Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein
1. Institute of Biomedical Chemistry, Moscow, Russia 2. Institute of Biomedical Chemistry, Moscow, Russia; Zakusov Institute of Pharmacology, Moscow, Russia
Effects of the endogenous neuroprotector isatin and the pharmacological drug afobazole (exhibiting neuroprotective properties) on behavioral reactions and quantitative changes in the brain proteomic profile have been investigated in rats with experimental rotenone Parkinsonism. A single dose of isatin (100 mg/kg subcutaneously on the last day of a 7-day course of rotenone administration) improved the motor activity of rats with rotenone-induced Parkinsonism in the open field test (horizontal movements) and the rotating rod test. Afobazole (10 mg/kg intraperitoneally, daily during the 7-day course of rotenone administration) reduced the manifestations of rigidity and postural instability. Proteomic analysis, performed using brain samples obtained the day after the last administration of rotenone and neuroprotectors, revealed similar quantitative changes in the brain of rats with rotenone Parkinsonism. An increase in the relative content of 65 proteins and a decrease in the relative content of 21 proteins were detected. The most pronounced changes — an almost ninety-fold increase in the alpha-synuclein content — were found in the brains of rats treated with isatin. In animals of the experimental groups treated with “Rotenone + Isatin”, as well as “Rotenone + Afobazole”, the increase in the relative content of this protein in the brain was almost 60 and 50 times higher than the control values. Taking into consideration the known data on the physiological role of alpha-synuclein, an increase in the content of this protein in the brain upon administration of neuroprotectors to animals with rotenone Parkinsonism may represent a compensatory reaction, at least in the early stages of this disease and the beginning of its treatment.
Buneeva O.A., Kapitsa I.G., Zgoda V.G., Medvedev A.E. (2023) Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein. Biomeditsinskaya Khimiya, 69(5), 290-299.
Buneeva O.A. et al. Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein // Biomeditsinskaya Khimiya. - 2023. - V. 69. -N 5. - P. 290-299.
Buneeva O.A. et al., "Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein." Biomeditsinskaya Khimiya 69.5 (2023): 290-299.
Buneeva, O. A., Kapitsa, I. G., Zgoda, V. G., Medvedev, A. E. (2023). Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein. Biomeditsinskaya Khimiya, 69(5), 290-299.
References
Duty S., Jenner P. (2011) Animal models of Parkinson's disease: A source of novel treatments and clues to the cause of the disease. Br. J. Pharmacol., 164(4), 1357-1391. CrossRef Scholar google search
Fleming S.M., Zhu C., Fernagut P.O., Mehta A., Dicarlo C.D., Seaman R.L., Chesselet M.F. (2004) Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp. Neurol., 187(2), 418-429. CrossRef Scholar google search
Fleming S.M., Salcedo J., Fernagut P.O., Rockenstein E., Masliah E., Levine M.S., Chesselet M.F. (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J. Neurosci., 24(42), 9434-9440. CrossRef Scholar google search
Cannon J.R., Tapias V.M., Na H.M., Honick A.S., Drolet R.E., Greenamyre J.T. (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol. Dis., 34(2), 279-290. CrossRef Scholar google search
Medvedev A.E., Buneeva O.A., Kopylov A.T., Tikhonova O.V., Medvedeva M.V., Nerobkova L.N., Kapitsa I.G., Zgoda V.G. (2017) Brain mitochondrial subproteome of Rpn10-binding proteins and its changes induced by the neurotoxin MPTP and the neuroprotector isatin. Biochemistry (Moscow), 82(3), 330-339. CrossRef Scholar google search
Buneeva O., Kopylov A., Kapitsa I., Ivanova E., Zgoda V., Medvedev A. (2018) The effect of neurotoxin MPTP and neuroprotector isatin on the profile of ubiquitinated brain mitochondrial proteins. Cells, 7(8), 91. CrossRef Scholar google search
Medvedev A., Buneeva O., Gnedenko O., Ershov P., Ivanov A. (2018) Isatin, an endogenous non-peptide biofactor: A review of its molecular targets, mechanisms of actions and their biomedical implications. Biofactors, 44, 95-108. CrossRef Scholar google search
Medvedev A., Buneeva O. (2022) Tryptophan metabolites as mediators of microbiota-gut-brain communication: Focus on isatin. Front. Behav. Neurosci., 16, 922274. CrossRef Scholar google search
Tetrud J.W., Langston J.W. (1989) MPTP-induced parkinsonism as a model for Parkinson’s disease. Acta Neurol. Scand., 126, 35-40. CrossRef Scholar google search
Buneeva O., Gnedenko O., Zgoda V., Kopylov A., Glover V., Ivanov A., Medvedev A., Archakov A. (2010) Isatin binding proteins of rat and mouse brain: Proteomic identification and optical biosensor validation. Proteomics, 10, 23-37. CrossRef Scholar google search
Medvedev A., Kopylov A., Buneeva O., Kurbatov L., Tikhonova O., Ivanov A., Zgoda V.A. (2020) Neuroprotective dose of isatin causes multilevel changes involving the brain proteome: Prospects for further research. Int. J. Mol. Sci., 21(11), 4187. CrossRef Scholar google search
Medvedev A., Buneeva O., Gnedenko O., Fedchenko V., Medvedeva M., Ivanov Y., Glover V., Sandler M. (2006) Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: Partial agonism with deprenyl. J. Neural. Transm. Suppl., 71, 97-103. CrossRef Scholar google search
Saravanan K.S., Sindhu K.M., Senthilkumar K.S., Mohanakumar K.P. (2006) L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats. Neurochem. Int., 49(1), 28-40. CrossRef Scholar google search
Seredenin S.B., Voronin M.V. (2009) Neuroreceptor mechanisms involved in the action of afobazole. Russian Journal of Experimental and Clinical Pharmacology, 72(1), 3-11. CrossRef Scholar google search
Kapitsa I.G., Ivanova E.A., Val'dman E.A., Voronina T.A. (2017) Activity of afobazole in experimental models of Parkinson's disease. Russian Journal of Experimental and Clinical Pharmacology, 8(6), 3-7. CrossRef Scholar google search
Voronina T.A., Seredenin S.B., Yarkova M.A., Voronin M.V. (2012) Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv, chast' pervaya (Mironov A.N., ed.), Grif i K, Moskva, 994 p. Scholar google search
Kapitsa I.G., Kazieva L.S., Vavilov N.E., Zgoda V.G., Kopylov A.T., Medvedev A.E., Buneeva O.A. (2023) Characteristics of behavioral reactions and the profile of brain isatin-binding proteins of rats with the rotenone-induced experimental parkinsonism. Biomeditsinskaya Khimiya, 69(1), 46-54. CrossRef Scholar google search
Bradford M.M. (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. CrossRef Scholar google search
Buneeva O.A., Kapitsa I.G., Kazieva L.S., Vavilov N.E., Zgoda V.G., Medvedev A.E. (2023) Quantitative changes of brain isatin-binding proteins of rats with the rotenone-induced experimental parkinsonism. Biomeditsinskaya Khimiya, 69(3), 188-192. CrossRef Scholar google search
Bose A., Beal M.F. (2016) Mitochondrial dysfunction in Parkinson's disease. J. Neurochem., 139(Suppl 1), 216-231. CrossRef Scholar google search
Borsche M., Pereira S.L., Klein C., Grünewald A. (2021) Mitochondria and Parkinson's disease: Clinical, molecular, and translational aspects. J. Parkinsons Dis., 11(1), 45-60. CrossRef Scholar google search
Sohrabi T., Mirzaei-Behbahani B., Zadali R., Pirhaghi M., Morozova-Roche L.A., Meratan A.A. (2023) Common mechanisms underlying α-synuclein-induced mitochondrial dysfunction in Parkinson's disease. J. Mol. Biol., 435(12), 167992. CrossRef Scholar google search
Neves M., Grãos M., Anjo S.I., Manadas B. (2022) Modulation of signaling pathways by DJ-1: An updated overview. Redox Biol., 51, 102283. CrossRef Scholar google search
Buneeva O.A., Medvedev A.E. (2021) DJ-1 protein and its role in the development of Parkinson's disease: Studies on experimental models. Biochemistry (Moscow), 86(6), 627-640. CrossRef Scholar google search
Betarbet R., Canet-Aviles R.M., Sherer T.B., Mastroberardino P.G., McLendon C., Kim J.H., Lund S., Na H.M., Taylor G., Bence N.F., Kopito R., Seo B.B., Yagi T., Yagi A., Klinefelter G., Cookson M.R., Greenamyre J.T. (2006) Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Neurobiol. Dis., 22(2), 404-420. CrossRef Scholar google search
de Miranda B.R., Rocha E.M., Bai Q., El Ayadi A., Hinkle D., Burton E.A., Greenamyre J.T. (2018) Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease. Neurobiol. Dis., 115, 101-114. CrossRef Scholar google search
Vanle B.C., Florang V.R., Murry D.J., Aguirre A.L., Doorn J.A. (2017) Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde. Biochem. Biophys. Res. Commun., 492(2), 275-281. CrossRef Scholar google search
Nakajima H., Amano W., Kubo T., Fukuhara A., Ihara H., Azuma Y.T., Tajima H., Inui T., Sawa A., Takeuchi T. (2009) Glyceraldehyde-3-phosphate dehydrogenase aggregate formation participates in oxidative stress-induced cell death. J. Biol. Chem., 284(49), 34331-34341. CrossRef Scholar google search
Sofronova A.A., Pozdyshev D.V., Barinova K.V., Muronetz V.I., Semenyuk P.I. (2021) Glycation of glyceraldehyde-3- phosphate dehydrogenase inhibits the binding with α-synuclein and RNA. Arch. Biochem. Biophys., 698, 108744. CrossRef Scholar google search
Muronetz V.I, Melnikova A.K., Seferbekova Z.N., Barinova K.V., Schmalhausen E.V. (2017) Glycation, glycolysis, and neurodegenerative diseases: Is there any connection? Biochemistry (Moscow), 82(8), 874-886. CrossRef Scholar google search
Berry M.D. (2004) Glyceraldehyde-3-phosphate dehydrogenase as a target for small-molecule disease-modifying therapies in human neurodegenerative disorders. J. Psychiatry Neurosci., 29(5), 337-345. PMID: 15486605; PMCID: PMC518865. Scholar google search
Ylikallio E., Pöyhönen R., Zimon M., de Vriendt E., Hilander T., Paetau A., Jordanova A., Lönnqvist T., Tyynismaa H. (2013) Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum. Mol. Genet., 22(15), 2975-283. CrossRef Scholar google search
Balastik M., Ferraguti F., Pires-da Silva A., Lee T.H., Alvarez-Bolado G., Lu K.P., Gruss P. (2008) Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc. Natl. Acad. Sci USA, 105(33), 12016-1221. CrossRef Scholar google search
Yan C., Gong L., Chen L., Xu M., Abou-Hamdan H., Tang M., Désaubry L., Song Z. (2020) PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy, 16(3), 419-434. CrossRef Scholar google search
Dutta D., Ali N., Banerjee E., Singh R., Naskar A., Paidi R.K., Mohanakumar K.P. (2018) Low levels of prohibitin in substantia nigra makes dopaminergic neurons vulnerable in Parkinson's disease. Mol. Neurobiol., 55(1), 804-821. CrossRef Scholar google search
Li L., Venkataraman L., Chen S., Fu H. (2020) Function of WFS1 and WFS2 in the central nervous system: Implications for Wolfram syndrome and Alzheimer's disease. Neurosci. Biobehav. Rev., 118, 775-783. CrossRef Scholar google search
Mishra R., Chen B.S., Richa P., Yu-Wai-Man P. (2021) Wolfram syndrome: New pathophysiological insights and therapeutic strategies. Ther. Adv. Rare Dis., 2, 26330040211039518. CrossRef Scholar google search
Sulzer D., Edwards R.H. (2019) The physiological role of α-synuclein and its relationship to Parkinson’s disease. J. Neurochem., 150, 475-486. CrossRef Scholar google search
Ottolini D., Calí T., Szabò I., Brini M. (2017) Alpha-synuclein at the intracellular and the extracellular side: Functional and dysfunctional implications. Biol. Chem., 398(1), 77-100. CrossRef Scholar google search
Oliveira L.M.A., Gasser T., Edwards R., Zweckstetter M., Melki R., Stefanis L., Lashuel H.A., Sulzer D., Vekrellis K., Halliday G.M., Tomlinson J.J., Schlossmacher M., Jensen P.H., Schulze-Hentrich J., Riess O., Hirst W.D., El-Agnaf O., Mollenhauer B., Lansbury P., Outeiro T.F. (2021) Alpha-synuclein research: Defining strategic moves in the battle against Parkinson’s disease. NPJ Parkinsons Dis., 7, 65. CrossRef Scholar google search
Chen R., Gu X., Wang X. (2022) α-Synuclein in Parkinson's disease and advances in detection. Clin. Chim. Acta., 529, 76-86. CrossRef Scholar google search
Atik A., Stewart T., Zhang J. (2016) Alpha-synuclein as a biomarker for Parkinson's disease. Brain Pathol., 26(3), 410-418. CrossRef Scholar google search
Ostrerova N., Petrucelli L., Farrer M., Mehta N., Choi P., Hardy J., Wolozin B. (1999) α-Synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci., 19(14), 5782-5791. CrossRef Scholar google search
Sherer T.B., Betarbet R., Stout A.K., Lund S., Baptista M., Panov A.V., Cookson M.R., Greenamyre J.T. (2002) An in vitro model of Parkinson's disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J. Neurosci., 22(16), 7006-7015. CrossRef Scholar google search
Vasili E., Dominguez-Meijide A., Flores-Leуn M., Al-Azzani M., Kanellidi A., Melki R., Stefanis L., Outeiro T.F. (2022) Endogenous levels of alpha-synuclein modulate seeding and aggregation in cultured cells. Mol. Neurobiol., 59(2), 1273-1284. CrossRef Scholar google search
Bhattacharjee P., Öhrfelt A., Lashley T., Blennow K., Brinkmalm A., Zetterberg H. (2019) Mass spectrometric analysis of lewy body-enriched α-synuclein in Parkinson's disease. J. Proteome Res., 18(5), 2109-2120. CrossRef Scholar google search
Klucken J., Shin Y., Masliah E., Hyman B.T., McLean P.J. (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J. Biol. Chem., 279(24), 25497-25502. CrossRef Scholar google search
Jurkowitz-Alexander M.S., Altschuld R.A., Hohl C.M., Johnson J.D., McDonald J.S., Simmons T.D., Horrocks L.A. (1992) Cell swelling, blebbing, and death are dependent onATP depletion and independent of calcium during chemical hypoxia in a glial cell line (ROC-1). J. Neurochem., 59(1), 344-352. CrossRef Scholar google search
Kaul S., Anantharam V., Kanthasamy A., Kanthasamy A.G. (2005) Wild-type alpha-synuclein interacts with pro-apoptotic proteins PKCdelta and BAD to protect dopaminergic neuronal cells against MPP+-induced apoptotic cell death. Mol. Brain Res., 139(1), 137-152. CrossRef Scholar google search
da Costa C.A., Ancolio K., Checler F. (2000) Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha-synuclein protects neuronal cells from apoptotic stimuli. J. Biol. Chem., 275(31), 24065-24069. CrossRef Scholar google search
Manning-Bog A.B., McCormack A.L., Purisai M.G., Bolin L.M., di Monte D.A. (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J. Neurosci., 23(8), 3095-3099. CrossRef Scholar google search
Sulzer D., Edwards R.H. (2019) The physiological role of α-synuclein and its relationship to Parkinson's disease. J. Neurochem., 150(5), 475-486. CrossRef Scholar google search
