L-linalool exerts a neuroprotective action on hemiparkinsonian rats

Abstract

Linalool (LIN) is a monoterpene, responsible for the aroma of essential oils in some species. It presents a sedative and anxiolytic potential, enhancing GABAergic currents and behaving as a benzodiazepine-type of drug. The objectives of the present work were to study the neuroprotective effects of LIN on a model of Parkinson’s disease. For that, male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned and treated with LIN (25, 50, and 100 mg/kg, p.o.) for 2 weeks. Afterwards, the animals were subjected to behavioral tests (apomorphine-induced rotations, open field, and forced swimming tests). Then, the animals were euthanized, and the striatum, hippocampus, and prefrontal cortex were processed for neurochemistry (nitrite and lipoperoxidation measurements) and immunohistochemistry (TH and DAT) assays. The results were analyzed by ANOVA and Tukey’s test for multiple comparisons and considered significant at p < 0.05. LIN significantly improved the behavioral alterations of the 6-OHDA-lesioned group, as evaluated by the apomorphine-induced rotations, open field, and forced swimming tests. In addition, LIN partially reversed the decreased DA, DOPAC, and HVA contents observed in the 6-OHDA-lesioned striatum. The untreated 6-OHDA group presented increased nitrite contents and lipoperoxidation in all the brain areas studied, and these changes were completely reversed after LIN treatments. Finally, LIN significantly prevented the reduction in TH and DAT expressions demonstrated in the right 6-OHDA-lesioned striatum. All these data strongly suggest that LIN presents a neuroprotective action in hemiparkinsonian rats, probably related to the drug anti-inflammatory and antioxidant activities.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Ayaz M, Sadiq A, Junaid M, Ullah F, Subhan F, Ahmed J (2017) Neuroprotective and anti-aging potentials of essential oils from aromatic and medicinal plants. Front Aging Neurosci 9:168. https://doi.org/10.3389/fngi,2017.00168

    Article  PubMed  PubMed Central  Google Scholar 

  2. Batista PA, Werner MF, Oliveira EC, Burgos L, Pereira P, Brum LF, Story GM, Santos AR (2010) The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hipersensitivity in mice. J Pain 11:1229–1239.

  3. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson's disease. Front Neuroanat 9:91. https://doi.org/10.3389/fnana.2015.00091

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Brooks DJ (2010) Imaging dopamine transporters in Parkinson's disease. Biomark Med 4:651–660

    CAS  PubMed  Google Scholar 

  5. Brum LFS, Emanuelli T, Souza DO, Elisabetsky E (2001) Effects of linalool on glutamate release and uptake in mouse cortical synaptosomes. Neurochem Res 26:191–194

    CAS  Google Scholar 

  6. Caputo L, Reguilon MD, Minarro J, De Feo V, Rodriguez-Arias M (2018) Lavandula angustifólia essential oil and linalool counteract social aversion induced by social defeat. Molecules. 2018:23,2694. https://doi.org/10.3390/molecules23102694

    CAS  Article  Google Scholar 

  7. CONCEA (2010) Diretriz Brasileira para o Cuidado e Utilização de Animais para Fins Científicos e Didáticos. Resolução Normativa n.30. Ministériom da Ciência, Tecnologia e Inovação. http://www.mct.gov.br/upd_blob/0238/238685.pdf

  8. Dali LM, Ulrich H, Real CC, Feng ZP, Sun HS, Britto LR (2017) Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model. Neurosci. 356:176–181

    Google Scholar 

  9. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Meth Enzymol 186:421–431

    CAS  PubMed  Google Scholar 

  10. Elisabetsky E, Marschner J, Souza DO (1995) Effects of linalool on glutamatergic system in the rat cerebral cortex. Neurochem Res 20:461–465

    CAS  PubMed  Google Scholar 

  11. Elisabetsky E, Brum LF, Souza DO (1999) Anticonvulsant properties of linalool in glutamate-related seizure models. Phytomed. 6:107–113

    CAS  Google Scholar 

  12. Galvan A, Wichmann T (2008) Pathophysiology of parkinsonism. Clin Neurophysiol 119:1459–1474

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138

    CAS  PubMed  Google Scholar 

  14. Haavik J, Toska K (1998) Tyrosine hydroxylase and Parkinson's disease. Mol Neurobiol 16:285–309

    CAS  PubMed  Google Scholar 

  15. Harada H, Kashiwadani H, Kanmura Y, Kuwaki T (2018) Linalool odor-induced anxiolytic effects in mice. Front Behav Neurosci 12:241. https://doi.org/10.3389/fnbeh.2018.00241 eCollection 2018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Hefti F, Melamed E, Sahakian BJ, Wurtman RJ (1980) Circling behavior in rats with partial, unilateral nigro-striatal lesions: effect of amphetamine, apomorphine, and DOPA. Pharmacol Biochem Behav 12:185–188

    CAS  PubMed  Google Scholar 

  17. Hudson JL, van Horne CG, Strömberg I, Brock S, Clayton J, Masserano J, Hoffer BJ, Gerhardt GA (1993) Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats. Brain Res 626:167–174

    CAS  PubMed  Google Scholar 

  18. Hui L, He L, Huan L, Xiao Lan L, Al Guo Z (2010) Chemical composition of lavender essential oil and its antioxidant activity and inhibition against rhinitis-related bacterial. African J Microbiol Res 4:309–313

    Google Scholar 

  19. Huo M, Cui X, Xue J, Chi G, Gao R, Deng X, Guan S, Wei J, Soromou LW, Feng H, Wang D (2013) Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model. J Surg Res 180:e47–e54

    CAS  PubMed  Google Scholar 

  20. Hwang O (2013) Role of oxidative stress in Parkinson's disease. Exp Neurobiol 22:11–17

    PubMed  PubMed Central  Google Scholar 

  21. Jarvis GE, Barbosa R, and Thompson AJ (2016a). J Pharmacol Exp Ther. 356:549–562

  22. Jarvis GE, Barbosa R, Thompson AJ (2016b) Noncompetitive inhibition of 5-HT3 receptors by citral, linalool and eucalyptol revealed by nonlinear mixed-effects modeling. J Pharmacol Exp Ther 356:549–563

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jasinska-Myga B, Putzke JD, Wider C, Wszolek ZK, Uitti RJ (2010) Depression in Parkinson’s disease. Can J Neurol Sci 37:61–66

    PubMed  PubMed Central  Google Scholar 

  24. Jaul E, Barron J (2017) Age-related diseases and clinical and public health implications for the 85 years old and over population. Front Publ Health 11(5):335

    Google Scholar 

  25. Javed H, Azirnullah S, Khair SBA, Ojha S, Haque ME (2016) Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17:58. https://doi.org/10.1186/s12868-016-0293-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Javed H, Azimullah S, Meeran MFN, Ansari SA, Ojha S (2019) Neuroprotective effects of thymol, a dietary monoterpene against dopaminergic neurodegeneration in rotenone-induced rat model of Parkinson’s disease. Int J Mol Sci 20:1538. https://doi.org/10.3390/ijms20071538

    CAS  Article  PubMed Central  Google Scholar 

  27. Kasper S, Gastpar M, Muller WE, Volz HP, Moller HJ, Dienel A, Schlafke S (2010) Efficacy and safety of silexan, a new, orally administered lavender oil preparation, in subthreshold anxiety disorder-evidence from clinical trials. Wien Med Wochenschr 160:547–556

    PubMed  Google Scholar 

  28. Leszek J, Barreto GE, Gasiorowski K, Koutsouraki E, Ávila-Rodrigues M, Aliev G (2016) Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Disord Drug Targets 15(3):2016. https://doi.org/10.2174/187152731566660202125914

    Article  Google Scholar 

  29. Li XJ, Yang YJ, YS LI, Zhang WK, Tang HB (2016) α-Pinene, linalool, and 1-octanol contribute to the topical anti-inflammatory and analgesic activities of frankincense by inhibiting COX-2. J Ethnopharmacol 179:22–26

    CAS  PubMed  Google Scholar 

  30. Liu K, Chen Q, Liu Y, Zhou X, Wang X (2012) Isolation and biological activities of decanal, linalool, valencene, and octanal from sweet orange oil. J Food Sci 77:C1156–C1161

    CAS  PubMed  Google Scholar 

  31. Mehri S, Meshki MA, Hosseinzadeh H (2015) Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats. Drug Chem Toxicol 38:162–166

    CAS  PubMed  Google Scholar 

  32. Mercanti G, Bazzu G, Giusti P (2012) A 6-hydroxydopamine in vivo model of Parkinson's disease. Methods Mol Biol 846:355–364

    CAS  PubMed  Google Scholar 

  33. Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281

    CAS  PubMed  PubMed Central  Google Scholar 

  34. National Research Council (2011) Guide for the Care and Use of Laboratory 8th edition. The National Academies Press. Washington, D.C. www.nap.edu

  35. Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER Jr et al (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 14:69–73

    Google Scholar 

  36. Park SN, Lim YK, Freire MO, Cho E, Jin D, Kook JK (2012) Antimicrobial effect of linalool and α-terpineol against periodontopathic and cariogenic bacteria. Anaerobe 18:369–372

    CAS  PubMed  Google Scholar 

  37. Park H, Seol GH, Ryu S, Choi IY (2016) Neuroprotective effects of (−)-linalool against oxygen-glucose deprivation-induced neuronal injury. Arch Pharm Res 39:555–564

    CAS  PubMed  Google Scholar 

  38. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic Press, San Diego

    Google Scholar 

  39. Peana AT, D’Aquila PS, Panin F, Serra G, Pippia P, Moretti MDL (2002) Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils. Phytomed 9:721–726

    CAS  Google Scholar 

  40. Perez-Pardo P, Kliest T, Dodiya HB, Broersen LM, Garssen J, Keshavarzian A, Kraneveld AD (2017) The gut-brain axis in Parkinson’s disease: possibilities for food-base therapies. Eur J Pharmacol 817:86–95

    CAS  PubMed  Google Scholar 

  41. Porres-Martinez M, González-Burgos E, Carretero ME, Gómez-Serranillos MP (2016) In vitro neuroprotective potential of the monoterpenes alpha-pinene and 1,8-cineole against H2O2-induced oxidative stress in PC12 cells. Naturforsch C 71:191–199

    CAS  Google Scholar 

  42. Sabogal-Guáqueta AM, Osorio E, Cardona-Gómez GP (2016) Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer’s mice. Neuropharmacol 102:111–120

    Google Scholar 

  43. Salvatore MF (2014) Ser 31 Tyrosine hydroxylase phosphorilation parallels differences in dopamine recovery in nigrostriatal pathway following 6-OHDA lesion. J Neurochem 129:548–558

  44. Santos SF, Oliveira HL, Yamada ES, Neves BC, Pereira A Jr (2019) The gut and Parkinson’s disease- a bidirectional pathway. Front Neurol 10:574. https://doi.org/10.3389/fneur.2019.00574 eCollection 2019

    Article  PubMed  PubMed Central  Google Scholar 

  45. Silberman CD, Rodrigues CS, Engelhardt E, Laks J (2013) The impact of depression on survival of Parkinson’s disease patients: a five-year study. J Bras Psiquiatr 62:8–12

    Google Scholar 

  46. Silva LL, Balconi LS, Gressler LT, Garlet QI, Sutili FJ, Vargas APC, Baldisserotto B, Morel AF, Heinzmann BM (2017) S-(+)- and R-(−)-linalool: a comparison of the in vitro anti-Aeromonas hydrophila activity and anesthetic properties in fish. An Acad Bras Ciênc 89:203–212

    CAS  PubMed  Google Scholar 

  47. Simola N, Morelli M, Carta AR (2007) The 6-hydroxydopamine model of Parkinson's disease. Neurotox Res 11:151–167

    CAS  PubMed  Google Scholar 

  48. Snijders AH, Leunissen I, Bakker M, Overeem S, Helmich RC, Bloem BR, Toni I (2011) Gait-related cerebral alterations in patients with Parkinson's disease with freezing of gait. Brain 134(Pt 1):59–72

    PubMed  Google Scholar 

  49. Souto-Maior FN, de Carvalho FL, de Morais LC, Netto SM, de Sousa DP, de Almeida RN (2011) Anxiolytic-like effects of inhaled linalool oxide in experimental mouse anxiety models. Pharmacol Biochem Behav 100:259–263

    CAS  PubMed  Google Scholar 

  50. Storch A, Ludolph AC, Schwarz J (2004) Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. J Neural Transm 111:1267–1286

    CAS  PubMed  Google Scholar 

  51. Sugawara Y, Hara C, Tamura K, Fujii T, Nakamura K, Masujima T, Aoki T (1998) Sedative effect on humans of inhalation of essential oil of linalool: sensory evaluation and physiological measurements using optically active linalools. Anal Chim Acta 365:293–299

    CAS  Google Scholar 

  52. Sun Y, Sukumaran P, Schaar SBB (2015) TRPM7 and its role in neurodegenerative diseases. Channels. 95:253–261

    Google Scholar 

  53. Tabrez S, Jabir NR, Shaki S, Greig NH, Alam Q, Abuzenadah AM et al (2012) A synopsis on the role of tyrosine hydroxylase in Parkinson’s disease. CNS Neurol Disord Drug Targets 11:395–409

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62:803–819

    CAS  PubMed  Google Scholar 

  55. Tieu K (2011) A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med 1(1):a009316. https://doi.org/10.1101/cshperspect.a009316

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Tysnes OB, Storstein A (2017) Epidemiology of Parkinson's disease. J Neural Transm 124:901–905

    PubMed  Google Scholar 

  57. Uehleke B, Schaper S, Dienel A, Schlafke S, Stange R (2012) Phase II trial on the effects of silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder. Phytomed 19(665–671):2012

    Google Scholar 

  58. Wang Z-J, Heinbockel T (2018) Essential oils and their constituents targeting the GABAergic system and sodium channels as treatment of neurological diseases. Molecules 23(5):E1061. https://doi.org/10.3390/molecules23051061

    CAS  Article  PubMed  Google Scholar 

  59. Xu P, Wang K, Lu C, Dong L, Gao L, Yan M, Aibai S, Yang Y, Liu X (2017a) Protective effect of linalool against beta-induced cognitive deficits and damages in mice. Life Sci 174:21–27

    CAS  PubMed  Google Scholar 

  60. Xu P, Wang K, Lu C, Dong L, Gao L, Yan M, Aibai S, Yang Y, Liu X (2017b) The protective effect of lavender essential oil and its main component linalool against the cognitive deficits induced by d-galactose and aluminum trichloride in mice. Evid Based Complement Alternat Med 2017:7426538. https://doi.org/10.1155/2017/7426538

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zalachoras I, Kagiava A, Vokou D, Theophilidis G (2010) Assessing the local anesthetic effect of five essential oil constituents. Planta Med 76:1647–1653

    CAS  PubMed  Google Scholar 

  62. Zhu X, Libby RT, de Vries WN, Smith RS, Wright DL, Bronson RT, Seburn KL, John SW (2012) Mutations in a P-type ATPase gene cause axonal degeneration. PLoS Genet 8:e1002853. https://doi.org/10.1371/journal.pgen.1002853

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors are grateful to the financial supports of the Brazilian National Research Council (CNPq), Coordination for Improvement of Higher Level Personnel (CAPES), and Foundation for Scientific and Technological Development Support of the State of Ceará (FUNCAP).

Author information

Affiliations

Authors

Contributions

JDL was responsible for stereotaxic surgeries, treatment of animals, and behavioral tests; CVJG-F helped with the maintenance of animals and behavioral tests; ROC and DPA helped with biochemical measurements; FAVL and KRTN helped with immunohistochemical assays; and GSBV coordinated the study and wrote the manuscript submitted for the approval of all authors.

Corresponding author

Correspondence to Glauce Socorro de Barros Viana.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Experiments were carried out observing the guidelines of the USA National Research Council for care and use of laboratory animals (National Research Council 2011). The experimental procedures and protocols were approved by the Local Ethics Committee of the Faculty of Medicine of the Federal University of Ceará, Fortaleza, Brazil.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Lucena, J.D., Gadelha-Filho, C.V.J., da Costa, R.O. et al. L-linalool exerts a neuroprotective action on hemiparkinsonian rats. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1077–1088 (2020). https://doi.org/10.1007/s00210-019-01793-1

Download citation

Keywords

  • Parkinson’s disease
  • Neuroprotection
  • Anti-inflammatory and antioxidant activities