Skip to main content
SpringerLink
Log in

Effects of Limonene on Chronic Restraint Stress-Induced Memory Impairment and Anxiety in Male Rats

  • Published:
Neurophysiology Aims and scope

Limonene is a natural monoterpene having antioxidant, anti-inflammatory, and neuro-protective properties. We investigated the effects of limonene on memory impairment, hippocampal damage, and high anxiety induced by chronic immobilization stress in male rats. Fourty male Wistar rats were divided into the control (C), limonene (L), stress (S), and stress+limonene (S+L) groups. Animals of the S and S+L groups were put in a restrainer daily for 6 h for 21 consecutive days. Within the same period, the L and S+L groups were treated with limonene (10 mg/kg, gavaging). The Morris water maze (MWM) and elevated plus-maze (EPM) tests were used to evaluate spatial learning, formation of memory, and the anxiety level. At the end of the course, structural hippocampal damage was evaluated by Nissl’s staining. Chronic immobilization reduced memory, caused the emergence of anxiety, and induced neuronal loss in the CA1 area of the hippocampus. The duration and distance traveled to reach the hidden platform in the MWM test in the S+L group were significantly smaller compared with those in the S group (P < 0.05), while time spent in the target quadrant was significantly greater compared with the latter group (P < 0.01). Also, limonene provided a significant increase in the percentage of open-arm entries and stay in these arms of the EPM, as compared with the S group (respectively, P < 0.01 and P < 0.05), and reduced stress-induced damage in CA1 pyramidal neurons in these animals. It is concluded that limonene provides spatial memory improvement and reduces anxiety in rats exposed to immobilization stress; it may appear efficient in treating neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. J. I. Liu, X. Wang, M. K. Shigenaga, et al., “Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats,” FASEB J., 10, No. 13, 1532–1538 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. F. U. Fontella, I. R. Siqueira, A. P. Vasconcellos, et al., “Repeated restraint stress induces oxidative damage in rat hippocampus,” Neurochem. Res., 30, No. 1, 105–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Y. Zhang, W. Liu, Y. Zhou, et al., “Endoplasmic reticulum stress is involved in restraint stress-induced hippocampal apoptosis and cognitive impairments in rats,” Physiol. Behav., 131, 41–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. F. U. Fontella, D. A. Vendite, A. S. Tabajara, et al., “Repeated restraint stress alters hippocampal glutamate uptake and release in the rat,” Neurochem. Res., 29, No. 9, 1703–1709 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. V. Di Liberto, M. Frinchi, V. Verdi, et al., “Anxiolytic effects of muscarinic acetylcholine receptor agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex,” Psychopharmacology, 234, No. 4, 559–573 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. K. Kunisawa, K. Kido, N. Nakashima, et al., “Betaine attenuates memory impairment after water-immersion restraint stress and is regulated by the GABAergic neuronal system in the hippocampus,” Eur. J. Pharmacol., 796, 122–130 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. B. S. McEwen, C. Nasca, and J. D. Gray, “Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex,” Neuropsychopharmacology, 41, No. 1, 3–23 (2016).

    Article  CAS  Google Scholar 

  8. V. R. Bhagya, B. N. Srikumar, J. Veena, et al., “Shortterm exposure to enriched environment rescues chronic stress-induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits,” J. Neurosci. Res., 95, No. 8, 1602–1610 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. S. C. Chaudhary, M. S. Siddiqui, M. Athar, and M. S. Alam, “D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis,” Hum. Exp. Toxicol., 31, No. 8, 798–811 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. J. Bai, Y. Zheng, G. Wang, and P. Liu, “Protective effect of D-limonene against oxidative stress-induced cell damage in human lens epithelial cells via the p38 pathway,” Oxid. Med. Cell Longev., 2016, No. 14, 1–12 (2016).

    Google Scholar 

  11. R. Murali and R. Saravanan, “Antidiabetic effect of d-limonene, a monoterpene, in streptozotocin-induced diabetic rats,” Biom. Prev. Nutr., 2, No. 4, 269–275 (2012).

    Article  Google Scholar 

  12. X. Wang, G. Li, and W. Shen, “Protective effects of D-limonene against transient cerebral ischemia in stroke-prone spontaneously hypertensive rats,” Exp. Ther. Med., 15, No. 1, 699–706 (2018).

    CAS  PubMed  Google Scholar 

  13. P. A. d’Alessio, R. Ostan, J. F. Bisson, et al., “Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans,” Life Sci., 92, Nos. 24/26, 1151–1156 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. K. S. MacDowell, J. R. Caso, D. Martín-Hernández, et al., “Paliperidone prevents brain Toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress,” Int. J. Neuropsychopharmacol., 18, No. 3, pyu070 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  15. M. Asle-Rousta, S. Oryan, A. Ahmadiani, and M. Rahnema, “Activation of sphingosine 1-phosphate receptor-1 by SEW2871 improves cognitive function in Alzheimer’s disease model rats,” EXCLI J., 12, 449–461 (2013).

    PubMed  PubMed Central  Google Scholar 

  16. M. E. Rebuli, L. Camacho, M. E. Adonay, et al., “Impact of low-dose oral exposure to bisphenol A (BPA) on juvenile and adult rat exploratory and anxiety behavior: A CLARITY-BPA consortium study,” Toxicol. Sci., 148, No. 2, 341–354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. R. R. Huang, W. Hu, Y. Y. Yin, et al., “Chronic restraint stress promotes learning and memory impairment due to enhanced neuronal endoplasmic reticulum stress in the frontal cortex and hippocampus in male mice,” Int. J. Mol. Med., 35, No. 2, 553–559 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. K. Fukui, K. Onodera, T. Shinkai, et al., “Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems,” Ann. N.Y. Acad. Sci., 928, 168–175 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. B. S. Rao and T. R. Raju, “Restraint stress-induced alterations in the levels of biogenic amines, amino acids, and AChE activity in the hippocampus,” Neurochem. Res., 25, No. 12, 1547–1552 (2000).

    Article  PubMed  Google Scholar 

  20. M. Popoli, Z. Yan, B. S. McEwen, and G. Sanacora, “The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission,” Nat. Rev. Neurosci., 13, No. 1, 22–37 (2012).

    Article  CAS  Google Scholar 

  21. W. Zhou, M. Yoshioka, and H. Yokogoshi, “Sub-chronic effects of s-limonene on brain neurotransmitter levels and behavior of rats,” J. Nutr. Sci. Vitaminol., 55, No. 4, 367–373 (2009)

    Article  CAS  PubMed  Google Scholar 

  22. M. E. Hasselmo, “The role of acetylcholine in learning and memory,” Curr. Opin. Neurobiol., 16, No. 6, 710–715 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. A. Imperato, S. Puglisi-Allegra, P. Casolini, and L. Angelucci, “Changes in brain dopamine and acetylcholine release during and following stress are independent of the pituitary-adrenocortical axis,” Brain Res., 538, No. 1, 111–117 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. W. Zhou, S. Fukumoto, and H. Yokogoshi, “Components of lemon essential oil attenuate dementia induced by scopolamine,” Nutr. Neurosci., 12, No. 2, 57–64 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. J. Takito, M. Ota, C. Oba, et al., “Limonene enhances the cAMP response element (CRE)-dependent transcriptional activity activated via adenosine A2A receptor in a neural crest derived cell line, PC-12,” Planta Med., 3, No. 3, 60–62 (2016).

    Google Scholar 

  26. M. N. Hill, S. A. Kumar, S. B. Filipski, et al., “Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure,” Mol. Psychiat., 18, No. 10, 1125–1135 (2013).

    Article  CAS  Google Scholar 

  27. H. Rammal, J. Bouayed, C. Younos, and R. Soulimani, “Evidence that oxidative stress is linked to anxietyrelated behavior in mice,” Brain Behav. Immunol., 22, No. 8, 1156–1159 (2008).

    Article  CAS  Google Scholar 

  28. J. Bouayed, H. Rammal, and R. Soulimani, “Oxidative stress and anxiety: relationship and cellular pathways,” Oxid. Med. Cell Longev., 2, No. 2, 63–67 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. P. A. Manzanares, N. A. Isoardi, H. F. Carrer, and V. A. Molina, “Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala,” J. Neurosci., 25, No. 38, 8725–8734 (2005).

    Article  CAS  Google Scholar 

  30. C. B. Nemeroff, “The role of GABA in the pathophysiology and treatment of anxiety disorders,” Psychopharmacol. Bull., 37, No. 4, 133–146 (2003).

    PubMed  Google Scholar 

  31. A. A. de Almeida, J. P. Costa, R. B. de Carvalho, et al., “Evaluation of acute toxicity of a natural compound (+)-limonene epoxide and its anxiolytic-like action,” Brain Res., 1448, 56–62 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Animal Physiology, Zanjan Branch, Islamic Azad University, Zanjan, Iran

    Y. Bigdeli, M. Asle-Rousta & M. Rahnema

Authors
  1. Y. Bigdeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Asle-Rousta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Rahnema
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Asle-Rousta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bigdeli, Y., Asle-Rousta, M. & Rahnema, M. Effects of Limonene on Chronic Restraint Stress-Induced Memory Impairment and Anxiety in Male Rats. Neurophysiology 51, 107–113 (2019). https://doi.org/10.1007/s11062-019-09800-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11062-019-09800-0

Keywords

Search

Navigation