The Neuroprotective Effects of Flaxseed Oil Supplementation on Functional Motor Recovery in a Model of Ischemic Brain Stroke: Upregulation of BDNF and GDNF

  • Abolqasem Bagheri Department of Anatomy, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran.
  • Sahand Talei School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Negar Hassanzadeh School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Tahmineh Mokhtari Department of Anatomy, School of Medicine, Research Center of Nervous System Stem Cells, Semnan University of Medical Sciences, Semnan, Iran.
  • Mohammad Akbari Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Fatemeh Malek Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Seyed Behnamedin Jameie Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
  • Yousef Sadeghi Department of Anatomy, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
  • Gholamreza Hassanzadeh Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Keywords: Flaxseed oil, BDNF, GDNF, Motor cortex, Brain stroke

Abstract

Cerebral ischemic stroke is a common leading cause of disability. Flaxseed is a richest plant-based source of antioxidants. In this study, the effects of flaxseed oil (FSO) pretreatment on functional motor recovery and gene expression and protein content of neurotrophic factors in motor cortex area in rat model of brain ischemia/reperfusion (I/R) were assessed. Transient middle cerebral artery occlusion (tMCAo) in rats was used as model brain I/R. Rats (6 in each group) were randomly divided into four groups of Control (Co+normal saline [NS]), Sham (Sh+NS), tMCAo+NS and tMCAo+FSO. After three weeks of pretreatment with vehicle or FSO (0.2 ml~800 mg/kg body weight), the rats were operated in sham and ischemic groups. Ischemia was induced for 1 h and then reperfused. After 24 h of reperfusion, neurological examination was performed, and animals were sacrificed, and their brains were used for molecular and histopathological studies. FSO significantly improved the functional motor recovery compared with tMCAo+NS group (P<0.05). A significant reduction in brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) mRNAs and protein levels were observed in the tMCAo+NS group compared with Co+NS and Sh+NS group (P<0.05). A significant increase of BDNF and GDNF mRNAs and proteins was recorded in the tMCAo+FSO group compared with Co+NS, Sh+NS and tMCAO+NS groups (P<0.05). The results of the current study demonstrated that pretreatment with FSO had neuroprotective effects on motor cortex area following cerebral ischemic stroke by increasing the neurotrophic factors (BDNF, GDNF).

References

Delcroix GJ-R, Schiller PC, Benoit J-P, Montero-Menei CN. Adult cell therapy for brain neuronal damages and the role of tissue engineering. Biomaterials 2010;31:2105-20.

Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes. Stroke 2001;32:1732-8.

Bani-Yaghoub M, Tremblay RG, Ajji A, Nzau M, Gangaraju S, Chitty D, et al. Neuroregenerative strategies in the brain: emerging significance of bone morphogenetic protein 7 (BMP7). Biochem Cell Biol 2008;86:361-9.

Gurgo RD, Bedi KS, Nurcombe V. Current concepts in central nervous system regeneration. J Clin Neurosci 2002;9:613-7.

Case LC, Tessier-Lavigne M. Regeneration of the adult central nervous system. Curr Biol 2005;15:R749-53.

Ghaderi R, Afshar M. Topical application of honey for treatment of skin wound in mice. Iran J Med Sci 2015;29:185-8.

Jahanshahi M, Golalipour M, Afshar M. The effect of Urtica dioica extract on the number of astrocytes in the dentate gyrus of diabetic rats. Folia Morphol (Warsz) 2009;68:93-2.

Golalipour MJ, Ghafari S, Afshar M, Öztürk Y, Berktaş S, Soylu Öb, Et Al. Related articles editorial protective role of Urtica dioica L.(Urticaceae) extract on hepatocytes morphometric changes in STZ diabetic Wistar rats. Turk J Gastroenterol 2010;21:262-9.

Golalipour MJ, Jahanshahi M, Ghafari S, Afshar M. The preventive and treatment effect of Urtica dioica on astrocyte density in the CA1 and CA3 subfields of hippocampus in STZ induced diabetic rats. Int J Morphol 2013;31:693-9.

01 . Ghosh N, Ghosh R, Bhat ZA, Mandal V, Bachar SC, Nima ND, et al. Advances in herbal medicine for treatment of ischemic brain injury. Nat Prod Commun 2014;9:1045-55.

Connor WE. α-Linolenic acid in health and disease. Am J Clin Nutr 1999;69:827-8.

Mokhtari T, Ghanesefat HF, Hassanzadeh G, Moayeri A, Haeri SMJ, Kanavee AR, et al. Effects of Flaxseed oil supplementation on renal dysfunction due to ischemia/reperfusion in rat.

Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed. Atherosclerosis 2005;179:269-75.

Ander BP, Weber AR, Rampersad PP, Gilchrist JS, Pierce GN, Lukas A. Dietary flaxseed protects against ventricular fibrillation induced by ischemia-reperfusion in normal and hypercholesterolemic rabbits. J Nutr 2004;134:3250-6.

Nounou HA, Deif MM, Shalaby MA. Effect of flaxseed supplementation and exercise training on lipid profile, oxidative stress and inflammation in rats with myocardial ischemia. Lipids Health Dis 2012;11:129.

Burdge GC, Calder PC. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod Nutr Dev 2005;45:581-97.

Rao J, Ertley R, Lee H, DeMar J, Arnold J, Rapoport S, et al. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatr 2007;12:36-46.

Zanwar AA, Hegde M, Bodhankar S. In vitro antioxidant activity of ethanolic extract of Linum usitatissimum. Pharmacologyonline 2010;1:683-96.

Newairy A-SA, Abdou HM. Protective role of flax lignans against lead acetate induced oxidative damage and hyperlipidemia in rats. Food Chem Toxicol 2009;47:813-8.

Xu J, Gao H, Song L, Yang W, Chen C, Deng Q, et al.

Flaxseed oil and alpha-lipoic acid combination ameliorates hepatic oxidative stress and lipid accumulation in comparison to lard. Lipids Health Dis 2013;12:58.

Kitts D, Yuan Y, Wijewickreme A, Thompson L. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem 1999;202:91-100.

Ikemoto A, Nitta A, Furukawa S, Ohishi M, Nakamura A, Fujii Y, et al. Dietary n-3 fatty acid deficiency decreases nerve growth factor content in rat hippocampus. Neurosci Lett 2000;285:99-102.

Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function 1. Annu Rev Neurosci 2001;24:677-736.

Sabbaghziarani F, Mortezaee K, Akbari M, Soleimani M, Moini A, Ataeinejad N, et al. Retinoic acid-pretreated Wharton’s jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury. Metab Brain Dis 2017;32:185-93.

Schäbitz W-R, Schwab S, Spranger M, Hacke W. Intraventricular brain-derived neurotrophic factor size after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1997;17:500-6.

Schäbitz W-R, Sommer C, Zoder W, Kiessling M, Schwaninger M, Schwab S. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke 2000;31:2212-7.

Schäbitz W-R, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, et al. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke 2004;35:992-7.

Duarte EP, Curcio M, Canzoniero LM, Duarte CB. Neuroprotection by GDNF in the ischemic brain. Growth Factors 2012;30:242-57.

Kitagawa H, Hayashi T, Mitsumoto Y, Koga N, Itoyama Y, Abe K. Reduction of ischemic brain injury by topical application of glial cell line–derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 1998;29:1417-22.

Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002;3:383-94.

Sariola H, Saarma M. Novel functions and signalling pathways for GDNF. J Cell Sci 2003;116:3855-62.

Ibáñez CF. Beyond the cell surface: new mechanisms of receptor function. Biochem Biophys Res Commun 2010;396:24-7

Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 1986;17:472-6.

Paxinos G, Watson C, eds. The rat brain in stereotaxic coordinates. 6 ed. San Diego Boston New York: Harcourt Brace Jovanovich, 2007:11-30.

Mokhtari T, Akbari M, Malek F, Kashani IR, Rastegar T, Noorbakhsh F, et al. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru 2017;25:4.

Atlasi MA, Naderian H, Noureddini M, Fakharian E, Azami A. Morphology of Rat Hippocampal CA1 neurons following modified two and four-vessels global ischemia models. Arch Trauma Res 2013;2:124-8.

Mattson M, Duan W, Pedersen W, Culmsee C. Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001;6:69-81.

Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391-7.

Butler TL, Kassed CA, Sanberg PR, Willing AE, Pennypacker KR. Neurodegeneration in the rat hippocampus and striatum after middle cerebral artery occlusion. Brain Res 2002;929:252-60.

Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F, et al. Visfatin reduces hippocampal CA1 cells death and improves learning and memory deficits after transient global ischemia/reperfusion. Neuropeptides 2015;49:63-8.

Mao Y, Yang G-Y, Zhou L-F, Stern JD, Betz AL. Focal cerebral ischemia in the mouse: description of a model and effects of permanent and temporary occlusion. Mol Brain Res 1999;63:366-70.

Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-κB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull 2001;55:375-86.

Oruc S, Gönül Y, Tunay K, Oruc OA, Bozkurt MF, Karavelioğlu E, et al. The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats. Life Sci 2016;154:79-86.

Gupta S, Gupta YK. Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats. J Ethnopharmacol 2017;197:118-127.

Attari F, Sharifi ZN, Movassaghi S, Aligholi H, Alizamir T, Hassanzadeh G. Neuroprotective Effects of Curcumin Against Transient Global Ischemia are Dose and Area Dependent. Arch Neurosci 2016;3:e32600.

Bayat M, Tameh AA, Ghahremani MH, Akbari M, Mehr SE, Khanavi M, et al. Neuroprotective properties of Melissa officinalis after hypoxic-ischemic injury both in vitro and in vivo. Daru 2012;20:42.

Lee JC, Bhora F, Sun J, Cheng G, Arguiri E, Solomides CC, et al. Dietary flaxseed enhances antioxidant defenses and is protective in a mouse model of lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 2008;294:L255-65.

Hosseini S, Rahnema M, Bigdeli MR. Effect of Pre-nutrion of Flax Seed Oil (Linum Usitatissimum) on the amount of Cerebral ischemic lesion and motor nerve disorders in animal model rat. Armaghane Danesh 2015;20:558-71.

Hadjighassem M, Kamalidehghan B, Shekarriz N, Baseerat A, Molavi N, Mehrpour M, et al. Oral consumption of α-linolenic acid increases serum BDNF levels in healthy adult humans. Nutr J 2015;14:20.

Ma X, Wang R, Zhao X, Zhang C, Sun J, Li J, et al. Antidepressant-like effect of flaxseed secoisolariciresinol diglycoside in ovariectomized mice subjected to unpredictable chronic stress. Metab Brain Dis 2013;28:77-84.

Chen A, Xiong L-J, Tong Y, Mao M. The neuroprotective roles of BDNF in hypoxic ischemic brain injury (Review). Biomed Rep 2013;1:167-76.

Sutherland BA, Neuhaus AA, Couch Y, Balami JS, DeLuca GC, Hadley G, et al. The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke. J Cereb Blood Flow Metab 2015:0271678X15606722.

Shahjouei S, Cai PY, Ansari S, Sharififar S, Azari H, Ganji S, et al. Middle Cerebral Artery Occlusion Model of Stroke in Rodents: A Step-by-Step Approach. J Vasc Interv Neurol 2016;8:1-8.

Fernandes FS, de Souza AS, do Carmo MdGT, Boaventura GT. Maternal intake of flaxseed-based diet (Linum usitatissimum) on hippocampus fatty acid profile: implications for growth, locomotor activity and spatial memory. Nutrition 2011;27:1040-7.

de Barros Mucci D, Fernandes FS, dos Santos Souza A, de Carvalho Sardinha FL, Soares-Mota M, do Carmo MdGT. Flaxseed mitigates brain mass loss, improving motor hyperactivity and spatial memory, in a rodent model of neonatal hypoxic-ischemic encephalopathy. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) 2015;97:13-

Published
2018-01-16
How to Cite
1.
Bagheri A, Talei S, Hassanzadeh N, Mokhtari T, Akbari M, Malek F, Jameie SB, Sadeghi Y, Hassanzadeh G. The Neuroprotective Effects of Flaxseed Oil Supplementation on Functional Motor Recovery in a Model of Ischemic Brain Stroke: Upregulation of BDNF and GDNF. Acta Med Iran. 55(12):785-792.
Section
Articles