Cinnamaldehyde improves methamphetamine-induced spatial learning and memory deficits and restores ERK signaling in the rat prefrontal cortex

Document Type : Original Article


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy

3 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

5 Milad Infertility Center, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

6 Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

7 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Methamphetamine is a stimulant compound that penetrates readily into the central nervous system. Repeated exposure to methamphetamine leads to damage in the dopaminergic and serotonergic axons of selected brain regions. Previous studies showed that cinnamaldehyde improved memory impairment in animals. In the present study, we aimed to elucidate the effects of cinnamaldehyde on methamphetamine-induced memory impairment in rats.
Materials and Methods: Male Wistar rats received methamphetamine (10 mg/kg, intraperitoneally) for 7 days. Thirty minutes before each injection, animals were given cinnamaldehyde (20, 40, or 80 mg/kg) or rivastigmine (1 mg/kg). The spatial learning and memory were examined using the Morris water maze test. The expression of extracellular signal-regulated kinase (ERK) phosphorylation in the frontal cortex and hippocampus was also detected by immunohistochemical method.
Results: Administration of methamphetamine increased the latency to find the platform in the learning phase, while administration of cinnamaldehyde (40 mg/kg) or rivastigmine before methamphetamine reversed the increased latency. Administration of cinnamaldehyde, at the dose of 40 mg/kg with methamphetamine, increased the time and distance traveled in the target quadrant in comparison with the amphetamine group. Moreover, the methamphetamine and cinnamaldehyde-treated group had higher expression of phosphorylated ERK1/2 in the prefrontal cortex in comparison with the methamphetamine-treated animals.
Conclusion: The present data demonstrated that repeated METH administration impaired cognitive performance through the ERK pathway and decreased the phosphorylation of ERK1/2 in the prefrontal cortex while administration of cinnamaldehyde restored both effects. Accordingly, cinnamaldehyde may be a valuable therapeutic tool for the treatment of cognitive deficits associated with methamphetamine consumption.


Main Subjects

1. Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend 2014;143:11-21.
2. Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Medicine 2016;14:1-11.
3. Cruickshank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine. Addiction 2009;104:1085-1099.
4. Ghadiri A, Etemad L, Moshiri M, Moallem SA, Jafarian AH, Hadizadeh F, et al. Exploring the effect of intravenous lipid emulsion in acute methamphetamine toxicity. Iran J Basic Med Sci 2017;20:138-144.
5. Halpin LE, Collins SA, Yamamoto BK. Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci 2014;97:37-44.
6. Yu S, Zhu L, Shen Q, Bai X, Di X. Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology. Behav Neurol 2015;2015:1-11.
7. Chen YJ, Liu YL, Zhong Q, Yu YF, Su HL, Toque HA, et al. Tetrahydropalmatine protects against methamphetamine-induced spatial learning and memory impairment in mice. Neurosci Bull 2012;28:222-232.
8. Sun WL, Quizon PM, Zhu J. Molecular mechanism: ERK signaling, drug addiction, and behavioral effects. Prog Mol Biol Transl Sci 2016;137:1-40.
9. Liao JC, Deng JS, Chiu CS, Hou WC, Huang SS, Shie PH, et al. Anti-inflammatory activities of cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Alternat Med 2012;2012:1-12.
10. Zaidi SF, Aziz M, Muhammad JS, Kadowaki M. Review: Diverse pharmacological properties of Cinnamomum cassia: A review. Pak J Pharm Sci 2015;28:1433-1438.
11. Medagama AB. The glycaemic outcomes of Cinnamon, a review of the experimental evidence and clinical trials. Nutr J 2015;14:1-12.
12. Sohrabi R, Pazgoohan N, Seresht HR, Amin B. Repeated systemic administration of the cinnamon essential oil possesses anti-anxiety and anti-depressant activities in mice. Iran J Basic Med Sci 2017;20:708-714.
13. Bickers D, Calow P, Greim H, Hanifin JM, Rogers AE, Saurat JH, et al. A toxicologic and dermatologic assessment of cinnamyl alcohol, cinnamaldehyde and cinnamic acid when used as fragrance ingredients. Food Chem Toxicol 2005;43:799-836.
14. Lv C, Yuan X, Zeng HW, Liu RH, Zhang WD. Protective effect of cinnamaldehyde against glutamate-induced oxidative stress and apoptosis in PC12 cells. Eur J Pharmacol 2017;815:487-494.
15. Herdwiani W, Someradji AA, Elfahmi., TAN MI. A review of cinnamon as a potent anticancer drug. Asian J Pharm Clin Res 2016;9:8-13.
16. Rao PV, Gan SH. Cinnamon: a multifaceted medicinal plant. Evid Based Complement Alternat Med 2014;2014:642942.
17. Bae WY, Choi JS, Jeong JW. The neuroprotective effects of cinnamic aldehyde in an MPTP mouse model of parkinson’s disease. Int J Mol Sci 2018;19:1-10.
18. Momtaz S, Hassani S, Khan F, Ziaee M, Abdollahi M. Cinnamon, a promising prospect towards Alzheimer’s disease. Pharmacol Res 2018;130:241-258.
19. Montrucchio DP, Cordova MM, Santos AR. Plant derived aporphinic alkaloid S-(+)-dicentrine induces antinociceptive effect in both acute and chronic inflammatory pain models: evidence for a role of TRPA1 channels. PLoS One 2013;8:e67730.
20. Moghimi M, Parvardeh S, Zanjani TM, Ghafghazi S. Protective effect of alpha-terpineol against impairment of hippocampal synaptic plasticity and spatial memory following transient cerebral ischemia in rats. Iran J Basic Med Sci 2016;19:960-969.
21. Handra-Luca A, Bilal H, Bertrand J-C, Fouret P. Extra-cellular signal-regulated ERK-1/ERK-2 pathway activation in human salivary gland mucoepidermoid carcinoma: association to aggressive tumor behavior and tumor cell proliferation. Am J Pathol 2003;163:957-967.
22. Gonzalez R, Rippeth JD, Carey CL, Heaton RK, Moore DJ, Schweinsburg BC, et al. Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure. Drug Alcohol Depend 2004;76:181-190.
23. Thompson PM, Hayashi KM, Simon SL, Geaga JA, Hong MS, Sui Y, et al. Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 2004;24:6028-6036.
24. Vorhees CV, Williams MT. Assessing spatial learning and memory in rodents. ILAR J 2014;55:310-332.
25. Jain S, Sangma T, Shukla SK, Mediratta PK. Effect of Cinnamomum zeylanicum extract on scopolamine-induced cognitive impairment and oxidative stress in rats. Nutr Neurosci 2015;18:210-216.
26. González B, Raineri M, Cadet JL, García-Rill E, Urbano FJ, Bisagno V. Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice. Neuropharmacology 2014;87:188-197.
27. Moshiri M, Hosseiniyan SM, Moallem SA, Hadizadeh F, Jafarian AH, Ghadiri A, et al. The effects of vitamin B12 on the brain damages caused by methamphetamine in mice. Iran J Basic Med Sci 2018;21:434-438.
28. Stavinoha RC, Vattem DA. Potential neuroprotective effects of cinnamon. ICMJE 2015;8:24-46.
29. Zhang L, Zhang Z, Fu Y, Yang P, Qin Z, Chen Y, et al. Trans-cinnamaldehyde improves memory impairment by blocking microglial activation through the destabilization of iNOS mRNA in mice challenged with lipopolysaccharide. Neuropharmacology 2016;110:503-518.
30. Modi KK, Rangasamy SB, Dasarathi S, Roy A, Pahan K. Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement. J Neuroimmune Pharmacol 2016;11:693-707.
31. Iersel ML, Ploemen JP, Struik I, van Amersfoort C, Keyzer AE, Schefferlie JG, et al. Inhibition of glutathione S-transferase activity in human melanoma cells by alpha,beta-unsaturated carbonyl derivatives. Effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal. Chem Biol Interact 1996;102:117-132.