Volume 28, Issue 2 (July 2024)                   Physiol Pharmacol 2024, 28(2): 117-127 | Back to browse issues page

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Esfaniari E, Hosseinkhani A, Rashtiani S, Rohampour K, Jafari A. The effect of Neuropeptide Y Y2 receptor blockade on memory impairment and autophagy in a rat model of Alzheimer’s disease. Physiol Pharmacol 2024; 28 (2) : 3
URL: http://ppj.phypha.ir/article-1-2083-en.html
Abstract:   (656 Views)
Introduction: While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. Some studies suggest that NPY may also play a role in autophagy. In our investigation, we aimed to explore whether NPY and its Y2 receptor inhibitor could influence memory modulation or affect Beclin-1 expression in a rat model of Alzheimer’s disease (AD). NPY may also have a role in autophagy, according to some studies.
Methods: Intracerebroventricular (i.c.v) injections of amyloid-beta (Aβ1-42, 2µg/µl/ side) were used to establish an animal model of AD. NPY (10 ng/µl, 10 µl, i.c.v) was administered 30 minutes before the retrieval. Y2 antagonist BIIE-0246 was injected 15 minutes before NPY administration in the targeted groups. BIIE-0246 was used at three different concentrations (20 nM, 200 nM, and 2 µM). Passive avoidance memory and novel object recognition were both evaluated. Subsequently, Beclin-1 protein expression in the hippocampus was determined using western blot analysis.
Results: It was found that NPY administration improved passive avoidance and cognitive memory in animals treated with Aβ. Injecting BIIE-0246 before NPY did not reverse the improving effect of NPY on passive avoidance and Novel Object Recognition memories. Furthermore, compared to sham-operated animals, Aβ treatment significantly reduced the hippocampal expression of Beclin-1 protein (P≤0.05), and neither NPY nor NPY Y2 receptor inhibitors affected Beclin-1.
Conclusion: In Aβ-induced memory impairment, it is thought that NPY can improve both aversive and cognitive memory. Blocking NPY Y2 receptors with BIIE-0246 did not alter NPY’s memory-enhancing effect
Article number: 3
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1. Akanmu M A, Ukponmwan O E, Katayama Y, Honda K. Neuropeptide-Y Y2-receptor agonist, PYY3-36 promotes non-rapid eye movement sleep in rat. Neuroscience Research 2006; 54: 165-170. [DOI:10.1016/j.neures.2005.11.006]
2. Ashourpour F, Jafari A, Babaei P. Co-treatment of AMPA endocytosis inhibitor and GluN2B antagonist facilitate consolidation and retrieval of memory impaired by β amyloid peptide. International Journal of Neuroscience 2020: 1-10. [DOI:10.1080/00207454.2020.1837800]
3. Aveleira C A, Botelho M, Carmo-Silva S, Pascoal J F, Ferreira-Marques M, Nóbrega C, et al. Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proceedings of the National Academy of Sciences (PNAS) 2015; 112: 1642-1651. [DOI:10.1073/pnas.1416609112]
4. Bertocchi I, Mele P, Ferrero G, Oberto A, Carulli D, Eva C. NPY-Y1 receptor signaling controls spatial learning and perineuronal net expression. Neuropharmacology 2021; 184: 108425. [DOI:10.1016/j.neuropharm.2020.108425]
5. Borbély E, Scheich B, Helyes Z. Neuropeptides in learning and memory. Neuropeptides 2013; 47: 439-450. [DOI:10.1016/j.npep.2013.10.012]
6. Borroto-Escuela D O, Fores R, Pita M, Barbancho M A, Zamorano-Gonzalez P, Casares N G, et al. Intranasal delivery of galanin 2 and neuropeptide Y1 agonists enhanced spatial memory performance and neuronal precursor cells proliferation in the dorsal hippocampus in rats. Frontiers in Pharmacology 2022; 13: 820210. [DOI:10.3389/fphar.2022.820210]
7. Botelho M, Cavadas C. Neuropeptide Y: An anti-aging player? Trends in Neurosciences 2015; 38: 701-711. [DOI:10.1016/j.tins.2015.08.012]
8. Brothers S P, Saldanha S A, Spicer T P, Cameron M, Mercer B A, Chase P, et al. Selective and brain penetrant neuropeptide Y Y2 receptor antagonists discovered by whole-cell high-throughput screening. Molecular Pharmacology 2010; 77: 46-57. [DOI:10.1124/mol.109.058677]
9. Cai H, Cong W N, Ji S, Rothman S, Maudsley S, Martin B. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Current Alzheimer Research 2012; 9: 5-17. [DOI:10.2174/156720512799015064]
10. Cannizzaro C, Tel B C, Rose S, Zeng B Y, Jenner P. Increased neuropeptide Y mRNA expression in striatum in Parkinson’s disease. Brain Research Molecular Brain Research 2003; 110: 169-176. [DOI:10.1016/S0169-328X(02)00555-7]
11. Carrillo-Mora P, Luna R, Colín-Barenque L. Amyloid beta: multiple mechanisms of toxicity and only some protective effects? Oxidative Medicine and Cellular Longevity 2014; 2014. [DOI:10.1155/2014/795375]
12. Croce N, Ciotti M T, Gelfo F, Cortelli S, Federici G, Caltagirone C, et al. Neuropeptide Y protects rat cortical neurons against β-amyloid toxicity and re-establishes synthesis and release of nerve growth factor. ACS Chemical Neuroscience 2012; 3: 312-318. [DOI:10.1021/cn200127e]
13. Croce N, Dinallo V, Ricci V, Federici G, Caltagirone C, Bernardini S, et al. Neuroprotective effect of neuropeptide Y against β-amyloid 25-35 toxicity in SH-SY5Y neuroblastoma cells is associated with increased neurotrophin production. Neurodegenerative Diseases 2011; 8: 300-309. [DOI:10.1159/000323468]
14. Decressac M, Barker R A. Neuropeptide Y and its role in CNS disease and repair. Experimental Neurology 2012; 238: 265-272. [DOI:10.1016/j.expneurol.2012.09.004]
15. Domin H. Neuropeptide Y Y2 and Y5 receptors as potential targets for neuroprotective and antidepressant therapies: Evidence from preclinical studies. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2021; 111: 110349. [DOI:10.1016/j.pnpbp.2021.110349]
16. dos Santos V V, Santos D B, Lach G, Rodrigues A L, Farina M, De Lima T C, et al. Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ(1-40)) administration in mice. Behavioural Brain Research 2013; 244: 107-115. [DOI:10.1016/j.bbr.2013.01.039]
17. Doze V A, Papay R S, Goldenstein B L, Gupta M K, Collette K M, Nelson B W, et al. Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Molecular Pharmacology 2011; 80: 747-758. [DOI:10.1124/mol.111.073734]
18. Duarte-Neves J, de Almeida L P, Cavadas C. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiology of Disease 2016a; 95: 210-224. [DOI:10.1016/j.nbd.2016.07.022]
19. Fatoba O, Kloster E, Reick C, Saft C, Gold R, Epplen J T, et al. Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington’s disease. Experimental Neurology 2018; 302: 112-128. [DOI:10.1016/j.expneurol.2018.01.001]
20. Fendt M, Bürki H, Imobersteg S, Lingenhöhl K, McAllister K H, Orain D, et al. Fear-reducing effects of intra-amygdala neuropeptide Y infusion in animal models of conditioned fear: an NPY Y1 receptor independent effect. Psychopharmacology (Berl) 2009; 206: 291-301. [DOI:10.1007/s00213-009-1610-8]
21. Goswami P, Afjal M A, Akhter J, Mangla A, Khan J, Parvez S, et al. Involvement of endoplasmic reticulum stress in amyloid β. Brain Research Bulletin 2020; 165: 108-117. [DOI:10.1016/j.brainresbull.2020.09.022]
22. Gøtzsche C R, Woldbye D P. The role of NPY in learning and memory. Neuropeptides 2016; 55: 79-89. [DOI:10.1016/j.npep.2015.09.010]
23. Gupta S, Gautam M, Prasoon P, Kumar R, Ray S B, Kaler Jhajhria S. Involvement of neuropeptide Y in post-incisional nociception in rats. Annals of Neurosciences 2018; 25: 268-276. [DOI:10.1159/000495130]
24. Hörmer B A, Verma D, Gasser E, Wieselthaler-Hölzl A, Herzog H, Tasan R O. Hippocampal NPY Y2 receptors modulate memory depending on emotional valence and time. Neuropharmacology 2018; 143: 20-28. [DOI:10.1016/j.neuropharm.2018.09.018]
25. Ishida H, Shirayama Y, Iwata M, Katayama S, Yamamoto A, Kawahara R, et al. Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor. Hippocampus 2007; 17: 271-280. [DOI:10.1002/hipo.20264]
26. Jaeger P A, Wyss-Coray T. Beclin 1 complex in autophagy and Alzheimer disease. Archives of Neurology 2010; 67: 1181-1184. [DOI:10.1001/archneurol.2010.258]
27. Karl T, Chesworth R, Duffy L, Herzog H. Schizophrenia-relevant behaviours in a genetic mouse model for Y2 deficiency. Behavioural Brain Research 2010; 207: 434-440. [DOI:10.1016/j.bbr.2009.10.029]
28. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880-884. [DOI:10.1038/nature04723]
29. Komatsu M, Wang Q J, Holstein G R, Friedrich V L, Iwata J, Kominami E, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proceedings of the National Academy of Sciences (PNAS) 2007; 104: 144891448-144891494. [DOI:10.1073/pnas.0701311104]
30. Kornhuber J, Zoicas I. Neuropeptide Y prolongs non-social memory in a brain region- and receptor-specific way in male mice. Neuropharmacology 2020; 175: 108199. [DOI:10.1016/j.neuropharm.2020.108199]
31. Letra L, Santana I. The influence of adipose tissue on brain development, cognition, and risk of neurodegenerative disorders. Advances in Neurobiology 2017; 19: 151-161. [DOI:10.1007/978-3-319-63260-5_6]
32. Martel J C, Fournier A, St-Pierre S, Dumont Y, Forest M, Quirion R. Comparative structural requirements of brain neuropeptide Y binding sites and vas deferens neuropeptide Y receptors. Molecular Pharmacology 1990; 38: 494-502.
33. Mazrooie R, Rohampour K, Zamani M, Hosseinmardi N, Zeraati M. Intracerebroventricular administration of adiponectin attenuates streptozotocin-induced memory impairment in rats. Physiology International 2017; 104: 150-157. [DOI:10.1556/2060.104.2017.1.4]
34. Méndez-Couz M, Manahan-Vaughan D, Silva A P, González-Pardo H, Arias J L, Conejo N M. Metaplastic contribution of neuropeptide Y receptors to spatial memory acquisition. Behavioural Brain Research 2021; 396: 112864. [DOI:10.1016/j.bbr.2020.112864]
35. Michel M C, Beck-Sickinger A, Cox H, Doods H N, Herzog H, Larhammar D, et al. XVI. International :union: of pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacological Reviews 1998; 50: 143-150.
36. Minthon L, Edvinsson L, Gustafson L. Correlation between clinical characteristics and cerebrospinal fluid neuropeptide Y levels in dementia of the Alzheimer type and frontotemporal dementia. Alzheimer Disease & Associated Disorders 1996; 10: 197-203. [DOI:10.1097/00002093-199601040-00005]
37. Mittapalli G K, Roberts E. Ligands of the neuropeptide Y Y2 receptor. Bioorganic & Medicinal Chemistry Letters 2014; 24: 430-441. [DOI:10.1016/j.bmcl.2013.11.061]
38. Nilsson C L, Brinkmalm A, Minthon L, Blennow K, Ekman R. Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. Peptides 2001; 22: 2105-2112. [DOI:10.1016/S0196-9781(01)00571-X]
39. Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition: Elsevier, 2006.
40. Perez D M. α1-adrenergic receptors in neurotransmission, synaptic plasticity, and cognition. Frontiers in Pharmacology 2020; 11: 581098. [DOI:10.3389/fphar.2020.581098]
41. Persaud S J, Bewick G A. Peptide YY: more than just an appetite regulator. Diabetologia 2014; 57: 1762-1769 . [DOI:10.1007/s00125-014-3292-y]
42. Pickens C L, Adams-Deutsch T, Nair S G, Navarre B M, Heilig M, Shaham Y. Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear. Neuroscience 2009; 164: 1398-1406. [DOI:10.1016/j.neuroscience.2009.09.079]
43. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger P A, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. Journal of Clinical Investigation 2008; 118: 2190-2199. [DOI:10.1172/JCI33585]
44. Rangani R J, Upadhya M A, Nakhate K T, Kokare D M, Subhedar N K. Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer’s disease. Peptides 2012; 33: 317-328. [DOI:10.1016/j.peptides.2012.01.004]
45. Rashtiani S, Goudarzi I, Jafari A, Rohampour K. Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin. Neuroscience Letters 2021a; 749: 135721. [DOI:10.1016/j.neulet.2021.135721]
46. Rashtiani S, Goudarzi I, Jafari A, Rohampour K. Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin. Neuroscience Letters 2021b; 749: 135721. [DOI:10.1016/j.neulet.2021.135721]
47. Rohn T T, Wirawan E, Brown R J, Harris J R, Masliah E, Vandenabeele P. Depletion of beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiology of Disease 2011; 43: 68-78. [DOI:10.1016/j.nbd.2010.11.003]
48. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Medical Principles and Practice 2015; 24: 1-10. [DOI:10.1159/000369101]
49. Shende P, Desai D. Physiological and therapeutic roles of neuropeptide Y on biological functions. Advances in Experimental Medicine and Biology 2020; 1237: 37-47. [DOI:10.1007/5584_2019_427]
50. Silva A P, Pinheiro P S, Carvalho A P, Carvalho C M, Jakobsen B, Zimmer J, et al. Activation of neuropeptide Y receptors is neuroprotective against excitotoxicity in organotypic hippocampal slice cultures. FASEB journal 2003; 17: 1118-1120. [DOI:10.1096/fj.02-0885fje]
51. Śmiałowska M, Domin H, Zięba B, Koźniewska E, Michalik R, Piotrowski P, et al. Neuroprotective effects of neuropeptide Y-Y2 and Y5 receptor agonists in vitro and in vivo. Neuropeptides 2009; 43: 235-249. [DOI:10.1016/j.npep.2009.02.002]
52. Smiałowska M, Wierońska J M, Szewczyk B. Neuroprotective effect of NPY on kainate neurotoxicity in the hippocampus. Polish journal of pharmacology 2003; 55: 979-986.
53. Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E, et al. Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. Journal of Biological Chemistry 2016; 291: 1905-1920. [DOI:10.1074/jbc.M115.678185]
54. Stanić D, Mulder J, Watanabe M, Hökfelt T. Characterization of NPY Y2 receptor protein expression in the mouse brain. II. Coexistence with NPY, the Y1 receptor, and other neurotransmitter-related molecules. Journal of Comparative Neurology 2011; 519: 1219-1257. [DOI:10.1002/cne.22608]
55. van Wamelen D J, Aziz N A, Anink J J, Roos R A, Swaab D F. Neuropeptide alterations in the infundibular nucleus of Huntington’s disease patients. Journal of Neuroendocrinology 2013; 25: 198-205. [DOI:10.1111/j.1365-2826.2012.02379.x]
56. Verma D, Tasan R O, Herzog H, Sperk G. NPY controls fear conditioning and fear extinction by combined action on Y1 and Y2 receptors. British Journal of Pharmacology 2012; 166: 1461-1473. [DOI:10.1111/j.1476-5381.2012.01872.x]
57. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Molecular Cell 2008; 30: 678-688. [DOI:10.1016/j.molcel.2008.06.001]
58. Xapelli S, Silva A P, Ferreira R, Malva J O. Neuropeptide Y can rescue neurons from cell death following the application of an excitotoxic insult with kainate in rat organotypic hippocampal slice cultures. Peptides 2007; 28: 288-294. [DOI:10.1016/j.peptides.2006.09.031]
59. Xu H D, Qin Z H. Beclin 1, Bcl-2 and autophagy. Advances in Experimental Medicine and Biology 2019; 1206: 109-126. [DOI:10.1007/978-981-15-0602-4_5]
60. Zhang L, Bijker M S, Herzog H. The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. Pharmacology & Therapeutics 2011; 131: 91-113. [DOI:10.1016/j.pharmthera.2011.03.011]

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