Neuroprotective Effect of Capsaicin Against Rotenone-Induced Parkinson’s Disease in Mice
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Abstract
Capsaicin, the active ingredient of hot pepper exerts neuroprotective effects. In this study, the effect of capsaicin on rotenone-induced Parkinson’s disease in mice was investigated. Mice were given subcutaneous rotenone injections (1.5 mg/kg, every other day) and at the same time treated with the vehicle, L-dopa (25 mg/kg) or capsaicin at doses of 0.5 or 1.0 mg/kg orally once a day for two weeks. Biochemical indices of oxidative stress, malondialdehyde, reduced glutathione and nitric oxide were determined in brain tissue and histopathological study of the brain was done. Behavioral tests included stair, wire hanging and wood walking tests. Results showed that rotenone treatment led to significant increases in brain malondialdehyde and nitric oxide contents parallel with marked depletion of reduced glutathione. Rotenone induced degeneration of pigmented neurons in substantia nigra and of cerebral cortex and hippocampus neurons. Rotenone impaired neuromuscular strength, motor balance and coordination. Treatment with capsaicin significantly ameliorated the neuronal degeneration caused by rotenone and improved motor function. Capsaicin alleviated the increase in lipid peroxidation (malondialdehyde) and nitric oxide and prevented the depletion of reduced glutathione in brain of rotenone-treated animals. These data indicate that capsaicin protects against rotenone-induced neuronal damage and this involves decreased level of oxidative stress. Capsaicin therefore might prevent cell death in the brain of Parkinson’s disease patients.
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O. M. Abdel-Salam, M. E.-S. El-Shamarka, and N. Shaffie, “Neuroprotective Effect of Capsaicin Against Rotenone-Induced Parkinson’s Disease in Mice”, Int.J.Halal.Res, vol. 6, no. 1, pp. 1-11, Jun. 2024.
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References
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Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry, 79, 368–376.
Hughes, A.J., Daniel, S.E., Kilford, L., & Lees, A.J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson's disease: A clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry, 55(3), 181‒184.
DeLong, M.R., & Wichmann, T. (2007). Circuits and circuit disorders of the basal ganglia. Archives of Neurology. 64(1), 20-24..
Kumar, K.R., Djarmati-Westenberger, A., & Grunewald, A. (2011). Genetics of Parkinson's disease. Seminars in Neurology, 31(5), 433‒440.
Ritz, B.R., Paul, K.C., & Bronstein, J.M. (2016). Of pesticides and men: a California story of genes and environment in Parkinson's disease. Current Environmental Health Reports, 3, 40-52.
Dhillon, A.S., Tarbutton, G.L., Levin, J.L., Plotkin, G.M., Lowry, L.K., Nalbone, J.T., et al. (2008). Pesticide/environmental exposures and Parkinson's disease in East Texas. Journal of Agromedicine, 13(1),37–48.
Jenner, P. (2003). Oxidative stress in Parkinson's disease. Annals of Neurology, 53(Suppl 3), S26–36.
Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs & Aging, 18(9), 685‒716.
Halliwell, B. (2009).The wanderings of a free radical. Free Radical Biology and Medicine, 46(5), 531–542.
Sies, H. (1997). Oxidative stress: oxidants and antioxidants. Experimental Physiology, 82(2), 291-295.
Floyd, R.A. (1999). Antioxidants, oxidative stress, and degenerative neurological disorders. Proceedings of the Society for Experimental Biology and Medicine, 222(3), 236–245.
Schapira, A.H., Cooper, J.M., Dexter, D., Clark, J.B., Jenner, P., & Marsden CD. (1990). Mitochondrial complex I deficiency in Parkinson's disease. Journal of Neurochemistry, 54(3), 823–827.
Zorov, D.B., Juhaszova, M., & Sollott, S.J. (2006). Mitochondrial ROS-induced ROS release: an update and review. Biochimica et Biophysica Acta. 1757(5‒6), 509‒517.
LeWitt, P.A., & Fahn, S. (2016). Levodopa therapy for Parkinson disease. A look backward and forward. Neurology, 86(14 Suppl 1), S3-12.
Encarnacion, E.V., & Hauser, R.A. (2008). Levodopa-induced dyskinesias in Parkinson’s disease: etiology, impact on quality of life, and treatments. European Neurology, 60, 57–66.
Abdel-Salam, O.M.E. (2015a). Drug therapy for Parkinson’s disease: an update. World Journal of Pharmacology, 4(1),117-143.
Szolcsányi, J. (2014). Capsaicin and sensory neurones: a historical perspective. In: Capsaicin as a Therapeutic Molecule (Progress in Drug Research 68) (Abdel-Salam, O.M.E.). Springer, Berlin, Germany. pp. 1–37.
Steenland, H.W., Ko, S.W., Wu, L.J., & Zhuo, M. (2006). Hot receptors in the brain. Molecular Pain, 2, 34.
Abdel-Salam, O.M.E., Sleem, A,A., Youness, E.R., Yassen, N.N., Shaffie, N., & El-Toumy, S.A. (2018). Capsicum protects against rotenone-induced toxicity in mice brain via reduced oxidative stress and 5-lipoxygenase activation. Journal of Pharmacy and Pharmacology Research, 2 (3), 060-77.
Abdel-Salam, O.M.E., Sleem, A.A., Youness, E.R., Morsy, F.A., Shaffie, N.M., & Souleman, A.M.A. (2019). Hot Pepper extract protects against hypoglycemia-induced brain and liver injury in mice. Reactive Oxygen Species, 8(23), 297–311.
Hien, P.P., Gortnizka, H., & Kraemer, R. (2003) Rotenone-potential and prospect for sustainable agriculture. Omonrice, 11, 83–92.
Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., & Greenamyre, J.T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neuroscience, 3(12), 1301–6.
Abdel-Salam, OME. (2015b). The rotenone model of parkinson’s disease in studying the mechanisms of nigrostriatal cell death. Jacobs Journal of Pharmacology and Pharmacovigilance, 1(1), 007.
Nair, V., & Turner, G.A. (1984). The thiobarbituric acid test for lipid peroxidation: structure of the adduct with malondialdehyde. Lipids, 19(10), 804-805.
Ellman, G.L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1), 70‒77.
Archer, S. (1993). Measurement of nitric oxide in biological models. The FASEB Journal, 7(2), 349–60.
Crawley, J.N. (2017). What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Second edition ed. Hoboken: Wiley.
Rogers, D.C., Campbell, C.A., Stretton, J.L., & Mackay, K.B. (1997). Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke, 28(10), 2060–2065.
Baird, A.L., Meldrum, A., & Dunnett, S.B. (2001). The staircase test of skilled reaching in mice. Brain Research Bulletin, 54(2), 243–250.
Pegorini, S., Braida, D., Verzoni, C., Guerini-Rocco, C., Consalez, G.G., Croci, L., et al. (2005). Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils. British Journal of Pharmacology, 144(5), 727–735.
Chung, Y.C., Baek, J.Y., Kim, S.R., Ko, H.W., Bok, E., Shin, W.H., et al. (2017). Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson's disease. Experimental & Molecular Medicine, 49(3), e298.
Abdel-Salam, O.M.E., Abdel-Rahman, R.F., Sleem, A.A., & Farrag, A.R. (2012). Modulation of lipopolysaccharide-induced oxidative stress by capsaicin. Inflammopharmacology, 20(4), 207–217.
Demirbilek, S., Ersoy, M.O., Demirbilek, S., Karaman, A., Gürbüz, N., Bayraktar, N., et al (2004). Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesthesia & Analgesia, 99(5), 1501–1507.
Abdel-Salam, O.M.E., Sleem, A,A., Sayed, MAEM.,Youness, E.R., & Shaffie, N. (2020). Capsaicin exerts anti-convulsant and neuroprotective effects in pentylenetetrazole-induced seizures. Neurochemical Research, 45(5),1045-1061.
Sherer, T.B., Betarbet, R., Testa, C.M., Seo, B.B., Richardson, J.R., & Kim, J.H. (2003). Mechanism of toxicity in rotenone models of Parkinson's disease. Journal of Neuroscience, 23(34),10756–64.
Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., & Melendez, J.A. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Journal of Biological Chemistry, 278(10), 8516-25.
Han, G., Casson, R.J., Chidlow, G., & Wood, J.P.M. (2014). The mitochondrial complex I inhibitor rotenone induces endoplasmic reticulum stress and activation of GSK-3b in cultured rat retinal cells. Investigative Ophthalmology & Visual Science, 55,5616–5628.
Gao, H.M., Liu, B., & Hong, J.S. (2003). Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. Journal of Neuroscience, 23(15), 6181–7.
Chang, C.Y., Song, M.J., Jeon, S.B., Yoon, H.J., Lee, D.K., & Kim, I.H. (2011). Dual functionality of myeloperoxidase in rotenone-exposed brain-resident immune cells. American Journal of Pathology, 179(2), 964–79.
Townsend, D.M., Tew, K.D., & Tapiero, H. (2003). The importance of glutathione in human disease. Biomed Pharmacother, 57(3‒4), 145‒155.
Abdel-Salam, O.M.E., Medhat, D., Sleem, A.A., & Shaffie, N. (2018). Neuroprotection by montelukast against rotenone-induced rat brain damage. Reactive Oxygen Species, 5(15), 209–219.
Abdel-Salam, O.M.E., Morsy, S.M.Y., Youness, E.R., Yassen, N.N., Shaffie, N., & Sleem, A.A. (2020). Citric acid protects dopaminergic cells against rotenone-induced neurodegeneration. Reactive Oxygen Species 9(27),118–135.
Abdel-Salam, O.M.E, Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., Abdel-Rahman, R.F., & Omara, E.A. (2015c ).The effect of cannabis on oxidative stress and neurodegeneration induced by intrastriatal rotenone injection in rats. Comparative Clinical Pathology, 24, 359–378.
Testa, C.M., Sherer, T.B., & Greenamyre, J.T. (2005). Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Research. Molecular Brain Research, 134(1), 109–118.
Ibrahim, N.A., Abdel-Salam, O.M., Khadrawy, Y.A., Hashem, A.M., & Sameer, E.M. (2017). Non-steroidal anti-inflammatory drugs and vitamin C in the rotenone induced nigrostriatal damage in mice. European Journal of Clinical and Biomedical Sciences, 3(4), 67–79.
Abdel-Salam, O.M.E., Sleem, A.A., Youness, E.R., Mohammed, N.A., Omara, E.A., & Shabana, M.E. (2019). Neuroprotective effects of the glutathione precursor N-acetylcysteine against rotenone-induced neurodegeneration. Reactive Oxygen Species, 8(22), 231–244.
Bashkatova, V., Alam, M., Vanin, A., & Schmidt, WJ. (2004). Chronic administration of rotenone increases levels of nitric oxide and lipid peroxidation products in rat brain. Experimental Neurology, 186(2), 235-241.
Xiong, Z.K., Lang, J., Xu, G., Li, H.Y., Zhang, Y., Wang, L., et al. (2015). Excessive levels of nitric oxide in rat model of Parkinson's disease induced by rotenone. Experimental and Therapeutic Medicine, 9(2), 553–558.
Abdel-Salam, O.M.E., Youness, E.R., Ahmed, N.A., El-Toumy, S.A., Souleman, A.M.A., Shaffie, N., et al. (2017). Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity. Asian Pacific Journal of Tropical Medicine, 10(5), 478–490.
Pacher, P., Beckman, J.S., & Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiological Reviews, 87(1), 315–424.
Moncada, S., & Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry, 97(6),1676–89.
Weidinger, A., & Kozlov, A.V. (2015). Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction. Biomolecules, 5(2), 472–484.
Abdel-Salam, O.M.E., Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., Abdel-Rahman, R.F., Omara, E.A., et al. (2015d). The effect of cannabis on oxidative stress and neurodegeneration induced by intrastriatal rotenone injection in rats. Comparative Clinical Pathology, 24:359–378.
He, Y., Imam, S.Z., Dong, Z., Jankovic, J., Ali, S.F., & Appel, S.H. (2003). Role of nitric oxide in rotenone induced nigrostriatal injury. Journal of Neurochemistry, 86(6), 1338–45.
Gao, H.M., Liu, B., & Hong, J.S. (2003). Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. Journal of Neuroscience, 23(15), 6181–7.
Abdel-Salam, O.M.E., Omara, E.A., Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., & Sleem, A.A. (2014). Rotenone-induced nigrostriatal toxicity is reduced by methylene blue. Journal of Neurorestoratology, 2(1), 65–80.
Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry, 79, 368–376.
Hughes, A.J., Daniel, S.E., Kilford, L., & Lees, A.J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson's disease: A clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry, 55(3), 181‒184.
DeLong, M.R., & Wichmann, T. (2007). Circuits and circuit disorders of the basal ganglia. Archives of Neurology. 64(1), 20-24..
Kumar, K.R., Djarmati-Westenberger, A., & Grunewald, A. (2011). Genetics of Parkinson's disease. Seminars in Neurology, 31(5), 433‒440.
Ritz, B.R., Paul, K.C., & Bronstein, J.M. (2016). Of pesticides and men: a California story of genes and environment in Parkinson's disease. Current Environmental Health Reports, 3, 40-52.
Dhillon, A.S., Tarbutton, G.L., Levin, J.L., Plotkin, G.M., Lowry, L.K., Nalbone, J.T., et al. (2008). Pesticide/environmental exposures and Parkinson's disease in East Texas. Journal of Agromedicine, 13(1),37–48.
Jenner, P. (2003). Oxidative stress in Parkinson's disease. Annals of Neurology, 53(Suppl 3), S26–36.
Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs & Aging, 18(9), 685‒716.
Halliwell, B. (2009).The wanderings of a free radical. Free Radical Biology and Medicine, 46(5), 531–542.
Sies, H. (1997). Oxidative stress: oxidants and antioxidants. Experimental Physiology, 82(2), 291-295.
Floyd, R.A. (1999). Antioxidants, oxidative stress, and degenerative neurological disorders. Proceedings of the Society for Experimental Biology and Medicine, 222(3), 236–245.
Schapira, A.H., Cooper, J.M., Dexter, D., Clark, J.B., Jenner, P., & Marsden CD. (1990). Mitochondrial complex I deficiency in Parkinson's disease. Journal of Neurochemistry, 54(3), 823–827.
Zorov, D.B., Juhaszova, M., & Sollott, S.J. (2006). Mitochondrial ROS-induced ROS release: an update and review. Biochimica et Biophysica Acta. 1757(5‒6), 509‒517.
LeWitt, P.A., & Fahn, S. (2016). Levodopa therapy for Parkinson disease. A look backward and forward. Neurology, 86(14 Suppl 1), S3-12.
Encarnacion, E.V., & Hauser, R.A. (2008). Levodopa-induced dyskinesias in Parkinson’s disease: etiology, impact on quality of life, and treatments. European Neurology, 60, 57–66.
Abdel-Salam, O.M.E. (2015a). Drug therapy for Parkinson’s disease: an update. World Journal of Pharmacology, 4(1),117-143.
Szolcsányi, J. (2014). Capsaicin and sensory neurones: a historical perspective. In: Capsaicin as a Therapeutic Molecule (Progress in Drug Research 68) (Abdel-Salam, O.M.E.). Springer, Berlin, Germany. pp. 1–37.
Steenland, H.W., Ko, S.W., Wu, L.J., & Zhuo, M. (2006). Hot receptors in the brain. Molecular Pain, 2, 34.
Abdel-Salam, O.M.E., Sleem, A,A., Youness, E.R., Yassen, N.N., Shaffie, N., & El-Toumy, S.A. (2018). Capsicum protects against rotenone-induced toxicity in mice brain via reduced oxidative stress and 5-lipoxygenase activation. Journal of Pharmacy and Pharmacology Research, 2 (3), 060-77.
Abdel-Salam, O.M.E., Sleem, A.A., Youness, E.R., Morsy, F.A., Shaffie, N.M., & Souleman, A.M.A. (2019). Hot Pepper extract protects against hypoglycemia-induced brain and liver injury in mice. Reactive Oxygen Species, 8(23), 297–311.
Hien, P.P., Gortnizka, H., & Kraemer, R. (2003) Rotenone-potential and prospect for sustainable agriculture. Omonrice, 11, 83–92.
Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., & Greenamyre, J.T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neuroscience, 3(12), 1301–6.
Abdel-Salam, OME. (2015b). The rotenone model of parkinson’s disease in studying the mechanisms of nigrostriatal cell death. Jacobs Journal of Pharmacology and Pharmacovigilance, 1(1), 007.
Nair, V., & Turner, G.A. (1984). The thiobarbituric acid test for lipid peroxidation: structure of the adduct with malondialdehyde. Lipids, 19(10), 804-805.
Ellman, G.L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1), 70‒77.
Archer, S. (1993). Measurement of nitric oxide in biological models. The FASEB Journal, 7(2), 349–60.
Crawley, J.N. (2017). What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Second edition ed. Hoboken: Wiley.
Rogers, D.C., Campbell, C.A., Stretton, J.L., & Mackay, K.B. (1997). Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke, 28(10), 2060–2065.
Baird, A.L., Meldrum, A., & Dunnett, S.B. (2001). The staircase test of skilled reaching in mice. Brain Research Bulletin, 54(2), 243–250.
Pegorini, S., Braida, D., Verzoni, C., Guerini-Rocco, C., Consalez, G.G., Croci, L., et al. (2005). Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils. British Journal of Pharmacology, 144(5), 727–735.
Chung, Y.C., Baek, J.Y., Kim, S.R., Ko, H.W., Bok, E., Shin, W.H., et al. (2017). Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson's disease. Experimental & Molecular Medicine, 49(3), e298.
Abdel-Salam, O.M.E., Abdel-Rahman, R.F., Sleem, A.A., & Farrag, A.R. (2012). Modulation of lipopolysaccharide-induced oxidative stress by capsaicin. Inflammopharmacology, 20(4), 207–217.
Demirbilek, S., Ersoy, M.O., Demirbilek, S., Karaman, A., Gürbüz, N., Bayraktar, N., et al (2004). Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesthesia & Analgesia, 99(5), 1501–1507.
Abdel-Salam, O.M.E., Sleem, A,A., Sayed, MAEM.,Youness, E.R., & Shaffie, N. (2020). Capsaicin exerts anti-convulsant and neuroprotective effects in pentylenetetrazole-induced seizures. Neurochemical Research, 45(5),1045-1061.
Sherer, T.B., Betarbet, R., Testa, C.M., Seo, B.B., Richardson, J.R., & Kim, J.H. (2003). Mechanism of toxicity in rotenone models of Parkinson's disease. Journal of Neuroscience, 23(34),10756–64.
Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., & Melendez, J.A. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Journal of Biological Chemistry, 278(10), 8516-25.
Han, G., Casson, R.J., Chidlow, G., & Wood, J.P.M. (2014). The mitochondrial complex I inhibitor rotenone induces endoplasmic reticulum stress and activation of GSK-3b in cultured rat retinal cells. Investigative Ophthalmology & Visual Science, 55,5616–5628.
Gao, H.M., Liu, B., & Hong, J.S. (2003). Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. Journal of Neuroscience, 23(15), 6181–7.
Chang, C.Y., Song, M.J., Jeon, S.B., Yoon, H.J., Lee, D.K., & Kim, I.H. (2011). Dual functionality of myeloperoxidase in rotenone-exposed brain-resident immune cells. American Journal of Pathology, 179(2), 964–79.
Townsend, D.M., Tew, K.D., & Tapiero, H. (2003). The importance of glutathione in human disease. Biomed Pharmacother, 57(3‒4), 145‒155.
Abdel-Salam, O.M.E., Medhat, D., Sleem, A.A., & Shaffie, N. (2018). Neuroprotection by montelukast against rotenone-induced rat brain damage. Reactive Oxygen Species, 5(15), 209–219.
Abdel-Salam, O.M.E., Morsy, S.M.Y., Youness, E.R., Yassen, N.N., Shaffie, N., & Sleem, A.A. (2020). Citric acid protects dopaminergic cells against rotenone-induced neurodegeneration. Reactive Oxygen Species 9(27),118–135.
Abdel-Salam, O.M.E, Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., Abdel-Rahman, R.F., & Omara, E.A. (2015c ).The effect of cannabis on oxidative stress and neurodegeneration induced by intrastriatal rotenone injection in rats. Comparative Clinical Pathology, 24, 359–378.
Testa, C.M., Sherer, T.B., & Greenamyre, J.T. (2005). Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Research. Molecular Brain Research, 134(1), 109–118.
Ibrahim, N.A., Abdel-Salam, O.M., Khadrawy, Y.A., Hashem, A.M., & Sameer, E.M. (2017). Non-steroidal anti-inflammatory drugs and vitamin C in the rotenone induced nigrostriatal damage in mice. European Journal of Clinical and Biomedical Sciences, 3(4), 67–79.
Abdel-Salam, O.M.E., Sleem, A.A., Youness, E.R., Mohammed, N.A., Omara, E.A., & Shabana, M.E. (2019). Neuroprotective effects of the glutathione precursor N-acetylcysteine against rotenone-induced neurodegeneration. Reactive Oxygen Species, 8(22), 231–244.
Bashkatova, V., Alam, M., Vanin, A., & Schmidt, WJ. (2004). Chronic administration of rotenone increases levels of nitric oxide and lipid peroxidation products in rat brain. Experimental Neurology, 186(2), 235-241.
Xiong, Z.K., Lang, J., Xu, G., Li, H.Y., Zhang, Y., Wang, L., et al. (2015). Excessive levels of nitric oxide in rat model of Parkinson's disease induced by rotenone. Experimental and Therapeutic Medicine, 9(2), 553–558.
Abdel-Salam, O.M.E., Youness, E.R., Ahmed, N.A., El-Toumy, S.A., Souleman, A.M.A., Shaffie, N., et al. (2017). Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity. Asian Pacific Journal of Tropical Medicine, 10(5), 478–490.
Pacher, P., Beckman, J.S., & Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiological Reviews, 87(1), 315–424.
Moncada, S., & Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry, 97(6),1676–89.
Weidinger, A., & Kozlov, A.V. (2015). Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction. Biomolecules, 5(2), 472–484.
Abdel-Salam, O.M.E., Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., Abdel-Rahman, R.F., Omara, E.A., et al. (2015d). The effect of cannabis on oxidative stress and neurodegeneration induced by intrastriatal rotenone injection in rats. Comparative Clinical Pathology, 24:359–378.
He, Y., Imam, S.Z., Dong, Z., Jankovic, J., Ali, S.F., & Appel, S.H. (2003). Role of nitric oxide in rotenone induced nigrostriatal injury. Journal of Neurochemistry, 86(6), 1338–45.
Gao, H.M., Liu, B., & Hong, J.S. (2003). Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. Journal of Neuroscience, 23(15), 6181–7.
Abdel-Salam, O.M.E., Omara, E.A., Youness, E.R., Khadrawy, Y.A., Mohammed, N.A., & Sleem, A.A. (2014). Rotenone-induced nigrostriatal toxicity is reduced by methylene blue. Journal of Neurorestoratology, 2(1), 65–80.