본문 바로가기
KERD
논문KCI 등재

Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model

2

조회

0

다운로드

5

인용

0

참고문헌

키워드

주제분류의학일반

초록

Purpose: Alzheimer’s disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterationssimilar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigatedwhether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. Materials and Methods: We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateralventricle (5 μL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. Results: Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunctionin the STZ-Agm group was observed compared with the EC group. Westernblot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group. Conclusion:Our results showed that Agm is involved in the activation of antioxidant signalingpathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuatingapoptosis in AD.

Abstract

Purpose: Alzheimer’s disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterationssimilar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigatedwhether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. Materials and Methods: We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateralventricle (5 μL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. Results: Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunctionin the STZ-Agm group was observed compared with the EC group. Westernblot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group. Conclusion:Our results showed that Agm is involved in the activation of antioxidant signalingpathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuatingapoptosis in AD.

참고문헌 (89)

  1. Hyman BT, "Alzheimer’s disease", Annu Rev Public Health, 10, pp.115~140 (1989)
  2. Van Hoesen GW, "The parahippocampal gyrus in Alzheimer’s disease. Clinical and preclinical neuroanatomical correlates", Ann N Y Acad Sci, 911, pp.254~274 (2000)
  3. Arispe N, "Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum", Proc Natl Acad Sci U S A, 90, pp.567~571 (1993)
  4. Furukawa K, "Amyloid beta protein-induced irreversible current in rat cortical neurones", Neuroreport, 5, pp.2016~2018 (1994)
  5. Mattson MP, "beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease", Trends Neurosci, 16, pp.409~414 (1993)
  6. Alberdi E, "Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors", Cell Calcium, 47, pp.264~272 (2010)
  7. Kelly BL, "beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons", J Biol Chem, 281, pp.28079~28089 (2006)
  8. Lester-Coll N, "Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease", J Alzheimers Dis, 9, pp.13~33 (2006)
  9. Butterfield DA, "Proteomics: a new approach to investigate oxidative stress in Alzheimer’s disease brain", Brain Res, 1000, pp.1~7 (2004)
  10. Lannert H, "Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats", Behav Neurosci, 112, pp.1199~1208 (1998)
  11. Gibson GE, "Oxidative stress in Alzheimer’s disease", Neurobiol Aging, 26, pp.575~578 (2005)
  12. Grünblatt E, "Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein", J Neurochem, 101, pp.757~770 (2007)
  13. Weinstock M, "Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity", J Neural Transm, 111, pp.347~366 (2004)
  14. Dröge W, "Aberrant insulin receptor signaling and amino acid homeostasis as a major cause of oxidative stress in aging", Antioxid Redox Signal, 10, pp.661~678 (2008)
  15. Hoyer S, "Inhibition of the neuronal insulin receptor causes Alzheimer-like disturbances in oxidative", energy brain metabolism and in behavior in adult rats, 1999, pp.893, 301~303
  16. Hoyer S, "Glucose metabolism and insulin receptor signal transduction in Alzheimer disease", Eur J Pharmacol, 490, pp.115~125 (2004)
  17. Ahmad M, "Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-induced parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences", J Neurochem, 93, pp.94~104 (2005)
  18. Ansari MA, "Selenium protects cerebral ischemia in rat brain mitochondria", Biol Trace Elem Res, 101, pp.73~86 (2004)
  19. Arteni NS, "Agmatine facilitates memory of an inhibitory avoidance task in adult rats", Neurobiol Learn Mem, 78, pp.465~469 (2002)
  20. Liu P, "Behavioral effects of agmatine in naive rats are task- and delay-dependent", Neuroscience, 163, pp.82~96 (2009)
  21. Lu W, "Agmatine inhibits morphine-induced memory impairment in the mouse step-down inhibitory avoidance task", Pharmacol Biochem Behav, 97, pp.256~261 (2010)
  22. McKay BE, "Learning and memory in agmatine-treated rats", Pharmacol Biochem Behav, 72, pp.551~557 (2002)
  23. Zarifkar A, "Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis", Eur J Pharmacol, 634, pp.84~88 (2010)
  24. Feng Y, "Agmatine suppresses nitric oxide production and attenuates hypoxic-ischemic brain injury in neonatal rats", Pediatr Res, 52, pp.606~611 (2002)
  25. Kim JH, "Agmatine reduces infarct area in a mouse model of transient focal cerebral ischemia and protects cultured neurons from ischemia-like injury", EXPERIMENTAL NEUROLOGY, 189(1), pp.122~130 (2004)
  26. Regunathan S, "Agmatine levels in the cerebrospinal fluid of normal human volunteers", J Pain Palliat Care Pharmacother, 23, pp.35~39 (2009)
  27. Reis DJ, "Agmatine: a novel neurotransmitter?", Adv Pharmacol, 42, pp.645~649 (1998)
  28. Regunathan S, "Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation", J Pharmacol Exp Ther, 276, pp.1272~1282 (1996)
  29. Halaris A, "Agmatine: metabolic pathway and spectrum of activity in brain", CNS Drugs, 21, pp.885~900 (2007)
  30. Reis DJ, "Is agmatine a novel neurotransmitter in brain?", Trends Pharmacol Sci, 21, pp.187~193 (2000)
  31. Alam J, "Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene", J Biol Chem, 274, pp.26071~26078 (1999)
  32. Motohashi H, "Nrf2-Keap1 defines a physiologically important stress response mechanism", Trends Mol Med, 10, pp.549~557 (2004)
  33. Ramprasath T, "Potential impact of genetic variants in Nrf2 regulated antioxidant genes and risk prediction of diabetes and associated cardiac complications", Curr Med Chem, 20, pp.4680~4693 (2013)
  34. Wild AC, "Overlapping antioxidant response element and PMA response element sequences mediate basal and beta-naphthoflavone-induced expression of the human gamma-glutamylcysteine synthetase catalytic subunit gene", Biochem J, 332(Pt 2), pp.373~381 (1998)
  35. Tomobe K, "Age-related changes of Nrf2 and phosphorylated GSK-3β in a mouse model of accelerated aging (SAMP8)", Arch Gerontol Geriatr, 54, pp.e1~e7 (2012)
  36. Venugopal R, "Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene", Proc Natl Acad Sci U S A, 93, pp.14960~14965 (1996)
  37. Kanninen K, "Targeting Glycogen Synthase Kinase-3β for Therapeutic Benefit against Oxidative Stress in Alzheimer’s Disease: Involvement of the Nrf2-ARE Pathway", Int J Alzheimers Dis, 2011, pp.985085~ (2011)
  38. Li XH, "Allicin ameliorates cardiac hypertrophy and fibrosis through enhancing of Nrf2 antioxidant signaling pathways", Cardiovasc Drugs Ther, 26, pp.457~465 (2012)
  39. Yang Y, "Change of Nrf2 expression in rat hippocampus in a model of chronic cerebral hypoperfusion", Int J Neurosci (2013)
  40. Rodrigues L, "Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin", J Neural Transm, 117, pp.1295~1305 (2010)
  41. Morris R, "Developments of a water-maze procedure for studying spatial learning in the rat", J Neurosci Methods, 11, pp.47~60 (1984)
  42. Paul CA, "Perfusion of brain tissues with fixative", CSH Protoc, 2008 (2008)
  43. Flynn BL, "Pharmacologic management of Alzheimer disease, Part I: Hormonal and emerging investigational drug therapies", Ann Pharmacother, 33, pp.178~187 (1999)
  44. Sharma M, "Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats", Life Sci, 71, pp.2489~2498 (2002)
  45. Selkoe DJ, "Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein", J Alzheimers Dis, 3, pp.75~80 (2001)
  46. Salkovic-Petrisic M, "Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach", J Neural Transm Suppl, pp.217~233 (2007)
  47. Maftei M, "Increased levels of antigen-bound β-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer’s disease patients", PLoS One, 8, pp.e68996~ (2013)
  48. Selkoe DJ, "Alzheimer’s disease: a central role for amyloid", J Neuropathol Exp Neurol, 53, pp.438~447 (1994)
  49. Varadarajan S, "Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity", J Struct Biol, 130, pp.184~208 (2000)
  50. Varadarajan S, "Different mechanisms of oxidative stress and neurotoxicity for Alzheimer’s A beta(1--42) and A beta(25--35)", J Am Chem Soc, 123, pp.5625~5631 (2001)
  51. MK-801 at therapeutic concentrations in postmortem human frontal cortex, "Eur J Pharmacol", 1989, 589~590
  52. Piletz JE, "Agmatine: clinical applications after 100 years in translation", Drug Discov Today, 18, pp.880~893 (2013)
  53. Salloway S, "Disease-modifying therapies in Alzheimer’s disease", Alzheimers Dement, 4, pp.65~79 (2008)
  54. Wang WP, "Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons", Brain Res, 1084, pp.210~216 (2006)
  55. O’Neill C, "Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer’s disease", Biochem Soc Trans, 40, pp.721~727 (2012)
  56. Freude S, "Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer’s disease", FASEB J, 23, pp.3315~3324 (2009)
  57. Craft S, "Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose", Arch Gen Psychiatry, 56, pp.1135~1140 (1999)
  58. Park CR, "Intracerebroventricular insulin enhances memory in a passive-avoidance task", Physiol Behav, 68, pp.509~514 (2000)
  59. van der Heide LP, "Insulin signaling in the central nervous system: learning to survive", Prog Neurobiol, 79, pp.205~221 (2006)
  60. Wang YT, "Regulation of NMDA receptors by tyrosine kinases and phosphatases", Nature, 369, pp.233~235 (1994)
  61. van der Heide LP, "Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner", J Neurochem, 94, pp.1158~1166 (2005)
  62. Zhao WQ, "Insulin and the insulin receptor in experimental models of learning and memory", Eur J Pharmacol, 490, pp.71~81 (2004)
  63. Park CR, "Cognitive effects of insulin in the central nervous system", Neurosci Biobehav Rev, 25, pp.311~323 (2001)
  64. Liu Y, "Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes", J Pathol, 225, pp.54~62 (2011)
  65. Ahn SK, "Protective effects of agmatine on lipopolysaccharide-injured microglia and inducible nitric oxide synthase activity", LIFE SCIENCES, 91(25-26), pp.1345~1350 (2012), PERGAMON-ELSEVIER SCIENCE LTD
  66. Bokara KK, "Retroviral expression of arginine decarboxylase attenuates oxidative burden in mouse cortical neural stem cells", Stem Cells Dev, 20, pp.527~537 (2011)
  67. 서수경, "Overexpression of Human Arginine Decarboxylase Rescues Human Mesenchymal Stem Cells against H2O2 Toxicity through Cell Survival Protein Activation", Journal of Korean Medical Science, 28(3), pp.366~373 (2013), 대한의학회
  68. Liu P, "Differential effects of i.c.v. microinfusion of agmatine on spatial working and reference memory in the rat", Neuroscience, 159, pp.951~961 (2009)
  69. Frölich L, "Free radical mechanisms in dementia of Alzheimer type and the potential for antioxidative treatment", Arzneimittelforschung, 45, pp.443~446 (1995)
  70. Launer LJ, "Anti-oxidants and cognitive function: a review of clinical and epidemiologic studies", J Neural Transm Suppl, 53, pp.1~8 (1998)
  71. Mikati MA, "Hippocampal programmed cell death after status epilepticus: evidence for NMDA-receptor and ceramide-mediated mechanisms", Epilepsia, 44, pp.282~291 (2003)
  72. Brouillette J, "The Effects of Soluble Aβ Oligomers on Neurodegeneration in Alzheimer’s Disease", Curr Pharm Des (2013)
  73. Texidó L, "Amyloid β peptide oligomers directly activate NMDA receptors", Cell Calcium, 49, pp.184~190 (2011)
  74. Feng Z, "Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism", Free Radic Biol Med, 37, pp.1790~1801 (2004)
  75. Montiel T, "Role of oxidative stress on beta-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: protection by antioxidants", Exp Neurol, 200, pp.496~508 (2006)
  76. Pavlik VN, "Vitamin E use is associated with improved survival in an Alzheimer’s disease cohort", Dement Geriatr Cogn Disord, 28, pp.536~540 (2009)
  77. Sano M, "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study", N Engl J Med, 336, pp.1216~1222 (1997)
  78. Ishrat T, "Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats", Behav Brain Res, 171, pp.9~16 (2006)
  79. Pathan AR, "Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats", Life Sci, 79, pp.2209~2216 (2006)
  80. Sharma M, "Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment", Life Sci, 68, pp.1021~1029 (2001)
  81. Ferreiro E, "Bcl-2 overexpression protects against amyloid-beta and prion toxicity in GT1-7 neural cells", J Alzheimers Dis, 12, pp.223~228 (2007)
  82. Rohn TT, "Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of the anti-apoptotic protein Bcl-2", J Neurosci, 28, pp.3051~3059 (2008)
  83. Kong J, "Effects of nicorandil in neuroprotective activation of PI3K", AKT pathways in a cellular model of Alzheimer’s disease, 2013, pp.70, 233~241
  84. Kudo W, "Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity", Cell Death Dis, 3, pp.e309~ (2012)
  85. Lin MT, "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases", Nature, 443, pp.787~795 (2006)
  86. Slee EA, "Serial killers: ordering caspase activation events in apoptosis", Cell Death Differ, 6, pp.1067~1074 (1999)
  87. Montagnani M, "Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179)", J Biol Chem, 276, pp.30392~30398 (2001)
  88. Scheid MP, "PKB", AKT: functional insights from genetic models, 2001, pp.2, 760~768
  89. Brunet A, "Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway", Curr Opin Neurobiol, 11, pp.297~305 (2001)

관련 논문AI추천

Protective Effects of Citicoline and Benfotiamine Each Alone and in Combination on Streptozotocin-induced Memory Impairment in MiceAli Hosseini-Sharifabad, Maryam Safavi, Mohammad Rabbani, Yasaman Seyed-Yousefi대한정신약물학회 · Clinical Psychopharmacology and Neuroscience2020 · 제18권 제1호Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice김어수, 김철훈, 송재은, 송호택, 이종은, 최영숙연세대학교의과대학 · Yonsei Medical Journal2023 · 제64권 제10호Efficacy of Ulinastatin and Sulforaphane Alone or in Combination in Rat Model of Streptozotocin Diabetes Induced Vascular DementiaBhupesh Sharma, Brij Mohan Sharma, Giriraj Thirupathirao Kulkarni, Poonam Sharma, Prachi Kaushik, Rajendra Awasthi, Swati Jain대한정신약물학회 · Clinical Psychopharmacology and Neuroscience2021 · 제19권 제3호Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive ImpairmentAli Hosseini-Sharifabad, Maryam Safavi, Mohammad Rabbani, Yasaman Seyed-Yousefi대한정신약물학회 · Clinical Psychopharmacology and Neuroscience2020 · 제18권 제2호Protective role of caffeic acid in an Aβ25-35-induced Alzheimer’s disease model김지현, 이상현, 조은주, 최지명, Qian Wang한국영양학회 · Nutrition Research and Practice2015 · 제9권 제5호Protective effects of Populus tomentiglandulosa against cognitive impairment by regulating oxidative stress in an amyloid beta25–35-induced Alzheimer's disease mouse modelCho Eun Ju, Kim Hyun Young, Kim Ji-Hyun, Kwon Yu Ri, Lee Sanghyun한국영양학회 · Nutrition Research and Practice2022 · 제16권 제2호

이 간행물의 다른 논문 (17건)