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Amino Acids

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Moderate protective effect of Kyotorphin against the late consequences of intracerebroventricular streptozotocin model of Alzheimer’s disease

  • Hristina Angelova
  • Daniela PechlivanovaEmail author
  • Ekaterina Krumova
  • Jeny Miteva-Staleva
  • Nedelina Kostadinova
  • Elena Dzhambazova
  • Boycho Landzhov
Original Article
  • 7 Downloads

Abstract

The established decrease in the level of endogenous kyotorphin (KTP) into the cerebrospinal fluid of patients with an advanced stage of Alzheimer’s disease (AD) and the found neuroprotective activity of KTP suggested its participation in the pathophysiology of the disease. We aimed to study the effects of subchronic intracerebroventricular (ICV) treatment (14 days) with KTP on the behavioral, biochemical and histological changes in rats with streptozotocin (STZ-ICV)-induced model of sporadic AD (sAD). Three months after the administration of STZ-ICV, rats developed increased locomotor activity, decreased level of anxiety, impaired spatial and working memory. Histological data from the STZ-ICV group demonstrated decreased number of neurons in the CA1 and CA3 subfields of the hippocampus. The STZ-ICV group was characterized with a decrease of total protein content in the hippocampus and the prefrontal cortex as well as increased levels of the carbonylated proteins in the hippocampus. KTP treatment of STZ-ICV rats normalized anxiety level and regained object recognition memory. KTP abolished the protein loss in prefrontal cortex and decrease the neuronal loss in the CA3 subfield of the hippocampus. STZ-ICV rats, treated with KTP, did not show significant changes in the levels of the carbonylated proteins in specific brain structures or in motor activity and spatial memory compared to the saline-treated STZ-ICV group. Our data show a moderate and selective protective effect of a subchronic ICV administration of the dipeptide KTP on the pathological changes induced by an experimental model of sAD in rats.

Keywords

Kyotorphin Alzheimer’s disease Anxiety Memory Hippocampus 

Notes

Acknowledgements

The research was supported by Grant 18/2016 of the Medical University of Sofia, Bulgaria.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All experiments were approved by Bulgarian Food Safety Agency (No 144/04.08.2021) that is in accordance with EC Directive 2010/63/EU for animal experiments.

References

  1. Agrawal R, Tyagi E, Shukla R, Nath C (2011) Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol 21:261–273Google Scholar
  2. Amani M, Zolghadrnasab M, Salari A-A (2019) NMDA receptor in the hippocampus alters neurobehavioral phenotypes through inflammatory cytokines in rats with sporadic Alzheimer-like disease. Physiol Behav 202:52–61Google Scholar
  3. Angelova H, Pechlivanova D, Dzhambazova E, Landzhov B (2018) Effects of Kyotorphin on the early behavioural and histological changes induced by an experimental model of Alzheimer’s disease in rats. Compt Rend Bulg Acad Sci 71(3):424–430Google Scholar
  4. Arima T, Kitamura Y, Nishiya T, Takagi H, Nomura Y (1996) Kyotorphin (L-tyrosyl-l-arginine) as a possible substrate for inducible nitric oxide synthase in rat glial cells. Neurosci Lett 212:1–4Google Scholar
  5. Arima T, Kitamura Y, Nishiya T, Taniguchi T, Takagi H, Nomura Y (1997) Effects of kyotorphin (l-tyrosyl-l-arginine) ON[3H]NG-nitro-l-arginine binding to neuronal nitric oxide synthase in rat brain. Neurochem Int 30(6):605–611Google Scholar
  6. Bales KR, Dodart JC, DeMattos RB, Holtzman DM, Paul SM (2002) Apolipoprotein E, amyloid, and Alzheimer disease. Mol Interv 2:363–375Google Scholar
  7. Banks WA, Owen JB, Erickson MA (2012) Insulin in the brain: there and back again. Pharmacol Ther 136(1):82–93Google Scholar
  8. Barker GRI, Warburton EC (2011) When is the hippocampus involved in recognition memory? J Neurosci 31(29):10721–10731Google Scholar
  9. Blokland A, Jolles J (1993) Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav 44:491–494Google Scholar
  10. Bocheva AI, Dzambazova-Maximova EB (2004) Effects of kyotorphin and analogues on nociception and pentylenetetrazole seizures. Folia Med (Plovdiv) 46(1):40–44Google Scholar
  11. Chen Y, Liang Z, Blanchard J, Dai C-L, Sun S, Lee MH, Grundke-Iqbal I, Iqbal K, Liu F, Gong CX (2013) A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol 47(2):711–725Google Scholar
  12. Conceição K, Magalhães PR, Campos SR, Domingues MM, Ramu VG, Michalek M, Bertani P, Baptista AM, Heras M, Bardaji ER, Bechinger B, Ferreira ML, Castanho MA (2016) The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: insights of a lipid-mediated mechanism. Amino Acids 48(1):307–318Google Scholar
  13. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406Google Scholar
  14. de la Monte SM, Re E, Longato L, Tong M (2012) Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer’s Disease. J Alzheimers Dis 30(02):S217–S229Google Scholar
  15. de la Torre JC, Stefano GB (2000) Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev 34(3):119–136Google Scholar
  16. de Oliveira JS, Abdalla FH, Dornelles GL, Adefegha SA, Palma TV, Signor C, da Silva Bernardi J, Baldissarelli J, Lenz LS, Magni LP, Rubin MA, Pillat MM, de Andrade CM (2016) Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: involvement of acetylcholinesterase and cell death. Neuro Toxicol 57:241–250Google Scholar
  17. Deacon RM, Rawlins JN (2006) T-maze alternation in the rodent. Nat Protoc 1(1):7–12Google Scholar
  18. Dehghan-Shasaltaneh M, Naghdi N, Choopani S, Alizadeh L, Bolouri B, Masoudi-Nejad A, Riazi GH (2016) Determination of the Best Concentration of Streptozotocin to Create a Diabetic Brain Using Histological Techniques. J Mol Neurosci 59(1):24–35Google Scholar
  19. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer’s disease. Am J Pathol 175(5):2089–2098Google Scholar
  20. Detour J, Schroeder H, Desor D, Nehlig A (2005) A 5-month period of epilepsy impairs spatial memory, decreases anxiety, but spares object recognition in the lithium-pilocarpine model in adult rats. Epilepsia 46(4):499–508Google Scholar
  21. Dillon DG, Holmes AJ, Jahn AL, Bogdan R, Wald LL, Pizzagalli DA (2008a) Dissociation of neural regions associated with anticipatory versus consummatory phases of incentive processing. Psychophysiol 45(1):36–49Google Scholar
  22. Dillon GM, Qu X, Marcus JN, Dodart J-C (2008b) Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice. Neurobiol Learn Mem 90(2):426–433Google Scholar
  23. Dubey H, Gulati K, Ray A (2018) Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer’s disease in rats. Neurotoxicology 66:58–65Google Scholar
  24. Dzambazova E, Landzhov B, Bocheva A, Bozhilova-Pastirova A (2011) Effects of kyotorphin on NADPH-d reactive neurons in rat’s cerebral cortex after acute immobilization stress. Compt Rend Bulg Acad Sci 64(12):1779–1784Google Scholar
  25. El Khoury NB, Gratuze M, Papon M-A, Bretteville A, Planel E (2014) Insulin dysfunction and Tau pathology. Front Cell Neurosci 8:22Google Scholar
  26. España J, Giménez-Llort L, Valero J, Miñano A, Rábano A, Rodriguez-Alvarez J, LaFerla FM, Saura CA (2010) Intraneuronal β-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice. Biol Psychiatry 67:513–521Google Scholar
  27. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S, Zöchling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm (Vienna) 105:423–438Google Scholar
  28. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton PH, Rooke KP, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706Google Scholar
  29. Godlevsky LS, Shandra AA, Mikhaleva II, Vastyanov RS, Mazarati AM (1995) Seizure-protecting effects of kyotorphin and related peptides in an animal model of epilepsy. Brain Res Bull 37(3):223–226Google Scholar
  30. Grieb P (2016) Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol 5:1741–1752Google Scholar
  31. Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101:757–770Google Scholar
  32. Hellweg R, Nitsch R, Hock C, Jaksch M, Hoyer S (1992) Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism. J Neurosci Res 31:479–486Google Scholar
  33. Honey RC, Marshall VJ, Mcgregor A, Futter J, Good M (2007) Revisiting places passed: sensitization of exploratory activity in rats with hippocampal lesions. Q J Exp Psychol (Hove) 60(5):625–634Google Scholar
  34. Hoyer S, Nitsch R, Oesterreich K (1991) Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: a cross-sectional comparison against advanced late-onset and incipient early-onset cases. J Neural Transm Park Dis Dement Sect 3:1–14Google Scholar
  35. Ivanova NM, Atanasova D, Pechlivanova DM, Mitreva R, Lazarov N, Stoynev AG, Tchekalarova JD (2015) Long-term intracerebroventricular infusion of angiotensin II after kainate-induced status epilepticus: effects on epileptogenesis, brain damage, and diurnal behavioral changes. Epilepsy Behav 51:1–12Google Scholar
  36. Kinnavane L, Albasser MM, Aggleton JP (2015) Advances in the behavioural testing and network imaging of rodent recognition memory. Behav Brain Res 15(285):67–78Google Scholar
  37. Kjelstrup KG, Tuvnes FA, Steffenach H-A, Murison R, Moser EI, Moser MB (2002) Reduced fear expression after lesions of the ventral hippocampus. PNAS 99(16):10825–10830Google Scholar
  38. Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208Google Scholar
  39. Lee Y, Kim YH, Park SJ, Huh JW, Kim SH, Kim SU, Kim JS, Jeong KJ, Lee KM, Hong Y, Lee SR, Chang KT (2014) Insulin/IGF signaling-related gene expression in the brain of a sporadic Alzheimer’s diseasemonkeymodel induced by intracerebroventricular injection of streptozotocin. J Alzheimers Dis 38:251–267Google Scholar
  40. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte S (2006) Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 9:13–33Google Scholar
  41. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977Google Scholar
  42. Liu P, Zou LB, Wang LH, Jiao Q, Chi TY, Ji XF, Jin G (2014) Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats. Psychopharmacology 231:345–356Google Scholar
  43. Lowry OH, Rosenbrough HJ, Faar AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  44. Mayer G, Nitsch R, Hoyer S (1990) Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 532:95–100Google Scholar
  45. Mehla J, Pahuja M, Gupta YK (2013) Streptozotocin-induced sporadic Alzheimer’s disease: selection of appropriate dose. J Alzheimers Dis 33:17–21Google Scholar
  46. Nazarenko IV, Zvrushchenko MSh, Volkov AV, Kamenskiĭ AA, Zaganshin RKh (1999) Functional-morphologic evaluation of the effect of the regulatory peptide kyotorphin on the status of the CNS in the post-resuscitation period. Patol Fiziol Eksp Ter 2:31–33Google Scholar
  47. Nazem A, Sankowski R, Bacher M, Al-Abed Y (2015) Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation 12:74Google Scholar
  48. Norris PJ, Faull RL, Emson PC (1996) Neuronal nitric oxide synthase (nNOS) mRNA expression and NADPH-diaphorase staining in the frontal cortex, visual cortex and hippocampus of control and Alzheimer’s disease brains. Brain Res Mol Brain Res 41(1–2):36–49Google Scholar
  49. Paxinos G, Watson C (1998) The rat brain, 4th edn. Academic Press, Elsevier ScienceGoogle Scholar
  50. Pedersen NL, Gatz M, Berg S, Johansson B (2004) How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Ann Neurol 55:180–185Google Scholar
  51. Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24(3):525–529Google Scholar
  52. Peng D, Pan X, Cui J, Ren Y, Zhang J (2013) Hyperphosphorylation of tau protein in hippocampus of central insulin-resistant rats is associated with cognitive impairment. Cell Physiol Biochem 32:1417–1425Google Scholar
  53. Perazzo J, Lima C, Heras M, Bardají E, Lopes-Ferreira M, Castanho M (2017) Neuropeptide kyotorphin impacts on lipopolysaccharide-induced glucocorticoid-mediated inflammatory response. A molecular link to nociception, neuroprotection, and anti-inflammatory action. ACS Chem Neurosci 8:1663–1667Google Scholar
  54. Pezze MA, Marshall HJ, Fone KC, Cassaday HJ (2015) Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: role of the prelimbic cortex. Eur Neuropsychopharmacol 25(11):2145–2156Google Scholar
  55. Plaschke K, Hoyer S (1993) Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. Int J Dev Neurosci 11:477–483Google Scholar
  56. Porter VR, Buxton WG, Fairbanks LA, Strickland T, O’Connor SM, Rosenberg-Thompson S, Cummings JL (2003) Frequency and characteristics of anxiety among patients with Alzheimer’s disease and related dementias. J Neuropsychiatry Clin Neurosci 15(2):180–186Google Scholar
  57. Rodgers SP, Born HA, Das P, Jankowsky JL (2012) Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult. Mol Neurodegener 7:28Google Scholar
  58. Sá Santos S, Santos SM, Pinto AR, Ramu VG, Heras M, Bardaji E, Tavares I, Castanho MA (2016) Amidated and ibuprofen-conjugated kyotorphins promote neuronal rescue and memory recovery in cerebral hypoperfusion dementia model. Front Aging Neurosci 26(8):1Google Scholar
  59. Sachdeva AK, Misra S, Pal Kaur I, Chopra K (2015) Neuroprotective potential of sesamol and its loaded solid lipid nanoparticles in ICV-STZ-induced cognitive deficits: behavioral and biochemical evidence. Eur J Pharmacol 747:132–140Google Scholar
  60. Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK, Hoyer S, Arendt T, Riederer P (2011) Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. J Neural Transm 118:765–772Google Scholar
  61. Sansbury BE, Hill BG (2014) Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 73:383–399Google Scholar
  62. Santalova IM, Mavlyutov TA, Moshkov DA (2004) Morphofunctional changes in Mauthner neurons during exposure to the neuropeptide kyotorphin. Neurosci Behav Physiol 34(4):327–332Google Scholar
  63. Santos SM, Garcia-Nimo L, Sá Santos S, Tavares I, Cocho JA, Castanho MA (2013) Neuropeptide kyotorphin (tyrosy l-arginine) has decreased levels in the cerebro-spinal fluid of Alzheimer’s disease patients: potential diagnostic and pharmacological implications. Front Aging Neurosci 5:68Google Scholar
  64. Saxena G, Patro IK, Nath C (2011) ICV STZ induced impairment in memory and neuronal mitochondrial function: a protective role of nicotinic receptor. Behav Brain Res 224(1):50–57Google Scholar
  65. Senzai Y (2019) Function of local circuits in the hippocampal dentate gyrus-CA3 system. Neurosci Res 140:43–52Google Scholar
  66. Sharma M, Gupta YK (2001) Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci 68:1021–1029Google Scholar
  67. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760Google Scholar
  68. Shingo AS, Kanabayashi T, Kito S, Murase T (2013) Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res 241:105–111Google Scholar
  69. Shiomi H, Kuraishi Y, Ueda H, Harada Y, Amano H, Takagi H (1981) Mechanism of kyotorphin-induced release of Met-enkephalin from guinea pig striatum and spinal cord. Brain Res 221(1):161–169Google Scholar
  70. Steinert JR, Chernova T, Forsythe ID (2010) Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16(4):435–452Google Scholar
  71. Summy-Long JY, Bui V, Gestl S, Koehler-Stec E, Liu H, Terrell ML et al (1998) Effects of central injection of kyotorphin and L-arginine on oxytocin and vasopressin release and blood pressure in conscious rats. Brain Res Bull 45:395–403.  https://doi.org/10.1016/S0361-9230(97)00341-9 Google Scholar
  72. Tsukahara T, Yamagishi S, Neyama H, Ueda H (2018) Tyrosyl-tRNA synthetase: a potential kyotorphin synthetase in mammals. Peptides 101:60–68Google Scholar
  73. Ueda H, Shiomi H, Takagi H (1980) Regional distribution of a novel analgesic dipeptide kyotorphin (Tyr-Arg) in the rat brain and spinal cord. Brain Res 198(2):460–464Google Scholar
  74. Ueda H, Yoshihara Y, Misawa H, Fukushima N, Katada T, Ui M, Takagi H, Satoh M (1989) The kyotorphin (tyrosine-arginine) receptor and a selective reconstitution with purified Gi, measured with GTPase and phospholipase C assays. J Biol Chem 264(7):3732–3741Google Scholar
  75. Vloeberghs E, Van Dam D, Franck F, Staufenbiel M, de Deyn PP (2007) Mood and male sexual behaviour in the APP23 model of Alzheimer’s disease. Behav Brain Res 180:146–151Google Scholar
  76. Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL (2017) Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol 4:311–322Google Scholar
  77. Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R (2019) The Role of APOE and TREM2 in Alzheimer’s disease current understanding and perspectives. Int J Mol Sci 20:81Google Scholar
  78. Yang Y, Mailman RB (2018) Strategic neuronal encoding in medial prefrontal cortex of spatial working memory in the T-maze. Behav Brain Res 343:50–60Google Scholar

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Authors and Affiliations

  1. 1.Institute of NeurobiologyBulgarian Academy of SciencesSofiaBulgaria
  2. 2.Institute of MicrobiologyBulgarian Academy of SciencesSofiaBulgaria
  3. 3.Faculty of MedicineSofia UniversitySofiaBulgaria
  4. 4.Department of AnatomyMedical University-SofiaSofiaBulgaria

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