Neuroprotective and Therapeutic Role of Omega-3 Against Oxidative Stress and Neurotransmitter Disturbances in Rotenone-Induced Mice Model of Parkinson's Disease
Clinical Neurology and Neuroscience
Volume 2, Issue 1, March 2018, Pages: 12-22
Received: Nov. 16, 2017; Accepted: Dec. 5, 2017; Published: Feb. 7, 2018
Views 2273      Downloads 120
Nagi Ali Ibrahim, Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Yasser Ashry Khadrawy, Department of Medical Physiology, National Research Center, Dokki, Giza, Egypt
Soliman Sayed Ibrahim, Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Noura El-Sayed Ezzat, Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Article Tools
Follow on us
The present study aimed at evaluating the protective and therapeutic efficacy of omega-3 against motor impairment and brain biochemical disturbances in rotenone-induced mice model of Parkinson's disease (PD). Sixty animals were divided into six groups (10 each): mice of the 1st group were used as controls, they were injected subcutaneously ( s c ) with the vehicle (50 µl dimethylsulfoxide (DEMSO) + 950 µl sunflower oil /kg body weight) every other day for 30 days; the 2nd group, mice model of Parkinson’s disease (PD), were injected (s c ) with rotenone (3 mg/kg dissolved in vehicle every other day for 30 days ). the 3rd group, mice were given rotenone for 30 days followed by a stopping (recovery) period of other 30 days to validate the persistency of the PD model; the 4th group (protection group), mice received orally Omega-3 oil (300 mg/kg) daily an hour before every rotenone injection for 30 days; the 5th and 6th groups (therapeutic groups ), mice were treated orally with Omega-3 oil daily for 7 and 15 days respectively after the induction of PD mice model. Data obtained revealed an impairment of the motor activity in mice of PD model as indicated from the decreased time of the forelimb hanging test. This was associated with a state of oxidative stress in the brain of PD model as indicated from the increase in lipid peroxidation (increased malondialdehyed, MDA, level) and nitric oxide (NO), and the decrease in reduced glutathione (GSH). A significant decrease in the levels of dopamine, norepinephrine, serotonin, AChE activity and a significant increase in TNF-α level was recorded in the PD model. The present findings show that both the protection by or oral treatment with omega-3 for 15 days could ameliorate the rotenone- induced oxidative stress and inflammation in brain of PD mice model. In addition, omega-3 either as protection or treatment daily for 15 days was effective in restoring the decrease in dopamine and norepinephrine induced in the brain of PD mice model. In conclusion, the present study demonstrates that omega-3 supplementation potentially reverses the motor, and neurochemical alternations induced by rotenone in mice model of PD.
Parkinson's Disease, Omega-3, Oxidative Stress, Neurotransmitters
To cite this article
Nagi Ali Ibrahim, Yasser Ashry Khadrawy, Soliman Sayed Ibrahim, Noura El-Sayed Ezzat, Neuroprotective and Therapeutic Role of Omega-3 Against Oxidative Stress and Neurotransmitter Disturbances in Rotenone-Induced Mice Model of Parkinson's Disease, Clinical Neurology and Neuroscience. Vol. 2, No. 1, 2018, pp. 12-22. doi: 10.11648/j.cnn.20180201.13
Copyright © 2018 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
de Lau, L. M. L., Breteler, M. M. B. (2006). Epidemiology of Parkinson’s disease. Lancet Neurol, 5, 525-535.
Alves, G., Forsaa, E. B., Pedersen, K. F., Gjerstad, M. D., Larsen, J. P. (2008). Epidemiology of Parkinson's disease. J Neurol, 255, 18-32.
de Rijk, M. C., Rocca, W. A., Anderson, D. W., Melcon, M. O., Breteler, M. M., Maraganore, D. M. (1997). A population perspective on diagnostic criteria for Parkinson's disease. Neurology, 48, 1277-1281.
Massano, J., Bhatia, K. P. (2012). Clinical approach to Parkinson's disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med, 2, a008870.
Elbaz, A., Moisan, F. (2008). Update in the epidemiology of Parkinson’s disease. Curr Opin Neurol, 21, 454–460.
Bronstein, J., Carvey, P., Chen, H., Cory-Slechta, D., DiMonte, D., et al (2009). Meeting report: Consensus statement—Parkinson’s disease and the environment: Collaborative on health and the environment and Parkinson’s Action Network (CHE PAN) conference, 26–28 June 2007. Environ Health Perspect, 117, 117–121.
Moore, D. J., West, A. B., Dawson, V. L., Dawson, T. M. (2005). Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci., 28, 57- 87.
Smith, M. P., Cass, W. A. (2007). Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease. Neuroscience, 144, 1057–1066.
Exner, N., Lutz, A. K., Haass, C., Winklhofer, K. F. (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J., 31, 3038–3062.
Giza, E., Gotzamani-Psarrakou, A., Bostantjopoulou, S. (2012). Imaging beyond the striatonigral dopaminergic system in Parkinson's disease. Hell. J. Nucl. Med., 15, 224-232.
Schapira, A. H., Emre, M., Jenner, P., Poewe, W. (2009). Levodopa in the treatment of Parkinson’s disease. Eur J Neurol, 16, 982–986.
Pahwa, R., Koller, W. C. (1995). Dopamine agonists in the treatment of Parkinson's disease. Cleve Clin J Med, 62, 212-217.
Rivest, J., Barclay, C. L., Suchowersky, O. (1999). COMT inhibitors in Parkinson’s disease. Can. J. Neurol. Sci., 26, 34–38.
Bassi, S., Albizzati, M. G., Calloni, E., Sbacchi, M., Frattola, L. (1986). Treatment of Parkinson’s disease with or phenadrine alone and in combination with L-dopa. Br J ClinPract, 40, 273-275.
Fahn, S. (1996). Is levodopa toxic? Neurology, 47, 184-195.
Idem. (1997). Levodopa-induced neurotoxicity: does it represent a problem for the treatment of Parkinson’s disease? CNS Drugs, 8, 376-393.
Barzilai, A., Melamed, E., Shirvan, A. (2001). Is there a rationale for neuroprotection against dopamine toxicity in Parkinson’s disease? Cell MolNeurobiol, 21, 215-235.
Hoehn, M. M. M., Elton, R. L. (1985). Low dosages of bromocriptine added to levodopa in Parkinson's disease. Neurology, 35, 199-206.
Su Kp, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, Pariante CM. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008; 69, 644–651.
Krauss-Etschmann, S., Shadid, R., Campoy, C., Hoster, E., Demmelmair, H., Jimenez, M., Gil, A., Rivero, M., Veszpremi, B., Decsi, T., Koletzko, B. V., Nutrition and Health lifestyle (NUHEAL) Study Group. (2007). Effects of fish oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. Am J ClinNutr., 85, 1392–400.
Serhan, C. N., Chiang, N., Van Dyke, T. E. (2008). Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol, 8, 349–361.
Wang, Y., Li, L., Jiang, W., Yang, Z., Zhang, Z. (2006). Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate. Bioorg Med ChemLett., 16, 2974–2977.
Yehuda, S., Rabinovitz, S., Mostofsky, D. I. (1999). Essentialfatty acids are mediators of brain biochemistry and cognitive functions. J. Neurosci. Res., 56, 565–570.
Yurko-Mauro, K., McCarthy, D., Rom, D., Nelson, E. B., Ryan, A. S., Blackwell, A., Salem, N., Jr., Stedman, M., MIDAS Investigators. (2010). Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement., 6, 456–464.
Avramovic, N., Dragutinovic, V., Krstic, D., Colovic, M. B., Trbovic, A., de Luka, S., Milovanovic, I., Popovic, T. (2012). The effects of omega 3 fatty acid supplementation on brain tissue oxidative status in aged wistar rats. Hippokratia., 16, 241–245.
Bousquet, M., Saint-Pierre, M., Julien, C., Salem, N. Jr., Cicchetti, F. (2008). Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease. FASEB J, 22, 1213-1225.
Zimmer, L., Durand, G., Guilloteau, D., Chalon, S. (1999). n-3 polyunsaturated fatty acid deficiency and dopamine metabolism in the rat frontal cortex. Lipids, 34, 251.
Vancassel, S., Leman, S., Hanonick, L., Denis, S., Roger, J., Nollet, M., Bodard, S., Kousignian, I., Belzung, C., Chalon, S. (2008). n-3 Polyunsaturated fatty acid supplementation reverses stress-induced modifications on brain monoamine levels in mice. J Lipid Res, 49, 340-348.
Li, K., Huang, T., Zheng, J., Wu, K., Li, D., (2014). Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on C-Reactive Protein, Interleukin 6 and Tumor Necrosis Factor α: A Meta-Analysis. PLoS One, 9, e88103.
Zhang, L., Haraguchi, S., Koda, T., Hashimoto, K., Nakagawara, A. (2010). Muscle atrophy and motor neuron degeneration in human NEDL1 transgenic mice. J. Biomed. Biotechnol., 2011, 1-7.
Ruiz-Larrea, M. B., Leal, A. M., Liza, M., Lacort, M., de Groot, H (1994). Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids, 59, 383-388.
Montgomery, H. A. C., Dymock, J. F. (1961). The determination of nitrite in water. Analyst, 86, 414- 416.
Ellman, G. L. (1959). Tissue sulfhydryl groups, Arch Biochem., 82, 70-77.
Ellman, G. L., Courtney, K. D., Andres, V., Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 7, 88-95.
Gorun, V., Proinov, I., Baltescu V., Balaban, G., Barzu, O. (1978). Modified Ellman procedure for assay of cholinesterase in crude-enzymatic preparations. Anal. Biochem., 86, 324-326.
Ciarlone, A. E. (1978). Further modification of a fluoromertric method for analyzing brain amines. Microchem. J., 23, 9-12.
Talpade, D. J., Greene, J. G. Higgins, D. S. Jr., Greenamyre, J. T. (2000). In vivo labeling of mitochondrial complex I (NADH: ubiquinone oxidoreductase) in rat brain using [(3) H] dihydrorotenone.
Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., Greenmyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurobiol., 3, 1301-1306.
Kale, M., Rathore, N., John, S., Bhatnagar, D. (1999). Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species. Toxicol. Lett., 105, 197-205.
He, Y., Imam, S. Z., Dong, Z., Jankovic, J., Ali, S. F., Appel, S. H., Le, W. (2003). Role of nitric oxide in rotenone-induced nigro-striatal injury. J. Neurochem., 86, 1338-1345.
Korhonen, R., Lahti, A., Kankaanranta, H., Moilanen, E. (2005). Nitric oxide production and signaling in inflammation. Curr. Drug Targets Inflamm. Allergy., 4, 471- 479.
LaVoie, M. J., Hastings, T. G. (1999). Peroxynitrite- and nitrite-induced oxidation of dopamine: implications for nitric oxide in dopaminergic cell loss. J. Neurochem., 73, 2546- 2554.
Imam, S. Z., Newport, G. D., Itzhak, Y., Cadet, J. L., Islam, F., Slikker, W. Jr., Ali, S. F. (2001). Peroxynitrite plays a role in methamphetamine- induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase. J. Neurochem., 76, 745-749.
Dickinson, D. A., Forman, H. J. (2002). Cellular glutathione and thiols metabolism. Biochem. Pharm., 64, 1019–1026.
Frankola, K. A., Greig, N. H., Luo, W., Tweedie, D. (2011). Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS and Neurological Disorders— DrugTargets, 10, 391–403.
Montgomery, S. L., Bowers, W. J. (2012). Tumor necrosis factor alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. Jounal of Neuroimmune Pharmacology, 7, 42–59.
Zaitone, S. A., Abo-Elmatty, D. M., Elshazly, S. M. (2012). Piracetam and vinpocetine ameliorater otenone-induced Parkinsonism in rats. Indian J. Pharmacol., 44, 774-779.
Stoof, J. C., Drukarch, B., de Boer, P., Westerink, B. H., Groenewegen, H. J. (1992). Regulation of the activity of striatal cholinergic neurons by dopamine. Neuroscience, 47, 755-770.
Aosaki, T., Miura, M., Suzuki, T., Nishimura, K., Masuda, M. (2010). Acetylcholine-dopamine balance hypothesis in the striatum. GeriatrGerontolInt, 10, 148-157.
Swathi, G., Bhuvaneswar, C., Rajendra, W. (2013). Alterations of cholinergic neurotransmission in rotenone induced parkinson’s disease: protective role of bacopamonnieri. Int. J. Pharm. Biol. Sci., 3, 286-292.
Swathi, G., Rajendra, W. (2014). Protective role of bacopamonnierion induced Parkinson’s disease with particular reference to catecholamine system. Int. J. Pharm. Pharm. Sci., 6, 379-382.
Njus, D., Kelley, P. M., Hardabek, G. J. (1986). Bioenergetics of secretory vesicles. Biochim. Biophys. Acta., 853, 237-265.
Nirenberg, M. J., Chan, J., Liu, Y., Edwards, R. H., Pickel, V. M. (1996). Ultrastructural localization of the vesicular monoamine transporter-2 in midbrain dopaminergic neurons: potential sites for somatodendritic storage and release of dopamine. J. Neurosci., 16, 4135- 4145.
Watabe, M., Nakaki, T. (2008). Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells. Mol. Pharmacol., 74, 933-940.
Schwarting, R. K., Bonatz, A. E., Carey, R. J., Huston, J. P. (1991). Relationships between indices of behavioral asymmetries and neurochemical changes following mesencephalic 6-hydroxydopamine injections. Brain Res., 554, 46-55.
Infante, J. P., Huszagh, V. A. (2000). Secondary carnitine deficiency and impaired docosahexaenoic (22: 6n-3) acid synthesis: a common denominator in the pathophysiology of diseases of oxidative phosphorylation and β-oxidation. FEBS Lett, 468, 1–5.
Holloway, G. P., Fajardo, V. A., McMeekin, L., LeBlanc, P. J. (2012). Unsaturation of mitochondrial membrane lipids is related to palmitate oxidation in subsarcolemmal and intermyofibrillar mitochondria. J Membr Biol., 245, 165–176.
Peoples, G. E., McLennan, P. L. (2010). Dietary fish oil reduces skeletal muscle oxygen consumption, provides fatigue resistance and improves contractile recovery in the rat in vivo hindlimb. Br J Nutr, 104, 1771–1779.
Wang, J. Y., Sekine, S., Saito, M. (2003). Effect of docosahexaenoic acid and ascorbate on peroxidation of retinal membranes of ODS rats. Free Radic. Res., 37, 419–424.
Moncada, S., Palmer, R. M. J., Higgs, E. A. (1991). Nitric oxide: physiology, pathophysiology, and pharmacology. J. Pharm. Exp. Ther., 43, 109–141.
Garthwaite, J. (2008). Concepts of neural nitric oxide-mediated transmission. European Journal of Neuroscience, 27, 2783–2802.
Steinert, J. R., Chernova, T., Forsythe, I. D. (2010). Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist, 16, 435–452.
Lorrain, D. S., Hull, E. M. (1993). Nitric oxide increases dopamine and serotonin release in the medial preoptic area. Neuroreport, 5, 87-89.
Lo, C. J., Chiu, K. C., Fu, M., Lo, R., Helton, S. (1999). Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J. Surg. Res., 82, 216–221.
Babcock, T. A., Novak, T., Ong, E., Jho, D. H., Helton, W. S., Espat, N. J. (2002). Modulation of lipopolysaccharide-stimulated macrophage tumor necrosis factor-α production by ω-3 fatty acid is associated withdifferential cyclooxygenase-2 protein expression and is independent of interleukin-10. J. Surg. Res., 107, 135–139.
Siriwardhana, N., Kalupahana, N. S., Moustaid-Moussa, N. (2012). Health benefits of n-3 polyunsaturated fatty acids: eicosapentaenoic acid and docosahexaenoic acid. Adv Food Nutr Res., 65, 211–222.
Won, L., Ding, Y., Singh, P., Kang, U. J. (2014). Striatal cholinergic cell ablation attenuates L-DOPAinduceddyskinesia in Parkinsonian mice. J. Neurosci., 34, 3090-3094.
Das, U. N., Fams. (2003). Long-chain polyunsaturated fatty acids in the growth and development of the brain and memory. Nutrition, 19, 62-65.
Chalon, S., Delion-Vancassel, S., Belzung, C., Guilloteau, D., Leguisquet, A., Besnard, J. C., Durand, G. (1998). Dietary fish oil affects mono aminergicneuro transmission and behavior in rats. J Nutr., 128, 2512–2519.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186