDA receptor mechanisms of dorsal hippocampus and/or septum. Behavioural Brain Research, 231(1), 1-10. [DOI:10.1016/j.bbr.2012.02.049] [DOI:10.1016/j.bbr.2012.02.049]
26. Ki, Y. W., Park, J. H., Lee, J. E., Shin, I. C., & Koh, H. C. (2013). JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis. Toxicology Letters, 218(3), 235-45. [DOI:10.1016/j.toxlet.2013.02.003] [DOI:10.1016/j.toxlet.2013.02.003]
27. Kim, E. K., & Choi, E. J. (2010). Pathological roles of MAPK signaling pathways in human diseases. Biochimica et Biophysica Acta, 1802(4), 396-405. [DOI:10.1016/j.bbadis.2009.12.009] [DOI:10.1016/j.bbadis.2009.12.009]
28. Klinkenberg, I., & Blokland, A. (2010). The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neuroscience and Biobehavioral Reviews, 34(8), 1307-50. [DOI:10.1016/j.neubiorev.2010.04.001] [DOI:10.1016/j.neubiorev.2010.04.001]
29. Liu, L., Brown, J. C., Webster, W. W., Morrisett, R. A., & Monaghan, D. T. (1995). Insulin potentiates N-methyl-D-aspartate receptor activity in Xenopus oocytes and rat hippocampus. Neuroscience Letter, 192(1), 5-8. [DOI:10.1016/0304-3940(95)11593-L] [DOI:10.1016/0304-3940(95)11593-L]
30. Malikowska, N., Salat, K., & Podkowa, A. (2017). Comparison of pro-amnesic efficacy of scopolamine, biperiden, and phencyclidine by using passive avoidance task in CD-1 mice. Journal of Pharmacological and Toxicological Methods, 86(1), 76-80. [DOI:10.1016/j.vascn.2017.04.006] [DOI:10.1016/j.vascn.2017.04.006]
31. Markram, H., & Segal, M. (1990). Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine. Journal of Physiology, 427(2), 381-93. [DOI:10.1113/jphysiol.1990.sp018177] [PMID] [PMCID] [DOI:10.1113/jphysiol.1990.sp018177]
32. Mitsushima, D. (2011). Sex differences in the septo-hippocampal cholinergic system in rats: Behavioral consequences. Current Topics in Behavioral Neuroscience, 8(2), 57-71. [DOI:10.1007/7854_2010_95] [DOI:10.1007/7854_2010_95]
33. Moosavi, M., Ghasemi, R., Maghsoudi, N., Rastegar, K., & Zarifkar, A. (2011). The relation between pregnancy and stress in rats: considering corticosterone level, hippocampal caspase-3 and MAPK activation. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 158(2), 199-203. [DOI:10.1016/j.ejogrb.2011.05.005] [DOI:10.1016/j.ejogrb.2011.05.005]
34. Moosavi, M., Khales, G. Y., Abbasi, L., Zarifkar, A., & Rastegar, K. (2012). Agmatine protects against scopolamine-induced water maze performance impairment and hippocampal ERK and Akt inactivation. Neuropharmacology, 62(5-6), 2018-23. [DOI:10.1016/j.neuropharm.2011.12.031] [DOI:10.1016/j.neuropharm.2011.12.031]
35. Moosavi, M., Naghdi, N., Maghsoudi, N., & Zahedi Asl, S. (2007). Insulin protects against stress-induced impairments in water maze performance. Behavioural Brain Research, 176(2), 230-6. [DOI:10.1016/j.bbr.2006.10.011] [DOI:10.1016/j.bbr.2006.10.011]
36. Moosavi, M., Soukhak Lari, R., Moezi, L., & Pirsalami, F. (2018). Scopolamine-induced passive avoidance memory retrieval deficit is accompanied with hippocampal MMP2, MMP-9 and MAPKs alteration. European Journal of Pharmacology, 819(1), 248-53. [DOI:10.1016/j.ejphar.2017.12.007] [DOI:10.1016/j.ejphar.2017.12.007]
37. Ohno, M., & Watanabe, S. (1998). Enhanced N-methyl-D-aspartate function reverses working memory failure induced by blockade of group I metabotropic glutamate receptors in the rat hippocampus. Neuroscience Letter, 240(1), 37-40. [DOI:10.1016/j.neulet.2004.04.014] [DOI:10.1016/j.neulet.2004.04.014]
38. Paxinos, G., & Watson, C. (2007). The rat brain in stereotaxic coordinates/George Paxinos. Amsterdam: Charles Watson.[PMCID] [PMCID]
39. Ramin, M., Azizi, P., Motamedi, F., Haghparast, A., & Khodagholi, F. (2011). Inhibition of JNK phosphorylation reverses memory deficit induced by beta-amyloid (1-42) associated with decrease of apoptotic factors. Behavioural Brain Research, 217(2), 424-31. [DOI:10.1016/j.bbr.2010.11.017] [DOI:10.1016/j.bbr.2010.11.017]
40. Roskoski, R. (2012). ERK1/2 MAP kinases: structure, function, and regulation. Pharmacology Research, 66(2), 105-43. [DOI:10.1016/j.phrs.2012.04.005] [DOI:10.1016/j.phrs.2012.04.005]
41. Sarter, M., & Bruno, J. P. (1997). Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Research. Brain Research Reviews, 23(1-2), 28-46. [DOI:10.1016/S0165-0173(96)00009-4] [DOI:10.1016/S0165-0173(96)00009-4]
42. Seo, J. Y., Lim, S. S., Kim, J., Lee, K. W., & Kim, J. S. (2017). Alantolactone and Isoalantolactone Prevent Amyloid beta25-35 -induced Toxicity in Mouse Cortical Neurons and Scopolamine-induced Cognitive Impairment in Mice. Phytotherapy Research, 31(5), 801-11. [DOI:10.1002/ptr.5804] [DOI:10.1002/ptr.5804]
43. Skeberdis, V. A., Lan, J., Zheng, X., Zukin, R. S., & Bennett, M. V. (2001). Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3561-6. [DOI:10.1073/pnas.051634698] [DOI:10.1073/pnas.051634698]
44. Smedlund, K., Tano, J. Y., Margiotta, J., & Vazquez, G. (2011). Evidence for operation of nicotinic and muscarinic acetylcholine receptor-dependent survival pathways in human coronary artery endothelial cells. Journal of Cellular Biochemistry, 112(8), 1978-84. [DOI:10.1002/jcb.23169] [DOI:10.1002/jcb.23169]
45. Subramaniam, S., & Unsicker, K. (2010). ERK and cell death: ERK1/2 in neuronal death. FEBS Journal, 277(1), 22-9. [DOI:10.1111/j.1742-4658.2009.07367.x] [PMID] [DOI:10.1111/j.1742-4658.2009.07367.x]
46. Sunderland, T., Tariot, P. N., Weingartner, H., Murphy, D. L., Newhouse, P. A., Mueller, E. A. et al. (1986). Pharmacologic modelling of Alzheimer's disease. Progress in Neuro-psychopharmacology & Biological Psychiatry, 10(3-5), 599-610. [DOI:10.1016/0278-5846(86)90030-8] [DOI:10.1016/0278-5846(86)90030-8]
47. Tohgi, H., Abe, T., Kimura, M., Saheki, M., & Takahashi, S. (1996). Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. Journal of Neural Transmission, 103(10), 1211-20. [DOI:10.1007/BF01271206] [PMID] [DOI:10.1007/BF01271206]
48. Valjent, E., Pages, C., Herve, D., Girault, J. A., & Caboche, J. (2004). Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. European Journal of Neuroscience, 19(7), 1826-36. [DOI:10.1111/j.1460-9568.2004.03278.x] [DOI:10.1111/j.1460-9568.2004.03278.x]
49. Wang, Q., Walsh, D. M., Rowan, M. J., Selkoe, D. J., & Anwyl, R. (2004). Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. Journal of Neuroscience, 24(13), 3370-8. [DOI:10.1523/JNEUROSCI.1633-03.2004] [DOI:10.1523/JNEUROSCI.1633-03.2004]
50. Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & Delon, M. R. (1982). Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science, 215(4537), 1237-9. [DOI:10.1126/science.7058341] [PMID] [DOI:10.1126/science.7058341]
51. Wolfer, D. P., Stagljar-Bozicevic, M., Errington, M. L., & Lipp, H. P. (1998). Spatial Memory and Learning in Transgenic Mice: Fact or Artifact? News in Physiological Sciences, 13(1), 118-23. [DOI:10.1152/physiologyonline.1998.13.3.118] [DOI:10.1152/physiologyonline.1998.13.3.118]
52. Yi, J. H., Cho, S. Y., Jeon, S. J., Jung, J. W., Park, M. S., Kim, D. H. et al. (2016). Early immature neuronal death is partially involved in memory impairment induced by cerebral ischemia. Behavioural Brain Research, 308, 75-82. [DOI:10.1016/j.bbr.2016.04.019] [DOI:10.1016/j.bbr.2016.04.019]
53. Zhang, L., Fang, Y., Xu, Y., Lian, Y., Xie, N., Wu, T. et al. (2015). Curcumin Improves Amyloid beta-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway. PLoS One, 10(6), e0131525. [DOI:10.1371/journal.pone.0131525] [DOI:10.1371/journal.pone.0131525]

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

Send email to the article author

© 2019 All Rights Reserved | Basic and Clinical Neuroscience

Designed & Developed by : Yektaweb