Parkinson’s disease (PD) is a chronic relentlessly progressive neurodegenerative disease mainly affecting dopamine (DA)-ergic neurons in the nigrostriatal system of the brain. PD mostly affects elderly people and is incurable. Impairments to the conformation of α-synuclein protein and its hyperphosphorylation, along with the development of chronic neuroinflammation, are the main components in the pathogenesis of neurodegeneration in PD. Pharmacotherapy directed to mobilizing the stress-induced chaperone Hsp70, which plays a key role in controlling the quality of protein molecules and has immunomodulatory activity, has potential in developing preventive treatment for PD. This study used a model of the preclinical stage of PD in elderly rats created by intranasal administration of proteasome inhibitor lactacystin. Rats were treated with a scheme based on systemic administration of an Hsp70 chaperone inducer – the low molecular weight quinoid compound U133 (acetylated echinochrome 2,3,7-tris-O-glucoside). Compound U133 was found to induce a time-delayed increase in Hsp70 content in the pars compacta of the substantia nigra (SNpc) in elderly animals. Preventive Hsp70-induced therapy with U133 in the model of the preclinical stage of PD in elderly rats weakened the process of neurodegeneration in the SNpc and countered the development of neuroinflammation. There were reductions in the quantity of aggregated α-synuclein and regression of α-synuclein posttranslationally modified by phosphorylation at Ser129. These data provide evidence that the prodrug, low molecular weight substance U133, has significant therapeutic potential in the development of Parkinson’s-like pathology at elderly age. The study results have scientific and applied importance in terms of the development of innovatory technologies for the preventive pharmacotherapy of PD based on the Russian substance U133.
Similar content being viewed by others
References
M. G. Erkkinen, M. O. Kim, and M. D. Geschwind, “Clinical neurology and epidemiology of the major neurodegenerative diseases,” Cold Spring Harb. Perspect. Biol., 10, No. 4, a033118 (2018).
K. A. Fujita, M. Ostaszewski, Y. Matsuoka, et al., “Integrating pathways of Parkinson’s disease in a molecular interaction map,” Mol. Neurobiol., 49, No. 1, 88–102 (2014).
H. Braak, E. Ghebremedhin, U. Rüb, et al., “Stages in the development of Parkinson’s disease-related pathology,” Cell Tissue Res., 318, No. 1, 121–134 (2004).
M. Verma, S. Basu, M. Singh, et al., “Molecular interactions of a-synuclein, mitochondria, and cellular degradation pathways in Parkinson’s disease,” Qual. Control Cell. Protein Neurodegener. Disord., 212–234 (2020).
E. M. Rocha, B. De Miranda, and L. H. Sanders, “Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease,” Neurobiol. Dis., 109, 249–257 (2018).
B. I. Giasson, J. E. Duda, I. V. J. Murray, et al., “Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions,” Science, 290, No. 5493, 985–989 (2000).
J. Lotharius and P. Brundin, “Pathogenesis of Parkinson’s disease: Dopamine, vesicles and α-synuclein,” Nat. Rev. Neurosci., 3, No. 12, 932–942 (2002).
S. Hara, S. Arawaka, H. Sato, et al., “Serine 129 phosphorylation of membrane-associated α-synuclein modulates dopamine transporter function in a G protein-coupled receptor kinase-dependent manner,” Mol. Biol. Cell., 24, No. 11, 1649–1660 (2013).
O. Marques and T. F. Outeiro, “Alpha-synuclein: From secretion to dysfunction and death,” Cell Death Dis., 3, No. 7, e350 (2012).
J. C. Rochet, T. F. Outeiro, K. A. Conway, et al., “Interactions among α-synuclein, dopamine, and biomembranes: Some clues for understanding neurodegeneration in Parkinson’s disease,” J. Mol. Neurosci., 23, No. 1–2, 23–33 (2004).
M. Subramaniam, D. Althof, S. Gispert, et al., “Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels,” J. Neurosci., 34, No. 41, 13586–13599 (2014).
C. C. Ferrari, M. C. Pott Godoy, R. Tarelli, et al., “Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra,” Neurobiol. Dis., 24, No. 1, 183–193 (2006).
S. Perez-Alvarez, M. E. Solesio, J. Manzanares, et al., “Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria-mediated cell death,” Br. J. Pharmacol., 158, No. 4, 1121–1130 (2009).
M. N. Karpenko, Z. M. Muruzheva, N. S. Pestereva, and I. V. Ekimova, “An infection hypothesis of Parkinson’s disease,” Neurosci. Behav. Physiol., 49, No. 5, 555–561 (2019).
P. K. Auluck, H. Y. E. Chan, J. Q. Trojanowski, et al., “Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson’s disease,” Science, 295, No. 5556, 865–868 (2002).
J. B. Leverenz, I. Umar, Q. Wang, et al., “Proteomic identification of novel proteins in cortical Lewy bodies,” Brain Pathol., 17, No. 2, 139–145 (2007).
Y. Chu, H. Dodiya, P. Aebischer, et al., “Alterations in lysosomal and proteasomal markers in Parkinson’s disease: Relationship to alphasynuclein inclusions,” Neurobiol. Dis., 35, No. 3, 385–398 (2009).
Y. F. Pastukhov, D. V. Plaksina, K. V. Lapshina, et al., “Exogenous protein HSP70 blocks neurodegeneration in the rat model of the clinical stage of Parkinson’s disease,” Dokl. Biol. Sci., 457, No. 1 (2014).
D. V. Belan and I. V. Ekimova, “Heat shock proteins in conformational diseases of the brain,” Ros. Fiziol. Zh., 105, No. 12, 1465–1485 (2019).
E. M. Eremenko, O. I. Antimonova, O. G. Shekalova, et al., “Novel compounds that increase expression of Hsp70 and their biological activity,” Cell Tiss. Biol., 4, No. 3, 251–257 (2010).
V. F. Lazarev, K. V. Onokhin, O. I. Antimonova, et al., “Kinetics of chaperone activity of proteins Hsp70 and Hdj1 in human leukemia u-937 cells after preconditioning with thermal shock or compound u-133,” Biochemistry, 76, No. 5, 590 (2011).
I. V. Ekimova, D. V. Plaksina, Y. F. Pastukhov, et al., “New HSF1 inducer as a therapeutic agent in a rodent model of Parkinson’s disease,” Exp. Neurol., 306, 199–208 (2018).
L. M. de Lau and M. M. Breteler, “Epidemiology of Parkinson’s disease,” Lancet Neurol., 5, No. 6, 525–535 (2006).
J. Labbadia and R. I. Morimoto, “The biology of proteostasis in aging and disease,” Annu. Rev. Biochem., 84, No. 1, 435–464 (2015).
C. Soti and P. Csermely, “Chaperones and aging: Role in neurodegeneration and in other civilizational diseases,” Neurochem. Int., 41, No. 6, 383–389 (2002).
D. A. Jurivich, M. Choo, J. Welk, et al., “Human aging alters the first phase of the molecular response to stress in T-cells,” Exp. Gerontol., 40, No. 12, 948–958 (2005).
I. V. Ekimova, V. V. Simonova, M. A. Guzeev, et al., “Changes in sleep characteristics of rat preclinical model of Parkinson’s disease based on attenuation of the ubiquitin-proteasome system activity in the brain,” J. Evol. Biochem. Physiol., 52, No. 6, 463–474 (2016).
S. Polonik, A. Tolkach, and N. S. Uvarova, “Glycosylation of echinochrome and related hydroxynaphthazarines by the orthoester method,” Zh. Organ. Khim., 30, No. 2, 248–253 (1994).
N. P. Mishchenko, S. A. Fedoreyev, and V. L. Bagirova, “Histochrome: a new original domestic drug,” Pharm. Chem. J., 37, No. 1, 48-52 (2003).
V. F. Lazarev, A. D. Nikotina, E. R. Mikhaylova, et al., “Hsp70 chaperone rescues C6 rat glioblastoma cells from oxidative stress by sequestration of aggregating GAPDH,” Biochem. Biophys. Res. Commun, 470, No. 3, 766–771 (2016).
E. A. Yurchenko, E. S. Menchinskaya, S. G. Polonik, et al., “Hsp70 induction and anticancer activity of U-133, the acetylated trisglucosydic derivative of echinochrome,” Med. Chem., 5, No. 6, 263–271 (2015).
E. B. Lasunskaia, I. Fridlianskaia, A. V. Arnoldt, et al., “Sublethal heat shock induces plasma membrane translocation of 70-kDa heat shock protein in viable, but not in apoptotic, U-937 leukaemia cells,” APMIS, 118, No. 3, 179–187 (2010).
D. V. Plaksina, M. V. Chernyshev, M. N. Karpenko, et al., “Experimental modeling of a preclinical Parkinson’s disease stage in rats by intranasal lactacystin administration,” Neurodegen. Dis., Supplement, 17, No. 1, 1655 (2017).
I. V. Ekimova, A. R. Gazizova, M. N. Karpenko, and D. V. Plaksina, “Signs of anhedonia and destructive changes in the ventral tegmental area of the midbrain in the model of the preclinical Parkinson’s disease stage in experiment,” Zh. Nevrol. Psikhiat., 118, No. 9, 61–67 (2018).
I. N. Abdurasulova, I. V. Ekimova, A. V. Matsulevich, et al., “Impairment of non-associative learning in a rat experimental model of preclinical stage of Parkinson’s disease,” Dokl. Biol. Sci., 476, No. 1, 188–190 (2017).
Y. F. Pastukhov, V. V. Simonova, M. V. Chernyshev, et al., “Signs of sleep and behavior disorders indicating the initial stage of neurodegeneration in a rat model of Parkinson’s disease,” J. Evol. Biochem. Physiol., 53, No. 5, 431–434 (2017).
Y. F. Pastukhov, V. V. Simonova, T. S. Shemyakova, et al., “U-133, a heat shock proteins inducer, precludes sleep disturbances in a model of the preclinical stage of Parkinson’s disease in aged rats,” Adv. Gerontol., 32, No. 6, 935 (2019).
S. K. Calderwood, A. Murshid, and T. Prince, “The shock of aging: Molecular chaperones and the heat shock response in longevity and aging,” Gerontology, 55, No. 5, 550–558 (2009).
N. Shemesh and A. Ben-Zvi, “HSF1 regulation in aging and its role in longevity,” in: Heat Shock Factor (2016), pp. 93–113.
A. Y. Chesnokova, I. V. Ekimova, and Y. F. Pastukhov, “Parkinson’s disease and aging,” Adv. Gerontol., 9, No. 2, 164–173 (2019).
W. W. Yu, S. N. Cao, C. X. Zang, et al., “Heat shock protein 70 suppresses neuroinflammation induced by α-synuclein in astrocytes,” Mol. Cell. Neurosci., 86, 58–64 (2018).
I. V. Guzhova, Z. A. Darieva, A. R. Melo, and B. A. Margulis, “Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells,” Cell Stress Chaperones, 2, No. 2, 132 (1997).
A. Asea, S. K. Kraeft, E. A. Kurt-Jones, et al., “HSP70 stimulates cytokine production through a CD 14-dependent pathway, demonstrating its dual role as a chaperone and cytokine,” Nat. Med., 6, No. 4, 435–442 (2000).
S. K. Calderwood, S. S. Mambula, P. J. Gray, and J. R. Theriault, “Extracellular heat shock proteins in cell signaling,” FEBS Lett., 581, No. 19, 3689–3694 (2007).
M. Tunesi, I. Raimondi, T. Russo, et al., “Hydrogel-based delivery of Tat-fused protein Hsp70 protects dopaminergic cells in vitro and in a mouse model of Parkinson’s disease,” NPG Asia Mater., 11, No. 1, 1–15 (2019).
D. V. Plaksina and I. V. Ekimova, “Age-related features of α-synuclein pathology in the brain on modeling the preclinical stage of Parkinson’s disease in rats,” Neurosci. Behav. Physiol., 50, No. 1, 109–114 (2020).
K. L. Ma, L. K. Song, Y. H. Yuan, et al., “The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle,” Neuropharmacology, 82, 132–142 (2014).
C. C. Raiss, T. S. Braun, I. B. M. Konings, et al., “Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology,” Sci. Rep., 6, No. 1, 1–13 (2016).
X. Q. Bao, X. L. Wang, and D. Zhang, “FLZ attenuates α-synuclein-induced neurotoxicity by activating heat shock protein 70,” Mol. Neurobiol., 54, No. 1, 349–361 (2017).
J. P. Anderson, D. E. Walker, J. M. Goldstein, et al., “Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease,” J. Biol. Chem., 281, No. 40, 29739–29752 (2006).
H. Sato, S. Arawaka, S. Hara, et al., “Authentically phosphorylated α-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson’s disease,” J. Neurosci., 31, No. 46, 16884–16894 (2011).
L. Xie, H. Kang, Q. Xu, et al., “Sleep drives metabolite clearance from the adult brain,” Science, 342, No. 6156, 373–377 (2013).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 106, No. 10, pp. 1251–1265, October, 2020.
Rights and permissions
About this article
Cite this article
Belan, D.V., Polonik, S.G. & Ekimova, I.V. Assessment of the Efficacy of Preventive Therapy with Chaperone Inducer U133 in a Model of the Preclinical Stage of Parkinson’s Disease in Elderly Rats. Neurosci Behav Physi 51, 673–680 (2021). https://doi.org/10.1007/s11055-021-01120-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-021-01120-3