Pharmacological evidence for lithium-induced neuroprotection against methamphetamine-induced neurodegeneration via Akt-1/GSK3 and CREB-BDNF signaling pathways

Document Type: Original Article


1 Department of pharmaceutical chemistry, faculty of pharmaceutical chemistry, pharmaceutical sciences branch, Islamic Azad University (IUAPS), Tehran, Iran

2 Research Center for Addiction and Risky Behaviors (ReCARB), Iran Psychiatric Center, Iran University of Medical Sciences, Tehran, Iran

3 Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

4 Department of Physiology, Tehran University of Medical Sciences-International Campus (TUMS-IC), Tehran, Iran


Objective(s): Neurodegeneration is an outcome of Methamphetamine (METH) abuse. Studies have emphasized on the neuroprotective properties of lithium. The current study is designed towards evaluating the role of Akt-1/GSK3 and CREB-BDNF signaling pathways in mediating lithium neuroprotection against METH-induced neurodegeneration in rats.
Materials and Methods: Sixty adult male rats were randomly divided into five groups: control group (received 0.7 ml normal saline per rat for 28 days), METH group (given 10 mg/kg of METH intraperitoneally for 28 days), groups 3, 4, and 5 (given  METH (10 mg/kg) and lithium (75, 150, and 300 mg/kg intraperitoneally, individually for 28 days). Morris water maze (MWM) was used to assess mental functions. In addition to hippocampal neurodegeneration, Brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Glycogen synthase kinase 3 (GSK3), and Protein kinase B (Akt-1) were assessed in isolated hippocampus.
Results: METH abuse caused marked disorders in learning and memory that were dramatically improved with various doses of lithium. Furthermore, METH increased lipid peroxidation and the levels of oxidized form of interleukin 1 beta (IL-1β), glutathione (GSSG), Bax, tumor necrosis factor alpha (TNF-α), and GSK3,  while attenuating the extent of glutathione (reduced form (GSH)), P-CREB, Bcl-2, BDNF,  and Akt-1 in the hippocampus. Moreover, METH declined superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) activity in the hippocampus. Conversely, lithium attenuated METH-stimulated apoptosis, oxidative stress, and inflammation; while improving the extent of BDNF and P-CREB.
Conclusion: Probably lithium possesses neuroprotection against METH-stimulated neurodegeneration in the hippocampus via Akt-1/GSK3β and CREB/BDNF signaling pathways.


Main Subjects

1. Darke S, Darke S, Kaye S, Darke S, Kaye S, McKetin R, et al. Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev 2008; 27:253-262.
2. Barr AM, Panenka WJ, MacEwan GW, Thornton AE, Lang DJ, Honer WG, et al. The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci 2006; 31:301-313
3. Krasnova IN, Justinova Z, Ladenheim B, Jayanthi S, McCoy MT, Barnes C, et al. Methamphetamine self-administration is associated with persistent biochemical alterations in striatal and cortical dopaminergic terminals in the rat. PloS One 2010;5:e8790.
4. Volkow ND, Chang L, Wang G-J, Fowler JS, Leonido-Yee M, Franceschi D, et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 2001;158:377-382.
5. Thrash B, Karuppagounder SS, Uthayathas S, Suppiramaniam V, Dhanasekaran M. Neurotoxic effects of methamphetamine. Neuroch Res. 2010;35:171-179.
6. Brecht M-L, O’Brien A, Von Mayrhauser C, Anglin MD. Methamphetamine use behaviors and gender differences. Addictive Behaviors 2004;29:89-106.
7. Narita M, Aoki K, Takagi M, Yajima Y, Suzuki T. Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine. Neuroscience 2003;119:767-775.
8. Nouri M, Movassaghi S. Protective effect of pentoxifylline on male wistar rat testicular germ cell apoptosis induced by 3, 4-methylenedioxymeth amphetamine. Iran J Basic Med Sci 2016;19:646-652.
9. Cadet JL, Jayanthi S, Deng X. Methamphetamine-induced neuronal apoptosis involves the activation of multiple death pathways. Review. Neurotox Res 2005;8:199-206.
10. Wu CW, Ping YH, Yen JC, Chang CY, Wang SF, Yeh CL, et al. Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis. Toxicol Appl Pharmacol 2007;220:243-251.
11. Zhang X, Banerjee A, Banks WA, Ercal N. N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells. Brain Res. 2009;1275:87-95.
12. Jumnongprakhon P, Govitrapong P, Tocharus C, Tocharus J. Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells. Brain Res. 2016;1646:182-192.
13. Marmol F. Lithium: bipolar disorder and neurodegenerative diseases possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry.2008;32:1761-1771.
14. Emamghoreishi M, Keshavarz M, Nekooeian AA. Acute and chronic effects of lithium on BDNF and GDNF mRNA and protein levels in rat primary neuronal, astroglial and neuroastroglia cultures. Iran J Basic Med Sci. 2015;18:240-246.
15. Rowe MK, Chuang D-M. Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med. 2004;6:1-18.
16. Rockenstein E, Torrance M, Adame A, Mante M, Bar-On P, Rose JB, et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3β signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 2007;27:1981-1991.
17.  Motaghinejad M, Motevalian M, Shabab B, Fatima S. Effects of acute doses of methylphenidate on inflammation and oxidative stress in isolated hippocampus and cerebral cortex of adult rats . J Neural Transm (Vienna) 2017 ;124:121-131.
18. Motaghinejad M, Motevalian M, Fatima S, Beiranvand T, Mozaffari S. Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats. J Neural Transm (Vienna) 2017;124:1369-1387.
19. Pláteník J, Fišar Z, Buchal R, Jirák R, Kitzlerová E, Zvěřová M, et al. GSK3β, CREB, and BDNF in peripheral blood of patients with Alzheimer’s disease and depression. Prog Neuropsychopharmacol Biol Psychiatry 2014;50:83-93.
20. Dong H, Zhang X, Dai X, Lu S, Gui B, Jin W, et al. Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway. J Neuroinflammation 2014;11:140-144.
21. Chen G, Rajkowska G, Du F, Seraji‐Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem. 2000;75:1729-1734.
22. Tsaltas E, Kontis D, Boulougouris V, Papadimitriou GN. Lithium and cognitive enhancement: leave it or take it? Psychopharmacology (Berl). 2009;202:457-476.
23. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 2010;160:1577-1579.
24. McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 2010;160:1573-1576.
25. D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 2001;36:60-90.
26. Motaghinejad M, Motevalian M, Larijani SF, Khajehamedi Z. Protective effects of forced exercise against methylphenidate-induced anxiety, depression and cognition impairment in rat. Adv Biomed Res 2015;4 doi: 10.4103/2277-9175.161528.
27. Motaghinejad M, Fatima S, Karimian M, Ganji S. Protective effects of forced exercise against nicotine-induced anxiety, depression and cognition impairment in rat. J Basic Clin Physiol Pharmacol 2015;27:19-27.
28. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006;1:848-858.
29. Bromley-Brits K, Deng Y, Song W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp: JoVE 2011. doi: 10.3791/2920
30. Motaghinejad M, Motevalian M, Abdollahi M, Heidari M, Madjd Z. Topiramate confers neuroprotection against methylphenidate-induced neurodegeneration in dentate gyrus and CA1 regions of Hippocampus via CREB/BDNF pathway in rats. Neurotox Res 2017;31:373-399.
31. Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M. Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. Biomed Pharmacother. 2017;87:721-740.
32. Motaghinejad M, Seyedjavadein Z, Motevalian M, Asadi M. The neuroprotective effect of lithium against high dose methylphenidate: possible role of BDNF. Neurotoxicology 2016;56:40-54.
33. Motaghinejad M, Motevalian M, Fatima S, Faraji F, Mozaffari S. The neuroprotective effect of curcumin against nicotine-induced neurotoxicity is mediated by CREB–BDNF signaling pathway. Neurochem Res 2017;42:2921-2932.
34. Motaghinejad M, Karimian SM, Motaghinejad O, Shabab B, Asadighaleni M, Fatima S. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats. Fundam Clin Pharmacol 2015;29:299-309.
35. Motaghinejad M, Motevalian M, Fatima S. Mediatory role of NMDA, AMPA/kainate, GABAA and Alpha2 receptors in topiramate neuroprotective effects against methylphenidate induced neurotoxicity in rat. Life Sci 2017;179:37-53.
36. Motaghinejad M, Motevalian M, Falak R, Heidari M, Sharzad M, Kalantari E. Neuroprotective effects of various doses of topiramate against methylphenidate-induced oxidative stress and inflammation in isolated rat amygdala: the possible role of CREB/BDNF signaling pathway. J Neural Transm (Vienna) 2016;123:1463-1477.
37.Motaghinejad M, Motevalian M, Babalouei F, Abdollahi M, Heidari M, Madjd Z. Possible involvement of CREB/BDNF signaling pathway in neuroprotective effects of topiramate against methylphenidate induced apoptosis, oxidative stress and inflammation in isolated hippocampus of rats: molecular, biochemical and histological evidences. Brain Res Bull 2017;132:82-98.
38. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 2005;2005:273-279.
39. Demircan N, Safran B, Soylu M, Ozcan A, Sizmaz S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond) 2006;20:1366-1369.
40. Shi YQ, Huang TW, Chen LM, Pan XD, Zhang J, Zhu YG, et al. Ginsenoside Rg1 attenuates amyloid-β content, regulates PKA/CREB activity, and improves cognitive performance in SAMP8 mice. J Alzheimers Dis 2010;19:977-989.
41. Lee B-H, Kim H, Park S-H, Kim Y-K. Decreased plasma BDNF level in depressive patients. J Affect Disord 2007;101:239-244.
42. Bruin JE, Gerstein HC, Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: a critical review. Toxicol Sci 2010;116:364-374.
43. Gonçalves J, Baptista S, Martins T, Milhazes N, Borges F, Ribeiro CF, et al. Methamphetamine‐induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. Eur J Neurosci 2010;31:315-326.
44. Johnson BA, Roache JD, Ait-Daoud N, Wallace C, Wells LT, Wang Y. Effects of isradipine on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition. Psychopharmacology (Berl) 2005;178:296-302.
45. Kutcher SP. Lithium and Cognition. J Child Adolesc Psychopharmacol 2004;9:8-15.
46. Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl) 2003;170:225-234.
47. Brown JM, Quinton MS, Yamamoto BK. Methamphetamine‐induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite. J Neurochem 2005;95:429-436.
48. Mashayekhi V, Eskandari MR, Kobarfard F, Khajeamiri A, Hosseini M-J. Induction of mitochondrial permeability transition (MPT) pore opening and ROS formation as a mechanism for methamphetamine-induced mitochondrial toxicity. Naunyn Schmiedebergs Arch Pharmacol. 2014;387:47-58.
49. Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S, et al. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol. 2009;12:805-22.
50. Zitka O, Skalickova S, Gumulec J, Masarik M, Adam V, Hubalek J, et al. Redox status expressed as GSH: GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett.2012;4:1247-53.
51. Griffith OW, Meister A. Origin and turnover of mitochondrial glutathione. Proceedings of the National Academy of Sciences of the United States of America. 1985;82:4668.
52. Harold C, Wallace T, Friedman R, Gudelsky G, Yamamoto B. Methamphetamine selectively alters brain glutathione. Eur J Pharmacol 2000;400:99-102.
53. Moszczynska A, Turenne S, Kish SJ. Rat striatal levels of the antioxidant glutathione are decreased following binge administration of methamphetamine. Neurosci Lett 1998;255:49-52.
54. Maurer IC, Schippel P, Volz HP. Lithium‐induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord 2009;11:515-22.
55. Cui J, Shao L, Young LT, Wang JF. Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience 2007;144:1447-1453.
56. Imam SZ, Ali SF. Selenium, an antioxidant, attenuates methamphetamine-induced dopaminergic toxicity and peroxynitrite generation. Brain Res 2000; 855:186-191.
57. Power JH, Blumbergs PC. Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol 2009;117:63-73.
58. Chuang DM, Wang Z, Chiu CT. GSK-3 as a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. Front Mol Neurosci 2011;4:15.
59. Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders. Neuropsychiatr Dis Treat 2013;9:493-500.
60. Huang MC, Lin SK, Chen CH, Pan CH, Lee CH, Liu HC. Oxidative stress status in recently abstinent methamphetamine abusers. Psychiatry Clin Neurosci 2013;67:92-100.
61. Chang L, Alicata D, Ernst T, Volkow N. Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 2007;102:16-32.
62. Cadet JL, Ordonez SV, Ordonez JV. Methamphetamine induces apoptosis in immortalized neural cells: Protection by the proto‐oncogene, bcl‐2. Synapse. 1997;25:176-184.
63. Deng X, Cai N-S, McCoy MT, Chen W, Trush MA, Cadet JL. Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway. Neuropharmacology 2002;42:837-845.
64. Carlezon WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005;28:436-445.
65. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2001;2:599-609.
66. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890-893.
67. Yoshii A, Constantine‐Paton M. Postsynaptic BDNF‐TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 2010;70:304-322.
68. Cao G, Zhu J, Zhong Q, Shi C, Dang Y, Han W, et al. Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex. Neuropharmacol. 2013;67:144-154.
69. Razavi BM, Sadeghi M, Abnous K, Vahdati F, Hosseinzadeh H. Study of the role of CREB, BDNF, and VGF neuropeptide in long term antidepressant activity of crocin in the rat cerebellum. Iran J Pharm Res 2017;16:1452-1462.