تاثیر بورنیل استات بر روی موش نر نژاد ویستار آلزایمری شده و فیبریل‌های آمیلوئید در شرایط in vitro و بررسی استرس بی حرکتی

محورهای موضوعی : فصلنامه زیست شناسی جانوری

حمیدرضا علیپور ¹ , پریچهره یغمایی ^{2 *} , شهین احمدیان ³ , مریم قبه ⁴ , آزاده ابراهیم حبیبی ⁵

1 - گروه زیست شناسی، واحد علوم و تحقیقات تهران، دانشگاه آزاد اسلامی، تهران، ایران
2 - گروه زیست شناسی، واحد علوم و تحقیقات تهران، دانشگاه آزاد اسلامی، تهران، ایران
3 - گروه بیوشیمی، مرکز تحقیقات بیوشیمی و بیوفیزیک، دانشگاه تهران، تهران، ایران
4 - گروه زیست شناسی، واحد علوم و تحقیقات تهران، دانشگاه آزاد اسلامی، تهران، ایران
5 - مرکز تحقیقات غدد و متابولیسم، پژوهشکده علوم بالینی غدد و متابولیسم، دانشگاه علوم پزشکی تهران، تهران، ایران

تاریخ دریافت : 1400/11/25 تاریخ پذیرش : 1400/11/30 تاریخ انتشار : 1401/09/01

کلید واژه: حافظه, بورنیل استات, پلاک‌های آمیلوئید, Aβ42, استرس بی حرکتی,

چکیده مقاله :

بیماری آلزایمر یک اختلال تخریبی نورونی است که باعث مرگ نورون و از دست دادن حافظه می شود و موجب تولید رادیکال های آزاد و فاکتورهای التهابی بروز می کند. مطالعات نشان می دهد بورنیل استات به عنوان یک مونوترپن دارای اثرات آنتی اکسیدانی و ضد التهابی می باشد. بنابراین در این مطالعه اثرات بورنیل استات با دوزهای20 و 50 میلی گرم/کیلوگرم در موش آلزایمری شده نر نژاد ویستار مورد بررسی قرار گرفت . برای ایجاد مدل آلزایمری از تزریق دو طرفه Aβ1-42 درون هیپوکامپ رت‌های نر استفاده شد. در این مطالعه آنزیم های بیوشیمیایی SOD و MDA، تست رفتاری شاتل باکس، بررسی های هیستولوژیکی و رنگ آمیزی هماتوکسیلین و ائوزین و تیوفیلاوین S جهت بررسی نوروژنز و پلاک های آمیلوئیدی و اثرات استرس بی حرکتی کوتاه مدت بر موش‌های آلزایمری و همچنین اثرات ترکیب ذکر شده در محیط in vitro نیز مورد بررسی قرار گرفت. فاکتورهای بیوشیمیایی، تصاویر بافت شناسی و آزمون رفتاری گروه آلزایمری در مقایسه با گروه های کنترل به طور معناداری متفاوت بود . به طوریکه شاخص های یادگیری و حافظه در گروه آلزایمری شده در مقایسه با گروه کنترل کاهش معنا داری نشان داد. همچنین دریافت ترکیب بورنیل استات باعث افزایش معنادار نوروژنز و کاهش معنادار تراکم پلاک ها و همچنین تغییرات شاخص های بیوشیمیایی و آزمون رفتاری شد. علاوه بر این، دریافت ترکیب بورنیل استات توام با استرس بی حرکتی باعث افزایش سرعت یاد گیری و بهبود حافظه نسبت به گروه آلزایمری شد. قابل ذکر است که ترکیب فوق در محیط in vitro باعث کاهش فیبریل های آمیلوئیدی شد. با توجه به نتایج به دست آمده در این مطالعه و گزارش‌های قبلی مبنی بر اثرات ضد التهابی و آنتی اکسیدان بورنیل استات به نظر می‌رسد این ترکیب می‌توانند اختلالات و عارضه‌های ایجاد شده در حافظه را بهبود ببخشند.

چکیده انگلیسی:

Alzheimer's disease is a neurodegenerative disorder that results in neuronal death and memory loss as it progresses. Following the progression of this disease, the production of free radicals and inflammatory factors occurs and it is now increasingly widespread, especially among the elderly. Studies show that Bornyl acetate, as a monoterpene, has antioxidant and anti-inflammatory effects. Therefore, the present study aims at assessing the effects of Bornyl acetate on AD male Wistar rats. Aβ1-42 was injected into the hippocampus of male rats bilaterally to create the Alzheimer's model. The therapeutic as well as the preventive effects of Bornyl acetate at a dosage (50, 20 mg/kg) were also investigated. Moreover, biochemical enzymes, SOD and MDA, shuttle box behavioral test, histological studies and hematoxylin & eosin and thioflavin-S staining were used to evaluate neurogenesis and amyloid plaques and the effects of short-term restraint stress on AD rats as well as the effects of the compound in vitro. Biochemical factors, histological images and behavioral test of the AD group were significantly different from the control groups and AD group showed a significant decline in learning and memory indices compared with the control group. Also, receiving a Bornyl acetate caused a significant increase in neurogenesis and a significant decrease in plaque density as well as significant changes in biochemical indices and behavioral tests. In addition, Bornyl acetate + restraint stress (R) group elevated learning speed and improved memory compared with the AD group. Notably, the above combination reduced amyloid fibrils in vitro. It seems that this compound can improve memory disorders and complications according to the results of the present study and previous reports suggest the anti-inflammatory and antioxidant effects of Bornyl acetate. 

منابع و مأخذ:

1. Bakkali F., Averbeck S., Averbeck D., Idaomar M.. 2008. Biological effects of essential oils–a review.Food Chemical Toxicolology, 46(2): 446-75.


2. Buchbaue G r., Jäger  W.,  Jirovetz  L., Meyer  F.,  Dietrich H. 1992. [Effects of valerian root oil, borneol, isoborneol, bornyl acetate and isobornyl acetate on the motility of laboratory animals (mice) after inhalation]. Pharmacy Journal, 47(8): 620-2.


3. Cassidy L.,Fernandez, F., Johnson JB., Naiker M., Owoola, AG., Broszczak, DA. 2020. Oxidative stress in alzheimer’s disease: A review on emergent natural polyphenolic therapeutics. Complementary Therapy and Medicince, 49, 102294.


4. Chen N.,Sun G ., Yuan  X ., Hou  J ., Wu Q ., Soromou LW ., Feng  H . 2014. Inhibition of lung inflammatory responses by bornyl acetate is correlated with regulation of myeloperoxidase activity. Surgical Research, 186(1): 436-45.


5. Crous-Bou M., Minguillon C., Gramunt N., Molinuevo JL. 2017.Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimer’s Research and Therapy, 12;9(1): 71.


6. Cutillas AB ., Carrasco A., Martinez-Gutierrez R. ., Tomas V., Tudela J. 2018. Thymus mastichina L. essential oils from Murcia (Spain): Composition and antioxidant, antienzymatic and antimicrobial bioactivities. PLoS One, 13(1): e0190790.


7. Dall’Igna OP., Fett P., Gomes MW., Souza DO., Cunha RA ., Lara DR. 2007. Caffeine and adenosine A2a receptor antagonists prevent β-amyloid (25–35)-induced cognitive deficits in mice Experimental neurology, 203(1): 241-245..


8. Darwish RS.,  Hammoda HM .,  Ghareeb DA .,  Abdelhamid ASA ., Bellah El Naggar EM .,  Harraz FM ., Shawky E . 2020. Efficacy-directed discrimination of the essential oils of three Juniperus species based on their in-vitro antimicrobial and anti-inflammatory activities. Comparative Study, 15;259: 11297.


9. Diego M A., Jones N A., Field T Hernandez-Reif M., Schanberg S., Kuhn C., McAdam V., Galamaga R ., Galamaga M. 1998, “Aromatherapy positively affects mood, EEG patterns of alertness and math computations. International Journal of Neuroscience, 96(3-4): 217-24.


10. Donna M., Wilcock A. 2012 .Changing Perspective on the Role of Neuroinflammation in Alzheimer's Disease. International Journal of Alzheimer's Disease, 12: 495243.


11. Doody RS., Thomas RG., Farlow M., Iwatsubo T., Vellas B., Joffe S.,Kieburtz K., Raman R.,Sun X., Aisen PS., Siemers E., Liu-Seifert H., Mohs R. 2014. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. New England Journal of Medicine , 370: 311–21.


12. Dubois B., Feldman HH., Jacova C., Hampel H.,Molinuevo JL., Blennow K., DeKosky ST., Gauthier S., Selkoe D., Bateman R., Cappa S., Crutch S., Engelborghs S., Frisoni GB., Fox NC., Galasko D., Habert MO., Jicha GA., Nordberg A., Pasquier F., Rabinovici G., Robert P., Rowe C., Salloway S., Sarazin M., Epelbaum S., de Souza LC., Vellas B., Visser PJ., Schneider L., Stern Y., Scheltens P., Cummings JL. 2014. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Journal of Lancet Neurololgy, 13(6): 614-29.


13. Fuchs E., Flugge G.,Ohl F., Lucassen P., Vollmann-Honsdorf GK., Michaelis T. 2001. Psychosocial stress, glucocorticoids, and structural alterations in the tree shrew hippocampus. Physiology and Behavior, 73: 285-291.


14. Gandy S. 2005. The role of cerebral amyloid β accumulation in common forms of Alzheimer disease. Journal of Clinical Investigations, 115(5): 1121-9.


15. Ghobeh M., Ahmadian S., Meratan AA., Ebrahim‐Habibi A., Ghasemi A., Shafizadeh M., Nemat‐Gorgani M.. 2014. Interaction of Aβ (25–35) fibrillation products with mitochondria: Effect of small‐molecule natural products. Peptide Science, 102(6): 473-86.


16. Granger RE.,Campbell EL ., Johnston GA. 2005. (+)- And (-)-borneol: efficacious positive modulators of GABA action at human recombinant alpha1beta2gamma2L GABA(A) receptors. Biochemical Pharmacology, 1;69(7): 1101-11.


17. Guaza C., Borrell J. 1985. Prolonged ethanol consumption influences shuttle box and passive avoidance performance in rats. Physiology and Behavior, 34(2): 163-5.


18. Hodaj-Çeliku E .,Tsiftsoglou O .,Shuka L ., Abazi S .,D Hadjipavlou-Litina ., Lazari D . 2017. Antioxidant Activity and Chemical Composition of Essential Oils of some Aromatic and Medicinal Plants from Albania. Natural Product Communications, 12(5): 785-790.


19. Hosseinzadeh S., Roshan VD., Pourasghar M. 2013. Effects of intermittent aerobic training on passive avoidance test (shuttle box) and stress markers in the dorsal hippocampus of wistar rats exposed to administration of homocysteine. . Iranian Journal of Psychiatry and Behaviral Science, 7(1): 37.


20. Hu NW.,Smith IM., Walsh DM., Rowan MJ. 2008. Soluble amyloid-β peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo. Brain, 131(9): 2414-24.


21. Iijima M., Osawa M., Nishitani N.,Iwata M., 2009. “Effects of incense on brain function: evaluation using electroencephalograms and event-related potentials. Neuropsychobiology, 59(2): 80–86.


22. Jemia MB.,  Chaabane S.,  Senatore F.,  Bruno M.,  Kchouk ME .2013 .Studies on the antioxidant activity of the essential oil and extract of Tunisian Tetraclinis articulata (Vahl) Mast. (Cupressaceae). Natural Product Research, 27(16): 1419-30.


23. Kennedy DO., Dodd FL., Robertson BC., Okello EJ., Reay JL., Scholey AB., Haskell CF. 2011 .Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults. Journal of Psychopharmacology, 25(8): 1088-100.


24. Kennedy DO., Wightman EL. 2011 Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Advances in Nutrition, 2(1): 32–50.


25. Khatoon S.S., Rehman M., Rahman A. 2018. The role of natural products in Alzheimer’s and Parkinson’s disease. Studies in natural products chemistry, 56: 69–127.


26. Kim JJ., Song EY., Kim JJ.,Song EY., Kosten TA. 2006. Stress effects in the hippocampus: synaptic plasticity and memory. Stress, 9(1): 1-11.


27. Kim K., Bu Y., Jeong.,Lim J., Kwon Y.,Cha DS.,Kim J., Jeon S., Eun J.,Jeon H. 2006. Memory-enhancing effect of a supercritical carbon dioxide fluid extract of the needles of Abies koreana on scopolamine-induced amnesia in mice. Bioscience, Biotechnology and Biochemistry, 70(8): 1821–1826.


28. Kim S.H.,  Lee S.Y.,  Hong C.Y.,  Gwak K.S.,  Park M.J.,  Smith D.,  Cho I.G. 2013. Whitening and antioxidant activities of bornyl acetate and nezukol fractionated from Cryptomeria japonica essential oil. International Journal of Cosmetics Sciences, 35(5): 484-90.


29. Lane CA., Hardy J., Schott JM. 2018. Alzheimer’s disease. European Journal of Neurology, 25(1): 59-70.


30. Orhan IE . 2021. A Review Focused on Molecular Mechanisms of Anxiolytic Effect of Valerina officinalis L. in Connection with Its Phytochemistry through in vitro/in vivo Studies. Current Pharmaceutical Design, 27(28): 3084-3090.


31. Paxinos, G., and Watson C. 2006. The Rat Brain in Stereotaxic Coordinates. 6^th Australia.


32. Perry N S  .,  Houghton P J.,  Theobald A., Jenner P .,  Perry E K . 2000. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. Pharmacy and  Pharmacololgy, 52(7): 895-902.


33. Perry N.S.L., Bollen C., Perry E.K., Ballard C., Salvia .2003. For dementia therapy: Review of pharmacological activity and pilot tolerability clinical trial. Pharmacology Biochemistry and Behavior, 75(3): 651-659.


34. Savelev S.,Okello E., Perry NSL., Wilkins RM., Perry EK. 2003 .Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil. Pharmacology Biochemistry and Behavior, 75: 661–668.


35. Sayorwan W.,Siripornpanich V., Piriyapunyaporn T., Hongratanaworakit T., Kotchabhakdi N., Ruangrungsi N. 2012. The effects of lavender oil inhalation on emotional states, autonomic nervous system, and brain electrical activity. Journal of Medical Association of Thailand, 95(4): 598-606.


36. Shanhong L., Ting Zh., Gu W., Ya X., Lu J., Ronghua Zh., Yu J. 2018.Volatile Oil of Amomum villosum Inhibits Nonalcoholic Fatty Liver Disease via the Gut-Liver Axis. Biomedical Research, e3589874.

37 . Subramaniyan, S.D., AshokKumar N., Citral A. 2017. Monoterpene Protect Against High Glucose Induced Oxidative Injury in HepG2 Cell In Vitro-An Experimental Study. Journal of Clinical Diagnosis Research, 11: BC10-BC15.

38 . Tildesley NTJ., Kennedy DO., Perry EK., Ballard CG., Savelev S., Wesnes KA.,Scholey AB. 2003, Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers. Pharmacology Biochemistry and Behavior 75: 669–674.

39. Tung YT., Chua MT., Wang Sh., Chang ST. 2008. Antiinflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresource and Technology, 99: 3908–13.


40. Van Cauwenberghe C. , Van Broeckhoven C., and Sleegers K. 2015 . The genetic landscape of Alzheimer disease: clinical implicationsand perspectives. Genetics in Medicine, 18(5): 421-430.

41 Wang  X., Ma  A., Shi  W., Geng  M., Zhong  X., Zhao Y. 2011. Quercetin and bornyl acetate regulate t-lymphocyte subsets and INF-y/IL-4 ratio in utero in pregnant mice. Evidence Based Complementary Alternative Medicine, e745262.

42 . Wellington D., Mikaelian I.,, Singer L. 2013. Comparison of ketamine–xylazine and ketamine–dexmedetomidine anesthesia and intraperitoneal tolerance in rats. Journal of the American association for laboratory animal science, 52(4): 481-7.

43 . Wu X., Li X., Xiao F., Zhang Z., Xu  Z., Wang H . 2004. Studies on the analgesic and anti-inflammatory effect of bornyl acetate in volatile oil from Amomum villosum. Zhong Yao Cai, 27(6): 438-439.

44 . Wu X ., Xiao F., Zhang Z., Li X., Xu  Z. 2005 . Research on the analgesic effect and mechanism of bornyl acetate in volatile oil from amomum villosum. Zhong Yao Cai, 28(6): 505-507.

45 . Yaghmaei P., Azarfar K., Dezfulian M., Ebrahim-Habibi A. 2014. Silymarin effect on amyloid-β plaque accumulation and gene expression of APP in an Alzheimer’s disease rat model. DARU, 22(1): 24.

46 . Yang L., Liu J ., Li Y ., Qi G . 2018. Bornyl acetate suppresses ox-LDL-induced attachment of THP-1 monocytes to endothelial cells. Biomedical Pharmacology, 103: 234-239.

47 . Yu N.N.,Wang X.X., Yu J.T., Wang N.D., Lu RC., Miao D.,Tian Y., Tan L. 2010. Blocking β2-adrenergic receptor attenuates acute stress-induced amyloid β peptides production. Brain Reserch, 1317: 305-310.

48 . Zhang  Y ., Long Y ., Yu  S ., Li  D ., Yang M., Guan Y ., Zhang  D ., Wan  J ., Liu S ., Shi  A ., Peng W . 2021. Natural volatile oils derived from herbal medicines: A promising therapy way for treating depressive disorder. Pharmacology Research, 164: 105376.