Investigation of The Effects of Trpc4/5 Inhibitor M084 in Experimental Alzheimer’s-LikeDementia Model

Year 2022, , 86 - 92, 22.04.2022

Ali Güneş , Hasan Akkoç , Emre Uyar

https://doi.org/10.46332/aemj.901315

Abstract

Purpose: This study aimed to research the effects of N-butyl-1H]-benzimidazole-2-amine (M084) on cognitive functions in an experimental Alzheimer-like dementia model.
Materials and Methods: In our study, male rats were divided into five groups (n:8). The control (C) had 1 ml 0.9% saline solution administered intraperitoneally (i.p.) for 14 days. Scopolamine (S) was administered intraperitoneally with 1 ml 0.9% saline solution for the first 7 days, followed by 3 mg/kg scopolamine on days 8-14.Scopolamine+M084 (SM) was administered i.p. dissolved in 1 ml 0.9% saline solution for the first 7 days, followed by 3 mg/kg scopolamine on days 8-14 and 20 mg/kg M084 on days 10-14. M084 (M) was administered i.p. 20 mg/kg M084 in a single daily dose from days 0-14. Positive control (D) had 5 mg/kg donepezil administrations on days 0-14 and 3 mg/kg scopolamine on days 8-14.
On days 14 and 15 of the study, passive avoidance, novel object recognition, and modified elevated plus maze tests were performed.
Results: In the passive avoidance test, transfer latencies were significantly lower in group S compared to group C. In the modified elevated plus maze test, the passing time to either closed arms on the 2nd-day test was significantly higher in group S compared to groups C and D. In the novel object recognition test, the values for groups C, SM, D, and other groups were significantly higher compared to group S.
Conclusion: In conclusion, in an Alzheimer-like dementia model, M084 provided positive results for visual memory; however, it was ineffective for other memory types. 

Keywords

M084, Alzheimer, scopolamine, memory functions

Supporting Institution

Dicle University Scientific Research Projects

Project Number

TIP.16.021.

Deneysel Alzheimer Benzeri Demans Modelinde Trpc4/5 İnhibitörü M084'ün Etkilerinin Araştırılması

Abstract

Amaç: Bu çalışmadaki amacımız skopolamin ile oluşturduğumuz deneysel Alzheimer benzeri demans modelinde N-butil-[lH]-benzimidazol-2-amin (M084)’in bilişsel fonksiyonlar üzerine etkilerini araştırmaktır.
Araçlar ve Yöntem: Çalışmamızda erkek BALB/c fareler beş gruba (n:8) ayrıldı. Kontrol grubu; 14 gün boyunca günde 1 ml 0.9% salin çözeltisi intraperitoneal (i.p.) olarak uygulandı. Skopolamin grubu: İlk 7 gün günde 1 ml 0.9% salin çözeltisi, ardından 8-14. günler arasında günde 3 mg/kg skopolamini.p. olarak uygulandı. Skopolamin + M084 grubu; İlk 7 gün günde 1 ml 0.9% salin çözeltisi uygulanan farelere 8-14. günler arasında günde 3 mg/kg skopolamini.p. + 10-14 günler arası günde 20 mg/kg M084 günde tek doz i.p. olarak uygulandı. M084 grubu; farelere 0-14. günler arası günde 20 mg/kg M084 günde tek doz i.p. uygulandı. Donepezil grubu: Pozitif kontrol grubu olarak farelere 0-14. günler arası günde 5 mg/kg donepezili.p + 8-14 günler arasında günde 3 mg/kg skopolamini.p. uygulandı. Çalışmanın 14 ve 15. günlerinde pasif sakınma, yeni obje tanıma ve modifiye yükseltilmiş artı labirenti testi uygulamaları yapıldı.
Bulgular: Pasif sakınma testinde karanlık odaya geçiş süreleri skopolamin grubunda kontrol grubuna kıyasla daha kısaydı. Modifiye Yükseltilmiş Artı Labirenti Testinde 2. gün kapalı kollardan birine geçiş süreleri skopolamin grubunda kontrol ve donezepil grubuna göre daha fazla bulundu. Yeni obje tanıma testinde diskriminasyon indeks değerleri kontrol, skopolamin + M084, donezepil ve diğer gruplardaki değerler skopolamin grubuna göre daha fazla bulundu.
Sonuç: Sonuç olarak Alzheimer benzeri demans modelinde M084 görsel bellek üzerine olumlu sonuçlar vermiş, fakat diğer bellek türleri üzerine etkisiz bulunmuştur.

Keywords

M084, Alzheimer, skopolamin, bellek fonksiyonları

Project Number

TIP.16.021.

References

• 1. Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(8): a006239.
• 2. Auld DS, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol. 2002;68(3):209-245.
• 3. Öztürk GB MAK. Alzheimer hastalığının fizyopatolojisi. 2009;22(3):32-46.
• 4. Berridge MJ. Calcium hypothesis of Alzheimer's disease. Pflugers Arch. 2010;459(3):441-449.
• 5. Edelberg HK, Wei JY. The biology of Alzheimer's disease. Mech Ageing Dev. 1996;91(2):95-114.
• 6. Pakaski M, Kalman J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease. Neurochem Int. 2008;53(5):103-111.
• 7. Hooijmans CR, Kiliaan AJ. Fatty acids, lipid metabolism and Alzheimer pathology. Eur J Pharmacol. 2008;585(1):176-196.
• 8. 2022 Alzheimer’s Disease Facts and Figures https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf. Erişim tarihi: 25 Haziran, 2020.
• 9. Supnet C, Bezprozvanny I. Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease. J Alzheimers Dis. 2010;20(2):487-498.
• 10. Small DH. Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression? Trends Mol Med. 2008;14(3):103-108.
• 11. Dietrich A, Kalwa H, Gudermann T. TRPC channels in vascular cell function. Thromb Haemost. 2010;103(2):262-270.
• 12. Greka A, Navarro B, Oancea E, Duggan A, Clapham DE. TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci. 2003;6(8):837-845.
• 13. Ding AJ, Wu GS, Tang B, Hong X, Zhu MX, Luo HR. Benzimidazole derivative M084 extends the lifespan of Caenorhabditis elegans in a DAF-16/FOXO-dependent way. Mol Cell Biochem. 2017;426(1-2):101-109.
• 14. Zhu J, Chen H, Guo XE, et al. Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors. Eur J Med Chem. 2015;96:196-208.
• 15. Chandrika NT, Shrestha SK, Ngo HX, Garneau-Tsodikova S. Synthesis and investigation of novel benzimidazole derivatives as antifungal agents. Bioorg Med Chem. 2016;24(16):3680-3686.
• 16. Aysel Ç. Investigation of the effects of agomelatin on scopolamine-induced dementia model in mice Dicle Üniversitesi; 2019.
• 17. Yang L-P, Jiang F-J, Wu G-S, et al. (2015) Acute Treatment with a Novel TRPC4/C5 Channel Inhibitor Produces Antidepressant and Anxiolytic-Like Effects in Mice. PLoS ONE 10(8): e0136255.
• 18. Bukhari SN, Lauro G, Jantan I, et al. Anti-inflammatory trends of new benzimidazole derivatives. Future Med Chem. 2016;8(16):1953-1967.
• 19. Zhu Y, Lu Y, Qu C, et al. Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. Br J Pharmacol. 2015;172(14):3495-3509.
• 20. Arora RK, Kaur N, Bansal Y, Bansal G. Novel coumarin-benzimidazole derivatives as antioxidants and safer anti-inflammatory agents. Acta Pharm Sin B. 2014;4(5):368-375.
• 21. Bhrigu B, Siddiqui N, Pathak D, Alam MS, Ali R, Azad B. Anticonvulsant evaluation of some newer benzimidazole derivatives: design and synthesis. Acta Pol Pharm. 2012;69(1):53-62.
• 22. Shingalapur RV, Hosamani KM, Keri RS, Hugar MH. Derivatives of benzimidazole pharmacophore: synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur J Med Chem. 2010;45(5):1753-1759.
• 23. Karakas S. A descriptive framework for information processing: an integrative approach. Int J Psychophysiol. 1997;26(1-3):353-368.
• 24. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochemistry International. 2004;45(5): 583-595.
• 25. Bollimuntha S, Selvaraj S, Singh BB. Emerging roles of canonical TRP channels in neuronal function. Adv Exp Med Biol. 2011;704:573-593.
• 26. Freichel M, Vennekens R, Olausson J, et al. Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies. J Physiol. 2005;567(1):59-66.
• 27. Sun Y, Sukumaran P, Bandyopadhyay BC, Singh BB. Physiological Function and Characterization of TRPCs in Neurons. Cells. 2014;3(2):455-475.
• 28. Wang Y, Bu J, Shen H, Li H, Wang Z, Chen G. Targeting Transient Receptor Potential Canonical Channels for Diseases of the Nervous System. Curr Drug Targets. 2017;18(12):1460-1465.
• 29. Li Y, Jia YC, Cui K, et al. Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature. 2005;434(7035):894-898.
• 30. Knowles J. Donepezil in Alzheimer's disease: an evidence-based review of its impact on clinical and economic outcomes. Core Evid. 2006;1(3):195-219.
• 31. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med. 1998;158(9):1021-1031.
• 32. Riedel G, Kang SH, Choi DY, Platt B. Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav Brain Res. 2009;204(1):217-225. 33. Xiang GQ, Tang SS, Jiang LY, et al. PPARgamma agonist pioglitazone improves scopolamine-induced memory impairment in mice. J Pharm Pharmacol. 2012;64(4):589-596.
• 34. Han RW, Yin XQ, Chang M, Peng YL, Li W, Wang R. Neuropeptide S facilitates spatial memory and mitigates spatial memory impairment induced by N-methyl-D-aspartate receptor antagonist in mice. Neurosci Lett. 2009;455(1):74-77.
• 35. Soukhaklari R, Moezi L, Pirsalami F, Ashjazadeh N, Moosavi M. Curcumin ameliorates scopolamine-induced mice memory retrieval deficit and restores hippocampal p-Akt and p-GSK-3beta. Eur J Pharmacol. 2018;841:28-32.
• 36. Dodart JC, Mathis C, Ungerer A. Scopolamine-induced deficits in a two-trial object recognition task in mice. Neuroreport. 1997;8(5):1173-1178.
• 37. Tomruk C, Şirin C, Buhur A, et al. The four horsemen of neurodegenerative diseases Alzheimer, Parkinson, Huntington and amyotrophic lateral skleroz; clinical definition and experimental models. FNG & Bilim Tıp Dergisi. 2018;4(1):37-43.