The nootropic effect of a dipeptide mimetic of NGF in an experimental model of Alzheimer's disease

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Abstract

Relevance. The role of nerve growth factor (NGF) deficiency in the pathogenesis of Alzheimer's disease (AD) is well-known. The clinical application of full-size neurotrophin is limited due to its low bioavailability and the risk of adverse effects. At the V.V. Zakusov Institute of Pharmacology, a dimeric dipeptide mimetic of the 4th loop of NGF, compound GK-2 (hexamethylenediamide bis-(N-monosuccinyl-L-glutamyl-L-lysine), was created. It selectively activates specific TrkA receptors and possesses neuroprotective and neuroregenerative properties. Additionally, GK-2 lacks the main side effects of NGF, namely hyperalgesia and weight loss.

The aim of the current study was to investigate the influence of GK-2 on rat memory under the conditions of the scopolamine-induced model of AD.

Material and Methods. Scopolamine was administered intraperitoneally to rats at a dose of 2 mg/kg for 32 days. Simultaneously with scopolamine, animals were intraperitoneally injected with GK-2 at doses of 0.5 and 1 mg/kg. Following the administration of the compounds, a novel object recognition test was conducted to assess both short-term and long-term memory.

Results. Rats receiving scopolamine exhibited a statistically significant decline in long-term memory. The dipeptide GK-2 at a dose of 1 mg/kg completely counteracted the development of this impairment.

Conclusion. The dipeptide mimetic of nerve growth factor, GK-2, shows promise for further investigation as a potential therapeutic agent for the treatment of AD.

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About the authors

A. A. Volkova

FSBI «V.V. Zakusov Institute of Pharmacology»

Email: volk3012@gmail.com

Post-graduate Student, Department of Human and Animal Physiology, Faculty of Biology,  M.V. Lomonosov Moscow State University;  Junior Researcher, Department of Medicinal Chemistry

Russian Federation, Moscow

P. Y. Povarnina

FSBI «V.V. Zakusov Institute of Pharmacology»

Author for correspondence.
Email: povarnina@gmail.com

Ph.D. (Biol.), Senior Researcher, Department of Medicinal Chemistry

Russian Federation, Moscow

T. A. Gudasheva

FSBI «V.V. Zakusov Institute of Pharmacology»

Email: gudasheva@academpharm.ru

Dr.Sc. (Biol.), Professor, Corresponding Member of the Russian Academy of Sciences,  Head of the Department of Medicinal Chemistry

Russian Federation, Moscow

References

  1. Mufson E.J., Counts S.E., Ginsberg S.D. et al. Nerve growth factor pathobiology during the progression of Alzheimer’s disease. Front. Neurosci. 2019; 13: 533.
  2. Capsoni S., Cattaneo A. On the molecular basis linking nerve growth factor (NGF) to Alzheimer’s disease. Cell. Mol. Neurobiol. 2006; 26(4–6): 617–631.
  3. Covaceuszach S., Capsoni S., Ugolini G. et al. Development of a non invasive NGF-based therapy for Alzheimer ’ s disease. Curr. Alzheimer Res. 2009; 6(2): 158–170.
  4. Gu H., Long D., Song C., Li X. Recombinant human NGF-loaded microspheres promote survival of basal forebrain cholinergic neurons and improve memory impairments of spatial learning in the rat model of Alzheimer’s disease with fimbria-fornix lesion. Neurosci. Lett. 2009; 453(3): 204–209.
  5. Winkler J., Thal L.J. Effects of nerve growth factor treatment on rats with lesions of the nucleus basalis magnocellularis produced by ibotenic acid, quisqualic acid, and AMPA. Exp. Neurol. 1995; 136(2): 234–50.
  6. Rocco M.L., Soligo M., Manni L., Aloe L. Nerve growth factor: early studies and recent clinical trials. Curr. Neuropharmacol. 2018; 16(10): 1455.
  7. Gudasheva T.A., Povarnina P.Y., Tarasiuk A.V., Seredenin S.B. Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: design and pharmacological properties. Med. Res. Rev. 2021; (41): 2746–74.
  8. Nguyen T.V., Shen L., Vander Griend L. et al. Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic dege-neration, and cognitive deficits in AβPP(L/S) transgenic mi-ce. J Alzheimers Dis. 2014; 42(2): 459–483.
  9. Антипова Т.А., Николаев С.В., Гудашева Т.А. Исследование in vitro нейропротекторных свойств нового оригинального миметика фактора роста нервов ГК-2. Бюллетень экспериментальной биологии и медицины. 2010; 150(11): 537–540 (Antipova T.A., Nikolaev S.V., Gudasheva T.A. Issledo-vanie in vitro nejroprotektornyh svojstv novogo original'nogo mimetika faktora rosta nervov GK-2. Bjulleten' jeksperi-mental'noj biologii i mediciny. 2010; 150(11): 537–540).
  10. Gudasheva T.A., Povarnina P.Y., Antipova T.A. et al. Dimeric dipeptide mimetics of the nerve growth factor loop 4 and loop 1 activate TRKA with different patterns of intracellular signal transduction. J. Biomed. Sci. 2015; 22(5): 106.
  11. Faldu K.G., Patel S.S., Shah J.S. Celastrus paniculatus oil ameliorates NF-KB mediated neuroinflammation and synaptic plasticity in the scopolamine-induced cognitive impairment rat model. Metab Brain Dis. 2023; 38(4): 1405–1419.
  12. Поварнина П.Ю., Воронцова О.Н., Гудашева Т.А. и соавт. Оригинальный дипептидный миметик фактора роста нер-вов ГК-2 восстанавливает нарушенные когнитивные функции в крысиных моделях болезни Альцгеймера. Acta Naturae. 2013; 5(3): 88–95 (Povarnina P.Ju., Voroncova O.N., Gudasheva T.A. i soavt. Original'nyj dipeptidnyj mimetik faktora rosta nervov GK-2 vosstanavlivaet narushennye kognitivnye funkcii v krysinyh modeljah bolezni Al'c-gejmera. Acta Naturae. 2013; 5(3): 88–95).
  13. Ennaceur A., Delacour J. A new one-trial test for neuro-biological studies of memory in rats. 1: Behavioral Data. Behav. Brain Res. 1988; 31(1): 47–59.
  14. Beldjoud H., Barsegyan A., Roozendaal B. Noradrenergic activation of the basolateral amygdala enhances object recognition memory and induces chromatin remodeling in the insular cortex. Front. Behav. Neurosci. 2015; 9: 108.
  15. Волкова А.А., Поварнина П.Ю., Гудашева Т.А., Середе-нин С.Б. Сравнительное изучение мнемотропной активности димерных дипептидных миметиков отдельных петель NGF и BDNF в тесте распознавания нового объекта у крыс. Химико-фармацевтический журнал. 2022; 56(4): 3–6 (Volkova A.A., Povarnina P.Ju., Gudasheva T.A., Serede-nin S.B. Sravnitel'noe izuchenie mnemotropnoj aktiv-nosti dimernyh dipeptidnyh mimetikov otdel'nyh petel' NGF i BDNF v teste raspoznavanija novogo ob’ekta u krys. Himiko-farmacevticheskij zhurnal. 2022; 56(4): 3–6).
  16. Grayson B., Leger M., Piercy C. et al. Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. Behav Brain Res. 2015; 285: 176–193.
  17. Chen W.N., Yeong K.Y. Scopolamine, a toxin-induced experimental model, used for research in alzheimer’s disease. CNS Neurol. Disord. Drug Targets. 2020; 19(2): 85–93.
  18. Foudah A.I., Devi S., Alam A. et al. Anticholinergic effect of resveratrol with vitamin E on scopolamine-induced Alzheimer's disease in rats: Mechanistic approach to prevent inflammation. Front Pharmacol. 2023; 14: 1115721.
  19. Reichardt L.F. Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. B Biol. Sci. 2006; 361(1473): 1545–1564.
  20. Azarafrouz F., Farhangian M., Chavoshinezhad S. et al. Interferon beta attenuates recognition memory impairment and improves brain glucose uptake in a rat model of Alzheimer’s disease: involvement of mitochondrial biogenesis and PI3K pathway. Neuropeptides. 2022; 95: 102262.
  21. Takada-Takatori Y., Kume T., Sugimoto M. et al. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology. 2006; 51(3): 474–486.
  22. Hoeffer CA, Klann E. MTOR Signaling: At the Crossroads of Plasticity, Memory and Disease. Trends Neurosci. 2010; 33(2): 67–75.
  23. Kirouac L., Rajic A.J., Cribbs D.H., Padmanabhan J. Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease. ENeuro 2017; 4(2): 149–165.

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2. Figure. Dimeric dipeptide mimetic of the 4th loop of NGF GK-2

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