Abstract
In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson’s disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.
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References
Allbutt HN, Henderson JM (2007) Use of the narrow beam test in the rat, 6-hydroxydopamine model of Parkinson’s disease. J Neurosci Methods 159:195–202. https://doi.org/10.1016/j.jneumeth.2006.07.006
Anandhan A, Jacome MS, Lei S, Hernandez-Franco P, Pappa A, Panayiotidis MI, Powers R, Franco R (2017) Metabolic dysfunction in Parkinson’s disease: bioenergetics, redox homeostasis and central carbon metabolism. Brain Res Bull 133:12–30. https://doi.org/10.1016/j.brainresbull.2017.03.009
Anis E, Zafeer MF, Firdaus F, Islam SN, Fatima M, Mobarak Hossain M (2018) Evaluation of phytomedicinal potential of perillyl alcohol in an in vitro Parkinson’s disease model. Drug Dev Res 79:218–224. https://doi.org/10.1002/ddr.21436
Baluchnejadmojarad T, Rabiee N, Zabihnejad S, Roghani M (2017) Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease: possible involvement of ERβ/Nrf2/HO-1 signaling. Brain Res 1662:23–30. https://doi.org/10.1016/j.brainres.2017.02.021
Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366. https://doi.org/10.1002/ana.410380304
Belanger JT (1998) Perillyl alcohol: applications in oncology. Altern Med Rev 3:448–57
Blanchard-Fillion B, Souza JM, Friel T, Jiang GC, Vrana K, Sharov V, Barrón L, Schöneich C, Quijano C, Alvarez B, Radi R, Przedborski S, Fernando GS, Horwitz J, Ischiropoulos H (2001) Nitration and inactivation of tyrosine hydroxylase by peroxynitrite. J Biol Chem 276:46017–46023. https://doi.org/10.1074/jbc.M105564200
Bolner A, Micciolo R, Bosello O, Nordera GP (2016) A Panel of Oxidative Stress Markers in Parkinson’s Disease. Clin Lab 62:105–12
Borlongan CV, Sanberg PR (1995) Elevated body swing test: a new behavioral parameter for rats with 6-hydroxydopamine-induced hemiparkinsonism. J Neurosci 15:5372–5378
Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson’s disease. J Neurochem 139(Suppl):216–231. https://doi.org/10.1111/jnc.13731
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Bruns I, Sauer B, Burger MC, Eriksson J, Hofmann U, Braun Y, Harter PN, Luger A-L, Ronellenfitsch MW, Steinbach JP, Rieger J (2019) Disruption of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α reverts key features of the neoplastic phenotype of glioma cells. J Biol Chem 294:3037–3050. https://doi.org/10.1074/jbc.RA118.006993
Choi HI, Kim HJ, Park JS, Kim IJ, Bae EH, Ma SK, Kim SW (2017) PGC-1α attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38 in HK-2 cells. Sci Rep 7:4319. https://doi.org/10.1038/s41598-017-04593-w
Corona JC, Duchen MR (2015) PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochem Res 40:308–16. https://doi.org/10.1007/s11064-014-1377-0
Crowell PL (1999) Prevention and therapy of cancer by dietary monoterpenes. J Nutr 129:775S-778S. https://doi.org/10.1093/jn/129.3.775S
Crowell PL, Elson CE (2001) Isoprenoids, health and disease. In: Handbook of Nutraceuticals and Funtional Foods
Cuadrado A (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP. Free Radic Biol Med 88:147–157. https://doi.org/10.1016/j.freeradbiomed.2015.04.029
Dabrowska A, Venero JL, Iwasawa R, Hankir M-K, Rahman S, Boobis A, Hajji N (2015) PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging (Albany NY) 7:629–47. https://doi.org/10.18632/aging.100790
De Jesús-Cortés H, Miller AD, Britt JK, DeMarco AJ, De Jesús-Cortés M, Stuebing E, Naidoo J, Vázquez-Rosa E, Morlock L, Williams NS, Ready JM, Narayanan NS, Pieper AA (2015) Protective efficacy of P7C3-S243 in the 6-hydroxydopamine model of Parkinson’s disease. NPJ Parkinsons Dis 1:15010. https://doi.org/10.1038/npjparkd.2015.10
Dipasquale B, Marini AM, Youle RJ (1991) Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. Biochem Biophys Res Commun 181:1442–1448
Elkon H, Melamed E, Offen D (2001) 6-Hydroxydopamine increases ubiquitin-conjugates and protein degradation: implications for the pathogenesis of Parkinson’s disease. Cell Mol Neurobiol 21:771–781
Eskes R, Antonsson B, Osen-Sand A, Montessuit S, Richter C, Sadoul R, Mazzei G, Nichols A, Martinou JC (1998) Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 143:217–224
Fasano A, Canning CG, Hausdorff JM, Lord S, Rochester L (2017) Falls in Parkinson’s disease: a complex and evolving picture. Mov Disord 32:1524–1536. https://doi.org/10.1002/mds.27195
Filichia E, Hoffer B, Qi X, Luo Y (2016) Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci Rep 6:32656. https://doi.org/10.1038/srep32656
Fontanesi F, Soto IC, Horn D, Barrientos A (2006) Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process. Am J Physiol Cell Physiol 291:C1129–C1147. https://doi.org/10.1152/ajpcell.00233.2006
Gim S-A, Sung J-H, Shah F-A, Kim M-O, Koh P-O (2013) Ferulic acid regulates the AKT/GSK-3β/CRMP-2 signaling pathway in a middle cerebral artery occlusion animal model. Lab Anim Res 29:63–69. https://doi.org/10.5625/lar.2013.29.2.63
Goodwill KE, Sabatier C, Marks C, Raag R, Fitzpatrick PF, Stevens RC (1997) Crystal structure of tyrosine hydroxylase at 2.3 A and its implications for inherited neurodegenerative diseases. Nat Struct Biol 4:578–585
Grassmann J (2005) Terpenoids as plant antioxidants. Vitam Horm 72:505–35. https://doi.org/10.1016/S0083-6729(05)72015-X
Grune T, Reinheckel T, Joshi M, Davies KJ (1995) Proteolysis in cultured liver epithelial cells during oxidative stress. Role of the multicatalytic proteinase complex, proteasome. J Biol Chem 270:2344–2351
Hattori N, Tanaka M, Ozawa T, Mizuno Y (1991) Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease. Ann Neurol 30:563–571. https://doi.org/10.1002/ana.410300409
Hoang T, Choi D-K, Nagai M, Wu D-C, Nagata T, Prou D, Wilson GL, Vila M, Jackson-Lewis V, Dawson VL, Dawson TM, Chesselet M-F, Przedborski S (2009) Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease. Free Radic Biol Med 47:1049–56. https://doi.org/10.1016/j.freeradbiomed.2009.07.013
Jensen EC (2013) Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec 296:378–381. https://doi.org/10.1002/ar.22641
Khan AQ, Nafees S, Sultana S (2011) Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NFκ-B activation and proinflammatory cytokine production. Toxicology 279:108–114. https://doi.org/10.1016/j.tox.2010.09.017
Kuter K, Kratochwil M, Berghauzen-Maciejewska K, Głowacka U, Sugawa MD, Ossowska K, Dencher NA (2016) Adaptation within mitochondrial oxidative phosphorylation supercomplexes and membrane viscosity during degeneration of dopaminergic neurons in an animal model of early Parkinson’s disease. Biochim Biophys Acta 1862:741–753. https://doi.org/10.1016/j.bbadis.2016.01.022
Lange KW (1989) Circling behavior in old rats after unilateral intranigral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci 45:1709–1714
Latchoumycandane C, Anantharam V, Jin H, Kanthasamy A, Kanthasamy A (2011) Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKCδ in cell culture and animal models of Parkinson’s disease. Toxicol Appl Pharmacol 256:314–23. https://doi.org/10.1016/j.taap.2011.07.021
Li R, Liang T, Xu L, Zheng N, Zhang K, Duan X (2013a) Puerarin attenuates neuronal degeneration in the substantia nigra of 6-OHDA-lesioned rats through regulating BDNF expression and activating the Nrf2/ARE signaling pathway. Brain Res 1523:1–9. https://doi.org/10.1016/j.brainres.2013.05.046
Li Z, Dong X, Liu H, Chen X, Shi H, Fan Y, Hou D, Zhang X (2013b) Astaxanthin protects ARPE-19 cells from oxidative stress via upregulation of Nrf2-regulated phase II enzymes through activation of PI3K/Akt. Mol Vis 19:1656–1666
Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370. https://doi.org/10.1016/j.cmet.2005.05.004
Norman AB, Norgren RB, Wyatt LM, Hildebrand JP, Sanberg PR (1992) The direction of apomorphine-induced rotation behavior is dependent on the location of excitotoxin lesions in the rat basal ganglia. Brain Res 569:169–172
Ong TP, Cardozo MT, de Conti A, Moreno FS (2012) Chemoprevention of hepatocarcinogenesis with dietary isoprenic derivatives: cellular and molecular aspects. Curr Cancer Drug Targets 12:1173–1190
Park J-H, Lee D-G, Yeon S-W, Kwon H-S, Ko J-H, Shin D-J, Park H-S, Kim Y-S, Bang M-H, Baek N-I (2011) Isolation of megastigmane sesquiterpenes from the silkworm (Bombyx mori L.) droppings and their promotion activity on HO-1 and SIRT1. Arch Pharm Res 34:533–542. https://doi.org/10.1007/s12272-011-0403-x
Paxinos G, Charles Watson (2007) The Rat Brain in Stereotaxic Coordinates Sixth Edition
Pradeep H, Sharma B, Rajanikant GK (2014) Drp1 in ischemic neuronal death: an unusual suspect. Curr Med Chem 21:2183–2189
Prasad SN, Muralidhara (2014) Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations. J Neurosci Res 92:1205–1216. https://doi.org/10.1002/jnr.23393
Qi X, Qvit N, Su Y-C, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126:789–802. https://doi.org/10.1242/jcs.114439
Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85. https://doi.org/10.1097/nen.0b013e31802d6da9
Randrup A, Munkvad I (1974) Pharmacology and physiology of stereotyped behavior. J Psychiatr Res 11:1–10
Rojo AI, Innamorato NG, Martín-Moreno AM, De Ceballos ML, Yamamoto M, Cuadrado A (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 58:588–598. https://doi.org/10.1002/glia.20947
Ryu J, Zhang R, Hong B-H, Yang E-J, Kang KA, Choi M, Kim KC, Noh S-J, Kim HS, Lee N-H, Hyun JW, Kim H-S (2013) Phloroglucinol attenuates motor functional deficits in an animal model of Parkinson’s disease by enhancing Nrf2 activity. PLoS One 8:e71178. https://doi.org/10.1371/journal.pone.0071178
Sanders LH, Timothy Greenamyre J (2013) Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 62:111–120. https://doi.org/10.1016/j.freeradbiomed.2013.01.003
Sarlette A, Krampfl K, Grothe C, von Neuhoff N, Dengler R, Petri S (2008) Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 67:1055–1062. https://doi.org/10.1097/NEN.0b013e31818b4906
Sawada M, Hirata Y, Arai H, Iizuka R, Nagatsu T (1987) Tyrosine hydroxylase, tryptophan hydroxylase, biopterin, and neopterin in the brains of normal controls and patients with senile dementia of Alzheimer type. J Neurochem 48:760–764
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787
Sell C (1995) Natural product-their chemistry and biological significance, Mann J, Davidson RS, Hobbs JB, Banthorpe DV, Harborne JB, Longman, Harlow, 1994. No of pages: xiv + 455, price £24.95. ISBN 0–582–06009-5. Flavour Fragr J 10:60–60 . https://doi.org/10.1002/ffj.2730100111
Sherman TG, Moody CA (1995) Alterations in tyrosine hydroxylase expression following partial lesions of the nigrostriatal bundle. Brain Res Mol Brain Res 29:285–296
Shrivastava P, Vaibhav K, Tabassum R, Khan A, Ishrat T, Khan MM, Ahmad A, Islam F, Safhi MM, Islam F (2013) Anti-apoptotic and anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson’s rat model. J Nutr Biochem 24:680–687. https://doi.org/10.1016/j.jnutbio.2012.03.018
Siddiqui A, Rane A, Rajagopalan S, Chinta SJ, Andersen JK (2016) Detrimental effects of oxidative losses in parkin activity in a model of sporadic Parkinson’s disease are attenuated by restoration of PGC1alpha. Neurobiol Dis 93:115–120. https://doi.org/10.1016/j.nbd.2016.05.009
Skaper SD (ed) (2012) Neurotrophic factors. Humana Press, Totowa
Soto-Otero R, Méndez-Alvarez E, Hermida-Ameijeiras A, Muñoz-Patiño AM, Labandeira-Garcia JL (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612
Spence J, Sadis S, Haas AL, Finley D (1995) A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol 15:1265–1273
Stewart D, Killeen E, Naquin R, Alam S, Alam J (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem 278:2396–2402. https://doi.org/10.1074/jbc.M209195200
Tabassum R, Vaibhav K, Shrivastava P, Khan A, Ahmed ME, Ashafaq M, Khan MB, Islam F, Safhi MM, Islam F (2015) Perillyl alcohol improves functional and histological outcomes against ischemia-reperfusion injury by attenuation of oxidative stress and repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion rats. Eur J Pharmacol 747:190–199. https://doi.org/10.1016/j.ejphar.2014.09.015
Tatton NA (2000) Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson’s disease. Exp Neurol 166:29–43. https://doi.org/10.1006/exnr.2000.7489
Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Olanow CW (1998) A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson’s disease. Ann Neurol 44:S142–S148
Thibaut F, Ribeyre JM, Dourmap N, Meloni R, Laurent C, Campion D, Ménard JF, Dollfus S, Mallet J, Petit M (1997) Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia. Schizophr Res 23:259–264
Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203
Todorovic M, Wood SA, Mellick GD (2016) Nrf2: a modulator of Parkinson’s disease? J Neural Transm 123:611–619. https://doi.org/10.1007/s00702-016-1563-0
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76:4350–4354
Vivekanantham S, Shah S, Dewji R, Dewji A, Khatri C, Ologunde R (2015) Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int J Neurosci 125:717–725. https://doi.org/10.3109/00207454.2014.982795
Wang P, Wang P, Liu B, Zhao J, Pang Q, Agrawal SG, Jia L, Liu F-T (2015) Dynamin-related protein Drp1 is required for Bax translocation to mitochondria in response to irradiation-induced apoptosis. Oncotarget 6:22598–22612. https://doi.org/10.18632/oncotarget.4200
Webster KA (2012) Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species. Futur Cardiol 8:863–884. https://doi.org/10.2217/fca.12.58
Xiao H, Lv F, Xu W, Zhang L, Jing P, Cao X (2011) Deprenyl prevents MPP(+)-induced oxidative damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression through the activation of PI3K/Akt and Erk. Toxicology 290:286–294. https://doi.org/10.1016/j.tox.2011.10.007
Xu Y, Wang W, Jin K, Zhu Q, Lin H, Xie M, Wang D (2017) Perillyl alcohol protects human renal tubular epithelial cells from hypoxia/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K/Akt/eNOS pathway. Biomed Pharmacother 95:662–669. https://doi.org/10.1016/j.biopha.2017.08.129
Yuan H, Gerencser AA, Liot G, Lipton SA, Ellisman M, Perkins GA, Bossy-Wetzel E (2007) Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death Differ 14:462–471. https://doi.org/10.1038/sj.cdd.4402046
Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47. https://doi.org/10.1016/j.pneurobio.2012.09.003
Zhang Z, Liu L, Jiang X, Zhai S, Xing D (2016) The essential role of Drp1 and its regulation by S-nitrosylation of Parkin in dopaminergic neurodegeneration: implications for Parkinson’s disease. Antioxid Redox Signal 25:609–622. https://doi.org/10.1089/ars.2016.6634
Zhao F, Wang W, Wang C, Siedlak SL, Fujioka H, Tang B, Zhu X (2017) Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo: implications for idiopathic Parkinson’s disease. Biochim Biophys Acta Mol basis Dis 1863:1359–1370. https://doi.org/10.1016/j.bbadis.2017.02.016
Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet J-C, Scherzer CR, Global PD Gene Expression (GPEX) Consortium (2010) PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2:52ra73. https://doi.org/10.1126/scitranslmed.3001059
Zhou W, Fukumoto S, Yokogoshi H (2009) Components of lemon essential oil attenuate dementia induced by scopolamine. Nutr Neurosci 12:57–64. https://doi.org/10.1179/147683009X388832
Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC (2000) Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol 427:440–454
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The authors are thankful to Dr. Pradeep Kumar Rai from JH-FACS Academy, Becton Dickinson Pvt. Ltd. for his invaluable assistance in the flow cytometric data acquisition.
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MFZ and FF designed the study. EA and SNI conducted the behavioural trials. EA and MFZ conducted the biochemical assays. EA and AAK wrote the first draft of the manuscript. MMH edited the final draft of the manuscript.
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Fig S1.
Histological changes in 6-OHDA lesioned rats: Tyrosine hydroxylase (TH) immunostaining (BCIP/NBT), and haematoxylin & eosin staining was visualized to observe cell death and chromatin condensation (pyknosis) in lesioned brain, respectively. Lesioned animals exhibited significantly reduced TH positive fibres/cells in striatum and substantia nigra, respectively. Comparatively, animals treated with PA exhibited a higher percentage of TH immunoreactive fibres/cells. (a) TH immunoreactive fibres (blue) at the striatum in respective groups (b) bar graph represents quantification of TH-positive fibre loss relative to intact side (c) TH immunoreactive cells (blue) at the substantia nigra in respective groups (d) bar graph represents quantification of TH-positive cell loss relative to intact side (e) microscopic images (× 40) of striatum in respective groups, red arrows representing pyknosis. All values are expressed as mean ± SD. Significant differences are expressed as (***p ≤ 0.001, unpaired t-test) compared with sham group. (JPG 2604 kb).
Fig S2.
Broad overview of protective action of PA in lesioned animals: PA treatment inhibits the oxidative stress, mitochondrial dysfunction, and consequent cell death induced by 6-OHDA lesioning. By virtue of alleviation of these factors, the motor impairment in lesioned animals, caused by cell death in nigrostriatal circuit, is also alleviated by PA. (JPG 670 kb).
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Anis, E., Zafeer, M.F., Firdaus, F. et al. Perillyl Alcohol Mitigates Behavioural Changes and Limits Cell Death and Mitochondrial Changes in Unilateral 6-OHDA Lesion Model of Parkinson’s Disease Through Alleviation of Oxidative Stress. Neurotox Res 38, 461–477 (2020). https://doi.org/10.1007/s12640-020-00213-0
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DOI: https://doi.org/10.1007/s12640-020-00213-0