Abstract
Close functional and anatomical interactions between the neurotensin (NT) and dopamine (DA) systems suggest that NT could be associated with Parkinson’s Disease (PD). However, clinical use of NT is limited due to its rapid degradation. This has led to the synthesis of a number of new NT fragment 8-13 [NT(8-13)] analogues, such as NT2 and NT4, to avoid the fast biodegradation of NT. The aim of this study was to investigate the neuroprotective effects of NT2 and NT4 on an experimental model of Parkinson’s disease in rats induced with 6-hydroxydopamine (6-OHDA) treatment, producing striatal lesions. Wistar male rats were divided into different groups: a sham-operated (SO) group, a striatal 6-OHDA-lesioned control group, two groups of 6-OHDA-lesioned rats treated for 5 days with NT2 or NT4 (10 mg/kg, intraperitoneally) and a NT-treated group as reference. During the first and second week post lesion the animals were subjected to a number of behavioral tests (apomorphine-induced rotations, rotarod, passive avoidance test), and brain tissue was evaluated histologically and also assessed for DA levels. The results showed that both the number of apomorphine-induced rotations and falls (rotarod test) increased in the 6-OHDA group relative to the SO group. At the same time, the 6-OHDA-treated group showed significant memory impairment, based on the to step-through test, compared to the SO group. Treatment with NT2 and NT4 significantly decreased the number of apomorphine-induced rotations and improved the memory of lesioned animals, with these NT analogues demonstrating better neuroprotective and neuromodulatory effects than NT. DA content in the brain of the PD rats treated with NT2 and NT4 increased, possibly due to attenuation of the loss of DA-ergic neurons. NT2 and NT4 were found to easily penetrate the blood–brain barrier and they showed a better stability than the reference NT neuropeptide. In conclusion, the NT approach represents an attractive strategy for the treatment of neurodegenerative disease.
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References
Blaha C, Coury A, Fibiger H, Phillips A (1990) Effects of neurotensin on dopamine release and metabolism in the rat striatum and nucleus accumbens: cross-validation using in vivo voltammetry and microdialysis. Neuroscience 34(2):3699–3705. https://doi.org/10.1016/0306-4522(90)90176-5
Carraway R, Leeman S (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 248:6854–6861
Chinaglia G, Probst A, Palacios J (1990) Neurotensin receptors in Parkinson’s disease and progressive supranuclear palsy: an autoradiographic study in basal ganglia. Neuroscience 39:351–360. https://doi.org/10.1016/0306-4522(90)90273-7
Culling C, Allison R, Barr T (1985) Amyloid and fibrin. In: Culling C (ed) Cellular pathology technique, 4th edn. Butterworths, Oxford, pp 465–473. https://doi.org/10.1016/B978-0-407-72903-2.50029-0
Dobner P (2005) Multitasking with neurotensin in the central nervous system. Cell Mol Life Sci 62(17):1946–1963. https://doi.org/10.1007/s00018-005-5128-x
Dzimbova T, Bocheva A, Pajpanova T (2014) Kyotorphin analogues containing unnatural amino acids: synthesis, analgesic activity and computer modeling of their interactions with μ-receptor. Med Chem Res 23:3694–3704. https://doi.org/10.1007/s00044-014-0953-9
Dzimbova T, Stoeva S, Tancheva L, Georgieva A, Kalfin R, Pajpanova T (2015) Synthesis and pharmacological evaluation of novel neurotensin(8-13) analogues. In: Naydenova E, Danalev D, Pajpanova T (eds) Peptides 2014. Bulgarian Peptide Society, Sofia, pp 260–261
Fernandez A, de Ceballos M, Jenner P, Marsden CD (1994) Neurotensin, substance P, delta and mu opioid receptors are decreased in basal ganglia of Parkinson’s disease patients. Neuroscience 61:73–79. https://doi.org/10.1016/0306-4522(94)90061-2
Ferraro L, Tomasini M, Mazza R, Fuxe K, Fournier J, Tanganelli S, Antonelli T (2008) Neurotensin receptors as modulators of glutamatergic transmission. Brain Res Rev 58:365–373. https://doi.org/10.1016/j.brainresrev.2007.11.001
García J, Remires D, Leiva A, González R (2000) Depletion of brain glutathione potentiates the effect of 6-hydroxydopamine in a rat model of Parkinson’s disease. J Mol Neurosci 14(3):147–153. https://doi.org/10.1385/JMN:14:3:147
Gheibi S, Aboutaleb N, Khaksari M, Kalalian-Moghaddam H, Vakili A, Asadi Y, Mehrjerdi F, Gheibi A (2014) Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci 54(2):264–270. https://doi.org/10.1007/s12031-014-0284-9
Gonzalez-Hernandez T, Barroso-Chinea P, de la Cruz MI, del Mar Pґerez-Delgado M (2004) Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. J Comp Neurol 479(2):198–215. https://doi.org/10.1002/cne.20323
Granier C, van Rietschoten J, Kitabgi P, Poustis C, Freychet P (1982) Synthesis and characterization of neurotensin analogue for structure-activity relationship studies. Acetyl-neurotensin-(8–13) is the shortest analogue with full binding and pharmacological activities. Eur J Biochem 124:117–125. https://doi.org/10.1111/j.1432-1033.1982.tb05913.x
Held C, Plomer M, Huebner H, Meltretter J, Pischetsrieder M, Gmeiner P (2013) Development of metabolically stable neurotensin receptor 2 (NTS2) ligand. Chem Med Chem 8:75–81. https://doi.org/10.1002/cmdc.201200376
Jarvik M, Kopp R (1967) An improved one-trial passive avoidance learning situation. Psychol Rep 21(1):221–224. https://doi.org/10.2466/pr0.1967.21.1.221
Jhala D, Chettiar S, Singh J (2012) Optimization and validation of an in vitro blood brain barrier permeability assay using artificial lipid membrane. J Bioequiv Bioavailab S14:009. https://doi.org/10.4172/jbb.S14-009
Jolicoeur F, Rivest R, St-Pierre S, Drumheller A (1991) Antiparkinson-like effects of neurotensin in 6-hydroxydopamine lesioned rats. Brain Res 538:187–192. https://doi.org/10.1016/0006-8993(91)90428-X
Khan S, Tabrez S, Priyadarshini M, Priyamvada S, Khan M (2012) Targeting Parkinson’s-tyrosine hydroxylase and oxidative stress as points of interventions. CNS Neurol Disord Drug Targets 11:369–380. https://doi.org/10.2174/187152712800792848
Klissurov R (2017) Experimental studies on metabolic effects of certain antiepileptic medicines. PhD thesis. Medical University, Sofia. http://nt-cmb.medun.acad.bg:8080/jspui/bitstream/10861/1255/1/Radoslav_Klisurov-dis.pdf
Lev N, Barhum Y, Ben-Zur T, Melamed E, Steiner I, Offen D (2013) Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity. J Mol Neurosci 50(3):542–550. https://doi.org/10.1007/s12031-013-9984-9
Lowry OH, Rosenbrough NJ, Farr AL, Randal RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–278
Mandel R (2000) Effect of acute L-dopa pretreatment on apomorphine-induced rotational behavior in a rat model of Parkinson’s disease. Exp Neurol 161(1):212–219. https://doi.org/10.1006/exnr.1999.7245
Marvanova M, Nichols C (2007) Identification of neuroprotective compounds of Caenorhabditis elegans dopaminergic neurons against 6-OHDA. J Mol Neurosci 31(2):127–137. https://doi.org/10.1385/JMN/31:02:127
Méndez M, Souazé F, Nagano M, Kelly P, Rostène W, Forgez P (1997) High affinity neurotensin receptor mRNA distribution in rat brain and peripheral tissues. J Mol Neurosci 9(2):93–102. https://doi.org/10.1007/BF02736853
Michailova S, Dzimbova T, Kalíkova K, Tesařová E, Pajpanova T (2017) Chemical stability of new neurotensin (8-13) analogues. Bulg Chem Commun 49(E):113–117
Mitra S, Tiwari K, Srivastava S (2017) Optimization for production and partial purification of laccase from ash gourd peels. Int J Curr Microbiol App Sci 6(2):997–1003. https://doi.org/10.20546/ijcmas.2017.602.112
Monville C, Torres E, Dunne S (2006) Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods 158(2):219–223. https://doi.org/10.1016/j.Jneumeth.2006.06.001
Moura L, Silva L, Leal E, Tellechea A, Cruz M, Carvalho E (2013) Neurotensin modulates the migratory and inflammatory response of macrophages under hyperglycemic conditions. Biomed Res Int 2013:941764. https://doi.org/10.1155/2013/941764
Nandhu M, Fabia E, Paulose S (2010) Dopamine D1 receptor gene expression studies in unilateral 6-hydroxydopamine-lesioned Parkinson’s rat: effect of 5-HT, GABA, and bone marrow cell supplementation. J Mol Neurosci 41(1):1–11. https://doi.org/10.1007/s12031-009-9213-8
Pajpanova T (2009) Design, synthesis, analysis and pharmacological evaluation of neuropeptide mimetics containing unnatural amino acids. Collect Czech Chem Suppl 11:98–103. https://doi.org/10.1135/css200911098
Patel A, Tsilioni I, Leeman S, Theoharides T (2016) Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci USA 113(45):E7049–E7058. https://doi.org/10.1073/pnas.1604992113
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, New York. ISBN: 9780125476126
Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (2008) Neurotensin modulation of acetylcholine, GABA, and aspartate erelease from rat prefrontal cortex studied in vivo with microdialysis. Brain Res Bull 77:129–135. https://doi.org/10.1016/j.brainresbull.2008.04.003
Rakovska A, Giovannini M, Della Corte L, Kalfin R, Bianchi L, Pepeu G (1998) Neurotensin modulation of acetylcholine and GABA release from the rat hippocampus: an invivo microdialysis study. Neurochem Int 33(4):335–340. https://doi.org/10.1016/S0197-0186(98)00036-9
Rochet J, Outeiro T, Conway K, Ding T, Volles M, Lashuel H, Bieganski R, Lindquist S, Lansbury P (2004) Interactions among α-synuclein, dopamine, and biomembranes. J Mol Neurosci 23(1-2):23–33. https://doi.org/10.1385/JMN:23:1-2:023
Roghani M, Niknam A, Jalali-Nadoushan M, Kiasalari Z, Khalili M, Baluchnejadmojarad T (2010) Oral pelargonidin exerts dose-dependent neuroprotection in 6-hydroxydopamine rat model of hemi-parkinsonism. Brain Res Bull 82:279–283. https://doi.org/10.1016/j.brainresbull.2010.06.004
Rozas G, Guerra M, Labandeira J (1997) An automated Rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Res Protocol 2(1):75–84
Sadoul J, Chécler F, Kitabgi P, Rostène W, Javoy-Agid F (1984) Loss of high affinity neurotensin receptors in substantia nigra from parkinsonian subjects. Biochem Biophys Res Commun 125:395–404. https://doi.org/10.1016/S0006-291X(84)80381-2
Schapira A, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055. https://doi.org/10.1002/mds.23732
Schimpff R, Avard C, Fenelon G, Lhiaubet A, Tenneze L, Vidailhet M, Rostene W (2001) Increased plasma neurotensin concentrations in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 70:784–786. https://doi.org/10.1136/jnnp.70.6.784
Schwarting R, Huston J (1997) Behavioral and neurochemical dynamics of neurotoxic meso-striatal dopamine lesions. NeuroToxicology 18:689–708
Serra P, Sciola L, Delogu M, Spano A, Monaco G, Miele E, Mighele R, Desole M (2002) The neurotoxin 1-methyl-4-phenyl-1,2, 3, 6-tetrahydropyridine induces apoptosis in mouse nigrostriatal glia relevance to nigral neuronal death and striatal neurochemical changes. J Biol Chem 277(37):34451–34461. https://doi.org/10.1074/jbc.M202099200
Shapira A, Bezard E, Brotchie J, Calon F, Collingridge G, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novère N, Obeso J, Schwarzschild M, Spampinato U, Davidai G (2006) Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 5:845–854. https://doi.org/10.1038/nrd2087
Shapiro R, Glick S, Camarota N (1987) A two-population model of rat rotational behavior: effects of unilateral nigrostriatal 6-hydroxydopamine on striatal neurochemistry and amphetamine-induced rotation. Brain Res 426:323–331. https://doi.org/10.1016/0006-8993(87)90885-7
Sharma S, Taliyan R, Ramagiri S (2015) Histone deacetylase inhibitor, trichostatin A, improves learning and memory in high-fat diet-induced cognitive deficits in mice. J Mol Neurosci 56(1):1–11. https://doi.org/10.1007/s12031-014-0461-x
Tanganelli S, von Euler G, Fuxe K, Agnati L, Ungerstedt U (1989) Neurotensin counteracts apomorphine-induced inhibition of dopamine release as studied by microdialysis in rat neostriatum. Brain Res 502(2):319–324. https://doi.org/10.1016/0006-8993(89)90627-6
Uhl G, Whitehouse P, Price D, Tourtelotte W, Kuhar M (1984) Parkinson’s disease: depletion of substantia nigra neurotensin receptors. Brain Res 308:186–190. https://doi.org/10.1016/0006-8993(84)90935-1
Vincent JP, Mazella J, Kitabgi P (1999) Neurotensin and neurotensin receptors. Trends Pharmacol Sci 20:302–309. https://doi.org/10.1016/S0165-6147(99)01357-7
Wang K, Zhang J, Xu Y, Zhang B, Shi Q, Liu Y, Ren K, Xie W, Yan Y, Dong X (2013) Abnormally upregulated αB-crystallin was highly coincidental with the astrogliosis in the brains of scrapie-infected hamsters and human patients with prion diseases. J Mol Neurosci 51(3):734–748. https://doi.org/10.1007/s12031-013-0057-x
Yelkenli İ, Ulupinar E, Korkmaz O, Şener E, Kuş G, Filiz Z, Tunçel N (2016) Modulation of Corpus striatal neurochemistry by astrocytes and vasoactive intestinal peptide (VIP) in parkinsonian rats. J Mol Neurosci 59(2):280–289. https://doi.org/10.1007/s12031-016-0757-0
Acknowledgements
This work was partially supported by a bilateral project between the Bulgarian Academy of Sciences and Tel Aviv University in Israel. Thanks are also due to Iris Biotech GMBH (Germany) for their kind supply of the solid phase peptide synthesis reagents.
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Lazarova, M., Popatanasov, A., Klissurov, R. et al. Preventive Effect of Two New Neurotensin Analogues on Parkinson’s Disease Rat Model. J Mol Neurosci 66, 552–560 (2018). https://doi.org/10.1007/s12031-018-1171-6
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DOI: https://doi.org/10.1007/s12031-018-1171-6