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The Chaperone Inducer U133 Eliminates Anhedonia and Prevents Neurodegeneration in Monoaminergic Emotiogenic Brain Structures in a Preclinical Model of Parkinson’s Disease in Aged Rats

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder mainly diagnosed in elderly patients, which is now considered incurable. To date, there are no effective neuroprotectors suitable to treat PD patients. We have previously demonstrated that U133 therapy, which induces the synthesis of Hsp70 and Hsp40 heat shock proteins in the brain, prevents the development of neurodegeneration in the nigrostriatal system and eliminates sleep disorders in an animal model of PD. In the present study, we assessed the antidepressant properties of preventive U133 therapy, as well as its neuroprotective effect on monoaminergic emotiogenic brain structures in a preclinical model of PD in aged (20-month-old) Wistar rats, created by intranasal administration of the proteasome inhibitor lactacystin. It was found that intraperitoneal U133 administration in aged animals led to a delayed (after 3–7 days) elevation of the Hsp70 (HSPA1) level in the midbrain ventral tegmental area and locus coeruleus. Preventive U133 therapy eliminated the manifestations of depression-like behavior in the form of anhedonia, which develops during the preclinical stage of PD in aged rats. It was established that the antidepressant-like effect of the chaperone inducer U133 is due to the ability of the Hsp70 chaperone to attenuate neurodegeneration and neuroinflammation in the dopaminergic mesolimbic reward system and locus coeruleus noradrenergic system. The data obtained may serve as a fundamental basis for the development of a novel chaperone inducer-based molecular technology for preventive therapy of polyetiological PD and concomitant anhedonia.

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Abbreviations

Hsp70:

70 kDa heat shock protein

PBS:

apyrogenic phosphate buffer, pH 7.4

PD:

Parkinson’s disease

VTA:

ventral tegmental area

DA:

dopamine; LC

NA:

noradrenaline

TH:

tyrosine hydroxylase

UPS:

ubiquitin-proteasome system

REFERENCES

  1. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https://doi.org/10.1038/nrdp

    Article  PubMed  Google Scholar 

  2. Chesnokova AY, Ekimova IV, Pastukhov YF (2019) Parkinson’s Disease and Aging. Adv Gerontol 9:164–173. https://doi.org/10.1134/S2079057019020085

    Article  Google Scholar 

  3. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68(5):384-386. https://doi.org/10.1212/01.wnl.0000247740.47667.03

    Article  CAS  PubMed  Google Scholar 

  4. Pastukhov IuF (2013) Changes in the characteristics of paradoxical sleep are an early feature of Parkison’s disease. Zhurn Vyssh Nervn Deiatelnosti im IP Pavlova 63(1):75–85 https://doi.org/10.7868/s0044467713010103.

    Article  CAS  Google Scholar 

  5. Stefani A, Högl B. Sleep in Parkinson’s disease (2020) Neuropsychopharmacology 45(1):121-128. https://doi.org/10.1038/s41386-019-0448-y

  6. Schrag A, Taddei RN (2017) Depression and Anxiety in Parkinson’s Disease. Int Rev Neurobiol 133:623-655. https://doi.org/10.1016/bs.irn.2017.05.024

    Article  PubMed  Google Scholar 

  7. Shen CC, Tsai SJ, Perng CL, Kuo BI, Yang AC (2013) Risk of Parkinson disease after depression: a nationwide population-based study. Neurology 81(17):1538-1544. https://doi.org/10.1212/WNL.0b013e3182a956ad

    Article  CAS  PubMed  Google Scholar 

  8. Szatmari S, Illigens B.M. W, Siepmann T, Pinter A, Takats A, Bereczki D (2017) Neuropsychiatric symptoms in untreated Parkinson’s disease. Neuropsychiatr Disease and Treatment 13:815-826. https://doi.org/10.2147/NDT.S130997

    Article  CAS  Google Scholar 

  9. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease related pathology. Cell Tissue Res 318:121–134. https://doi.org/10.1007/s00441-004-0956-9

    Article  PubMed  Google Scholar 

  10. Cummings JL (1992) Depression and Parkinson’s disease: a review. Am J Psychiatry 149 (4):443-454. https://doi.org/10.1176/ajp.149.4.443

    Article  CAS  PubMed  Google Scholar 

  11. Dunlop BW, Nemeroff CB (2007) The Role of Dopamine in the Pathophysiology of Depression. Arch Gen Psychiatry 64(3):327–337. https://doi.org/10.1001/archpsyc.64.3.327

    Article  CAS  PubMed  Google Scholar 

  12. Chaika AV, Khusainov DR, Cheretaev IV (2018) Chronic Blockade of D2 Receptors and Behavior in Low-Depressivity Rats. Neurosci Behav Physiol 48:564–570. https://doi.org/10.1007/s11055-018-0600-x

    Article  CAS  Google Scholar 

  13. Shen CC, Tsai SJ, Perng CL, Kuo BI, Yang AC (2013) Risk of Parkinson disease after depression: a nationwide population-based study. Neurology 81(17):1538-1544. https://doi.org/10.1212/WNL.0b013e3182a956ad

    Article  CAS  PubMed  Google Scholar 

  14. Uhl GR, Hedreen JC, Price DL (1985) Parkinson’s disease loss of neurons from the ventral tegmental area contralateral to therapeutic surgical lesions. Neurology 35 (8):1215. https://doi.org/10.1212/WNL.35.8.1215

    Article  CAS  PubMed  Google Scholar 

  15. Remy P, Doder M, Lees A, Turjanski N, Brooks D (2005) Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128:1314–1322. https://doi.org/10.1093/brain/awh445

    Article  PubMed  Google Scholar 

  16. Politis M, Niccolini F (2015) Serotonin in Parkinson’s disease. Behav Brain Res 277:136–145. https://doi.org/10.1016/j.bbr.2014.07.037

    Article  CAS  PubMed  Google Scholar 

  17. Dick O, Nozdrachev A (2016) Features of parkinsonian and essential tremor of the human hand. Hum Physiol 42:271–278. https://doi.org/10.1134/S0362119716030063

    Article  Google Scholar 

  18. Rocha EM, De Miranda B, Sanders LH (2018) Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 109(Pt B):249-257. https://doi.org/10.1016/j.nbd.2017.04.004

    Article  CAS  PubMed  Google Scholar 

  19. Calamini B, Morimoto RI (2012) Protein homeostasis as a therapeutic target for diseases of protein conformation. Curr Top Med Chem 12(22):2623-2640. https://doi.org/10.2174/1568026611212220014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47(3):e147. https://doi.org/10.1038/emm.2014.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ekimova IV, Gazizova AR, Karpenko MN, Plaksina DV (2018) 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. Zhurn Nevrol Psikhiatrii im SS Korsakova 118(9):61–67 https://doi.org/10.17116/jnevro201811809161

    Article  CAS  Google Scholar 

  22. Abdurasulova IN, Ekimova IV, Matsulevich AV, Gazizova AR, Klimenko VM, Pastukhov YF (2017) Impairment of non-associative learning in a rat experimental model of preclinical stage of Parkinson’s disease. Dokl Biol Sci 476(1):188-190. https://doi.org/10.1134/S0012496617050039

    Article  CAS  PubMed  Google Scholar 

  23. Ekimova IV, Simonova VV, Guzeev MA, Lapshina KV, Chernyshev MV, Pastukhov YuF (2016) 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 Phys 52:463–474 https://doi.org/10.1134/S1234567816060057

    Article  CAS  Google Scholar 

  24. Plaksina DV, Ekimova IV (2020) Age-related features of α-synuclein pathology in the brain on modeling the preclinical stage of Parkinson’s disease in rats. Neurosci Behav Physiol 50:109–1114. https://doi.org/10.1007/s11055-019-00875-0

    Article  Google Scholar 

  25. Ekimova IV, Guzeev MA, Simonova VV, Pastukhov YF (2020) Age-related differences in sleep disturbances in rat models of preclinical Parkinson’s disease. Zh Nevrol Psikhiatr Im SS Korsakova 120:26–33 https://doi.org/10.17116/jnevro202012009226

    Article  CAS  Google Scholar 

  26. Friesen EL, De Snoo ML, Rajendran L, Kalia LV, Kalia SK (2017) Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease. Parkinsons Dis 2017:5015307. https://doi.org/10.1155/2017/5015307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ekimova IV, Plaksina DV, Pastukhov YF, Lapshina KV, Lazarev VF, Mikhaylova ER, Polonik SG, Pani B, Margulis BA, Guzhova IV, Nudler E (2018) New HSF1 inducer as a therapeutic agent in a rodent model of Parkinson’s disease. Exp Neurol 306:199-208. https://doi.org/10.1016/j.expneurol.2018.04.012

    Article  CAS  PubMed  Google Scholar 

  28. Pastukhov YuF, Simonova VV, Shemyakova TS, Guzeev MA, Polonik SG, Ekimova IV (2020) U133, a chaperone inducer, eliminates sleep disturbances in a model of the preclinical stage of Parkinson’s disease in aged rats. Adv Gerontol 10(3):254-259. https://doi.org/10.1134/S2079057020030133

    Article  Google Scholar 

  29. Polonik S, Tolkach A, Uvarova N (1994) Glycosylation of echinochrome and related hydroxynaphthazarines by the orthoester method. Zhurn Organ Himii 30(2):248–253 (In Russ).

    CAS  Google Scholar 

  30. Mishchenko NP, Fedoreev SA, Bagirova VL (2003) Histochrome: a new original domestic drug. Pharmaceut Chem J 37:48–52. https://doi.org/10.1023/A:1023659331010

    Article  CAS  Google Scholar 

  31. Grønli J, Murison R, Fiske E, Bjorvatn B, Sørensen E, Portas CM, Ursin R (2005) Effects of chronic mild stress on sexual behavior, locomotor activity and consumption of sucrose and saccharine solutions. Physiol Behav 84 (4):571-577. https://doi.org/10.1016/j.physbeh.2005.02.007

    Article  CAS  PubMed  Google Scholar 

  32. Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Coordinates. CA Acad SanDiego.

    Google Scholar 

  33. Anisimov VN (2008) Evolution of concepts in gerontology and physiological mechanisms of aging. In: Molekulyarnye i fiziologicheskie mekhanizmy stareniya (Molecular and Physiological Mechanisms of Aging) Nauka, St Petersburg vol 1, parts 1–3, 49–95, 269–378 (In Russ).

    Google Scholar 

  34. Porseva V, Korzina M, Spirichev A, Vishnyakova PA, Aryaeva DA, Nozdrachev AD, Masliukov PM (2020) Changes in the Immunohistochemical Characteristics of Neurons in a Number of Hypothalamic Nuclei on Aging. Neurosci Behav Physiol 50:645–649. https://doi.org/10.1007/s11055-020-00947-6

    Article  CAS  Google Scholar 

  35. Emanuilov A, Konovalov V, Masliukov P, Polyakov E, Nozdrachev A (2018) Age-development changes of the sympathetic innervation of the rat stomach. Adv Gerontol 31(6):937-942. https://doi.org/10.1134/S2079057019020097

    Article  CAS  PubMed  Google Scholar 

  36. Jurivich D, Choo M, Welk J, Qiu L, Han K, Zhou X (2005) Human aging alters the first phase of the molecular response to stress in T-cells. Exp Gerontol 40(12):948-958. https://doi.org/10.1016/j.exger.2005.08.003

    Article  CAS  PubMed  Google Scholar 

  37. Labbadia J, Morimoto R (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435-464. https://doi.org/10.1146/annurev-biochem-060614-033955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nestler E, Carlezon W (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59 (12):1151-1159. https://doi.org/10.1016/j.biopsych.2005.09.018

    Article  CAS  PubMed  Google Scholar 

  39. Lee Y, Subramaniapillai M, Brietzke E, Mansur R, Ho R, Yim S, McIntyre R (2018) Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression. Ther Adv Psychopharmacol 8(12):337–348. https://doi.org/10.1177/2045125318791944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yokochi M (2007) Mesolimbic and mesocortical pathways in Parkinson disease. Brain Nerve 59(9):943-951. PMID: 17886476

    CAS  PubMed  Google Scholar 

  41. Liu A, Lin Z, Choi H, Sorhage F, Li B (1989) Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem 264 (20):12037–12045. https://doi.org/10.1007/978-3-0348-9088-5_26

    Article  CAS  PubMed  Google Scholar 

  42. Hashikawa N, Utaka Y, Ogawa T, Tanoue R, Morita Y, Yamamoto S, Yamaguchi S, Kayano M, Zamami Y, Hashikawa-Hobara N (2017) HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice. Sci Adv 3(5):e1603014. https://doi.org/10.1126/sciadv.1603014

    Article  PubMed  PubMed Central  Google Scholar 

  43. Auluck P, Chan H, Trojanowski J, Lee V, Bonini N (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science (New York) 295(5556):865-868. https://doi.org/10.1126/science.1067389

  44. Asea A, Rehli M, Kabingu E, Boch J, Bare O, Auron P, Stevenson M, Calderwood S (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277(17):15028-15034. https://doi.org/10.1074/jbc.M200497200

    Article  CAS  PubMed  Google Scholar 

  45. Guzhova I, Darieva Z, Melo A, Margulis B (1997). Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells. Cell Stress Chaperones 2(2):132–139. https://doi.org/10.1379/1466-1268(1997)002<0132:msphiw>2.3.co;2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was implemented within a governmental assignment to the IEPB (No. АААА-А18-118012290427-7).

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    I. V. Ekimova, M. B. Pazi, D. V. Belan & Yu. F. Pastukhov

  2. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia

    S. G. Polonik

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  1. I. V. Ekimova
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  2. M. B. Pazi
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  3. D. V. Belan
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  4. S. G. Polonik
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Contributions

The basic idea and planning (I.V.E.); experimenting and data collection (M.B.P. and D.V.B.); synthesizing U133 (S.G.P.); data analysis (I.V.E. and M.B.P.); preparing (M.B.P.) and writing (I.V.E.) a manuscript; revising and editing a manuscript (Yu.F.P.).

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Correspondence to I. V. Ekimova.

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The authors declare that they have neither evident nor potential conflict of interest associated with the publication of this article.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, No. 10, pp. 1194–1208https://doi.org/10.31857/S0869813921100046.

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Ekimova, I.V., Pazi, M.B., Belan, D.V. et al. The Chaperone Inducer U133 Eliminates Anhedonia and Prevents Neurodegeneration in Monoaminergic Emotiogenic Brain Structures in a Preclinical Model of Parkinson’s Disease in Aged Rats. J Evol Biochem Phys 57, 1130–1141 (2021). https://doi.org/10.1134/S0022093021050148

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