Piroglutamil Peptidlerin Farelerde Skopolaminle Oluşturulmuş Öğrenme-Bellek Bozukluğu Üzerine Etkisi

Abstract

Amaç: Önceki çalışmalarımızda adipokinetik hormonun (AKH) farelerde antidepresan, anksiyolitik, analjezik etkilerini, nörotrofik faktörleri ve nörojenezi artırdığını gösterdik. Önceki çalışmamızda, AKH’nun sıçanlara intraperitoneal uygulanmasından sonra diğer çalışmalarla desteklendiği şekilde piroglutamil peptidleri içeren AKH metabolitlerinin kan-beyin bariyerini geçtiğini hipotez ettik. Gereç ve Yöntemler: Bu çalışmada, iki piroglutamil peptidin öğrenme-bellek üzerine etkisini modifiye yükseltilmiş artı labirent testinde (mYAL) ve pasif sakınma testinde hem naif farelerde hem de skopolaminle indüklenen bellek bozukluğu üzerine etkisini incelemeyi amaçladık. Skopolamin (1 mg/kg) ile piroglutamil peptid olarak piroglutamik asid-valin (pGlu-Val; 10 ve 20 mg/kg), piroglutamik asid-lösin (pGlu-Leu; 10 ve 20 mg/kg) kullandık. Bulgular: mYAL testinde dipeptidlerin naif farelerde geçiş süresi-2 üzerine anlamlı etkisi yoktu. Skopolamin kısmi olarak ikinci denemede geçiş süresi-2’yi artırırken, bu etki pGlu-Leu (10 ve 20 mg/kg; p<0,01) tarafından anlamlı şekilde tersine çevrildi fakat pGlu-Val etkisizdi. Pasif sakınma testinde dipeptidlerin naif farelerde retansiyon latansı üzerine anlamlı etkisi yoktu. Skopolamin kontrol grubuna gore retansiyon latansını kısmen azaltırken dipeptidlerin hiçbiri skopolamin grubunun retansiyon latansını tersine çevirmedi. Sonuç: Sonuçta, piroglutamil peptidler naif farelerde öğrenme-bellek üzerine etki göstermedi. pGlu-Leu mYAL testinde skopolaminle indüklenen öğrenme bozukluğu üzerine düzeltici etki gösterirken, her iki peptid pasif sakınma testinde skopolaminle indüklenen bellek bozukluğu üzerine etki göstermedi.

Keywords

• Fare
• Modifiye yükseltilmiş artı labirent
• Öğrenme-bellek
• Pasif sakınma
• Piroglutamil peptidler
• Learning-memory
• Mice
• Modified elevated plus maze
• Passive avoidance
• Pyroglutamyl peptides

Effects Of Pyroglutamyl Peptides On Scopolamine Induced Learning-Memory Impairment In Mice

Abstract

Objective: Adipokinetic hormone (AKH) had antidepressant, anxiolytic and analgesic effects in mice and increased neurotrophic factors and neurogenesis in mice. Metabolites of AKH, including pyroglutamyl peptides, pass the blood-brain barrier which is supported by other studies. Materials and Methods: We aimed to investigate effects of two pyroglutamyl peptides on learning and memory in modified elevated plus maze (mEPM) and passive avoidance tests both in naive mice and in scopolamine-induced memory deterioration. We used scopolamine (1 mg/kg) and pyroglutamic acid-valine (pGlu-Val; 10 and 20 mg/kg), pyroglutamic acid-leucine (pGlu-Leu; 10 and 20 mg/kg) as pyroglutamyl peptides. Results: In mEPM test there was no significant effect of dipeptides on transfer latency-2 in naive mice. Scopolamine partially increased transfer latency-2 in second trial and this effect was significantly reversed by pGlu-Leu (10 and 20 mg/kg; p<0.01) although pGlu-Val had no effect. In passive avoidance test none of the dipeptides reversed retention latency of scopolamine group. Conclusion: We found that pyroglutamyl peptides had no effect on learning and memory in naive mice. pGlu-Leu had improving effect on scopolamine induced learning impairment in the mEPM test while both of the peptides had no effect on scopolamine induced memory impairment in the passive avoidance test.

Keywords

• Fare
• Modifiye yükseltilmiş artı labirent
• Öğrenme-bellek
• Pasif sakınma
• Piroglutamil peptidler
• Learning-memory
• Mice
• Modified elevated plus maze
• Passive avoidance
• Pyroglutamyl peptides

References

1. Gade G, Marco H.G. Adipokinetic and hypertrehalosemic neurohormones. Encyclopedia of Entomology 2008;44:5.
2. Yamamoto Y, Mizushige T, Mori Y, Shimmura Y, Fukutomi R, Kanamoto R, et al. Antidepressant-like effect of food-derived pyroglutamyl peptides in mice. Neuropeptides 2015;51:25–9.
3. Kumar A, Bachhawat AK. Pyroglutamic acid: throwing light on a lightly studied metabolite. Current Science 2012;102(2):288-97.
4. Pepeu, G, Spignoli, G. Nootropic drugs and brain cholinergic mechanisms. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:77-88.
5. Spignoli G, Magnani M, Giovannini MG, Pepeu G. Effect of pyroglutamic acid stereosomers on ECS and scopolamine-induced memory disruption and brain acetylcholine levels in the rat. Pharmacol Res Commun 1987;19:901-12.
6. Grioli S, Lomeo C, Quattropani MC, Spignoli G, Villardita C. Pyroglutamic acid improves the age associated memory impairment. Fundam Clin Pharmacol 1990;4:169-73.
7. Drago F, Valerio C, D'Agata V, Astuto C, Spadaro F, Continella G, et al. Pyroglutamic acid improves learning and memory capacities in old rats. Funct Neurol 1988;3(2):137–43.
8. Mesulam MM, Guillozet A, Shaw P, Levey A. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002;110(4):627–39.

9. Appleyard ME. Secreted acetylcholinesterase: non-classical aspects of a classical enzyme. Trends Neurosci 1992;15(12):485–90.
10. Soreq H, Seidman S. Acetylcholinesterase - - new roles for an old actor. Nat Rev Neurosci 2001;2(4):294–302.
11. Ozkul A, Akyol A, Yenisey C. Oxidative stress in acute ischemic stroke. J Clin Neurosci 2007;14(11):1062–6.
12. Chauhan V, Chauhan A. Oxidative stress in Alzheimer's disease. Pathophysiology 2006;13(3):195–208.
13. Kuhad A, Sethi R, Chopra K. Lycopene attenuates diabetes-associated cognitive decline in rats. Life Sci 2008;83(3-4):128–34.
14. Radionova KS, Belnik AP, Ostrovskaya RU. Original nootropic drug noopept prevents memory deficit in rats with muscarinic and nicotinic receptor blockade. Bull Exp Biol Med 2008;146(1):59-62.
15. Mutlu O, Gumuslu E, Kokturk S, Ulak G, Akar F, Erden F, et al. Effects of chronic administration of adipokinetic and hypertrehalosemic hormone on animal behavior, BDNF and CREB expression in the hippocampus and neurogenesis in mice. Fundam Clin Pharmacol 2016;30:4-13.
16. Mutlu O, Ulak G, Akar F, Erden F, Celikyurt IK, Bektas E, et al. Effects of Acute Administration of Adipokinetic Hormone on Depression, Anxiety, Pain, Locomotion and Memory in Mice. Chin J Physiol 2017;60:106-13.
17. Mutlu O, Páleníček, T, Pinterová N, Šíchová K, Horáček J, Holubová K, et al. Effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on MK-801-induced schizophrenia models. Fundam Clin Pharmacol 2018;32(6):589-602.
18. Mutlu O, Kurtas O, Kleteckova L, Pinterova N, Holubová K, Horacek J, et al. Effects of adipokinetic hormone/red pigment-concentrating hormone family of peptides in olfactory bulbectomy model and posttraumatic stress disorder model of rats. Peptides Epub 2020 Sep 18.
19. Sharma AC, Kulkarni SK. Evalution of learning and memory mechanisms employing elevated plus maze in rats and mice. Prog Neuropsychopharmacol Biol Psychiatry 1992;16(1):117-25.
20. Monleon S, Urquiza A, Arenas MC, Vinader-Caerols C, Para A. Chronic administration of fluoxetine impairs inhibitory avoidance in male but not female mice. Behav Brain Res 2002;136(2):483-8.
21. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data. Behav Brain Res 1988;31(1):47-59.
22. Ohinata K, Mizushige T, Yamamoto Y, Harada M, Niimura Y. Antidepressant agent or anti-anxiety agent. Japan Patent 2014162735A;2014.
23. Gade, G. The Explosion of Structural Information on Insect Neuropeptides, Fortschritte der Chemie organischer Naturstoffe 1997;71:1-128.
24. Gazmea B, Boachiea RT, Tsopmob A, Udenigwea CC. Occurrence, properties and biological significance of pyroglutamylpeptides derived from different food sources. Food Science and Human Wellness 2019;8(3):268–74
25. Mutlu O, Tanyeri P, Basarir S, Uygun İ, Akar F, Celebi G, et al. Effects of Pyroglutamyl Peptides on Depression, Anxiety and Analgesia in Mice. IJMRHS 2021:10(5):56-62.
26. Beni, M, Pellegrini-Giampietro DE, Moroni F. A new endogenous anxiolytic agent: L-pyroglutamic acid. Fundam Clin Pharmacol 1988;2(2):77-82.
27. Paoli F, Spignoli G, Pepeu G. Oxiracetam and D-pyroglutamic acid antagonize a disruption of passive avoidance behaviour induced by the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate. Psychopharmacology (Berl) 1990;100(1):130-1.
28. Oono S, Kurimoto T, Nakazawa T, Miyoshi T, Okamoto N, Kashimoto R, et al. Pyroglutamic acid promotes survival of retinal ganglion cells after optic nerve injury. Curr Eye Res 2009;34(7):598-605.
29. Antonelli T, Carlà V, Lambertini L, Moroni F, Bianchi C. Pyroglutamic acid administration modifies the electrocorticogram and increases the release of acetylcholine and GABA from the guinea-pig cerebral cortex. Pharmacol Res Commun 1984;16(2):189-97.
30. Trofimov SS, Ostrovskaia RU, Smol'nikova NM, Nemova EP, Gudasheva TA, Kuznetsova EA, et al. The correction with nooglutil and L-pyroglutamyl-D-alanine amide of cognitive disorders in rats due to intrauterine hypoxia. Eksp Klin Farmakol 1995;58(6):10-3.
31. Chepkova AN, Doreulee NV, Trofimov SS, Gudasheva TA, Ostrovskaya RU, Skrebitsky VG. Nootropic compound L-pyroglutamyl-D-alanine-amide restores hippocampal long-term potentiation impaired by exposure to ethanol in rats. Neurosci Lett 1995;188(3):163-6.
32. Pivtoraiko VN, Abrahamson EE, Leurgans SE, DeKosky ST, Mufson EJ, Ikonomovic MD. Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease. Neurobiol Aging 2015;36(1):12-9.
33. Sato T, Tanaka K, Ohnishi Y, Teramoto T, Hirate K, Nishikawa T. The improvement of memory retention and retrieval of a novel vasopressin fragment analog NC-1900. Nihon Yakurigaku Zasshi 2002;120(1):57-60.
34. Hori E, Uwano T, Tamura R, Miyake N, Nishijo H, Ono T. Effects of a novel arginine-vasopressin derivative, NC-1900, on the spatial memory impairment of rats with transient forebrain ischemia. Brain Res Cogn Brain Res 2002;13(1):1-15.
35. Beani L, Bianchi C, Baraldi PG, Manfredini S, Pollini GP. Protection by pyroglutamic acid and some of its newly synthesized derivatives against glutamate-induced seizures in mice. Arzneimittelforschung 1990;40(11):1187-91.
36. Giannola LI, De Caro V, Avellone G, Bousquet E. L-pyroglutamyl-L-tryptophan derivatives as potential drug carriers. II.: Permeation behaviour and stability in the gastro-intestinal tract. Pharmazie 1996;51(7):487-9.