Preferencje help
Widoczny [Schowaj] Abstrakt
Liczba wyników


2019 | 78 | 4 |

Tytuł artykułu

Expression of vascular endothelial growth factor and glial fibrillary acidic protein in a rat model of traumatic brain injury treated with honokiol: a biochemical and immunohistochemical study


Warianty tytułu

Języki publikacji



Background: Traumatic brain injury (TBI) leads to neuronal damage and neurological dysfunction. The aim of our study was to investigate the antioxidative effect of honokiol on TBI in rats with biochemical, histopathological and immunohistochemical methods. Materials and methods: Sprague–Dawley rats were subjected to TBI with a weight-drop device using 300 g/1 m weight/height impact. Forty-five rats were divided into three groups as control group, TBI group and TBI + honokiol group (5 mg/kg/day, i.p.). Honokiol (5 mg/kg) dissolved in dimethyl sulfoxide (DMSO) was intraperitoneally administered to rats for 7 days after the trauma. At the end of experiment, blood samples were taken from the animals and analysed with various biochemical markers. Results: Histopathological examination of the trauma group revealed some degenerated pyramidal cells, dilatation and congestion in blood vessels, hyperplasia in endothelial cells, inflammatory cell infiltration around the vein and disruptions in glial extensions. In TBI + honokiol group, pyramidal neurons showed a decrease in degeneration, slight dilatation in blood vessels, improvement of endothelial cells towards the lumen, and reduction of inflammatory cells in the vessel. In TBI + honokiol group, vascular endothelial growth factor expression was positive in the endothelial and few inflammatory cells of the mildly dilated blood vessels. In the blood brain barrier deteriorated after trauma, it was observed that the glial foot processes were positive expression and extended to the endothelial cells in the TBI + honokiol group. Conclusions: Glial fibrillary acidic protein expression showed a positive reaction in these processes. Considering the important role of antioxidants and inflammatory responses in cerebral damage induced by traumatic head injury, honokiol is thought to be important in decreasing lipid peroxidation, protecting the membrane structure of blood brain barrier, degeneration of neurons and glial cells. (Folia Morphol 2019; 78, 4: 684–694)

Słowa kluczowe









Opis fizyczny



  • Department of Neurosurgery, University of Health Sciences, Gazi Yaşargil Education and Research Hospital, Diyarbakır, Turkey
  • Department of Histology and Embryology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey


  • 1. Baldwin SA, Gibson T, Callihan CT, et al. Neuronal cell loss in the CA3 subfield of the hippocampus following cortical contusion utilizing the optical disector method for cell counting. J Neurotrauma. 1997; 14(6): 385–398, doi: 10.1089/neu.1997.14.385, indexed in Pubmed: 9219853.
  • 2. Baloğlu M, Çetin A, Tuncer MC. Neuroprotective effects of Potentilla fulgens on spinal cord injury in rats: an immunohistochemical analysis. Folia Morphol. 2018 [Epub ahead of print], doi: 10.5603/FM.a2018.0050, indexed in Pubmed: 30402877.
  • 3. Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 2012; 76(5): 886–899, doi: 10.1016/j.neuron.2012.11.021, indexed in Pubmed: 23217738.
  • 4. Chao LK, Liao PC, Ho CL, et al. Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS-induced TNFalpha and NO expression. J Agric Food Chem. 2010; 58(6): 3472–3478, doi: 10.1021/jf904207m, indexed in Pubmed: 20192217.
  • 5. Chiang J, Shen YC, Wang YH, et al. Honokiol protects rats against eccentric exercise-induced skeletal muscle damage by inhibiting NF-kappaB induced oxidative stress and inflammation. Eur J Pharmacol. 2009; 610(1-3): 119–127, doi: 10.1016/j.ejphar.2009.03.035, indexed in Pubmed: 19303869.
  • 6. Chodobski A, Chung I, Koźniewska E, et al. Early neutrophilic expression of vascular endothelial growth factor after traumatic brain injury. Neuroscience. 2003; 122(4): 853–867, doi: 10.1016/j.neuroscience.2003.08.055, indexed in Pubmed: 14643756.
  • 7. Chuang DY, Chan MH, Zong Y, et al. Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. J Neuroinflammation. 2013; 10: 15, doi: 10.1186/1742-2094-10-15, indexed in Pubmed: 23356518.
  • 8. Coles JP. Regional ischemia after head injury. Curr Opin Crit Care. 2004; 10(2): 120–125.
  • 9. Diaz-Arrastia R, Kochanek PM, Bergold P, et al. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma. 2014; 31(2): 135–158, doi: 10.1089/neu.2013.3019, indexed in Pubmed: 23968241.
  • 10. Dore-Duffy P, Wang X, Mehedi A, et al. Differential expression of capillary VEGF isoforms following traumatic brain injury. Neurol Res. 2007; 29(4): 395–403, doi: 10.1179/016164107X204729, indexed in Pubmed: 17626736.
  • 11. Feng Y, Cui Y, Gao JL, et al. Neuroprotective effects of resveratrol against traumatic brain injury in rats: Involvement of synaptic proteins and neuronal autophagy. Mol Med Rep. 2016; 13(6): 5248–5254, doi: 10.3892/mmr.2016.5201, indexed in Pubmed: 27122047.
  • 12. Greve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mt Sinai J Med. 2009; 76(2): 97–104, doi: 10.1002/msj.20104, indexed in Pubmed: 19306379.
  • 13. Gyoneva S, Ransohoff RM. Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci. 2015; 36(7): 471–480, doi: 10.1016/, indexed in Pubmed: 25979813.
  • 14. Hakan T, Toklu HZ, Biber N, et al. Effect of COX-2 inhibitor meloxicam against traumatic brain injury-induced biochemical, histopathological changes and blood-brain barrier permeability. Neurol Res. 2010; 32(6): 629–635, doi: 10.1179/016164109X12464612122731, indexed in Pubmed: 19660237.
  • 15. Hausmann R, Riess R, Fieguth A, et al. Immunohistochemical investigations on the course of astroglial GFAP expression following human brain injury. Int J Legal Med. 2000; 113(2): 70–75, indexed in Pubmed: 10741479.
  • 16. Hayashi T, Saito A, Okuno S, et al. Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J Cereb Blood Flow Metab. 2005; 25(1): 41–53, doi: 10.1038/sj.jcbfm.9600005, indexed in Pubmed: 15678111.
  • 17. Hillegass LM, Griswold DE, Brickson B, et al. Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods. 1990; 24(4): 285–295, indexed in Pubmed: 1963456.
  • 18. Kim BH, Cho JY. Anti-inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression. Acta Pharmacol Sin. 2008; 29(1): 113–122, doi: 10.1111/j.1745-7254.2008.00725.x, indexed in Pubmed: 18158873.
  • 19. Krum JM, Khaibullina A. Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair. Exp Neurol. 2003; 181(2): 241–257, doi: 10.1016/s0014-4886(03)00039-6, indexed in Pubmed: 12781997.
  • 20. Kuribara H, Kishi E, Kimura M, et al. Comparative assessment of the anxiolytic-like activities of honokiol and derivatives. Pharmacol Biochem Behav. 2000; 67(3): 597–601, doi: 10.1016/s0091-3057(00)00401-9, indexed in Pubmed: 11164091.
  • 21. Kuribara H, Stavinoha WB, Maruyama Y. Honokiol, a putative anxiolytic agent extracted from magnolia bark, has no diazepam-like side-effects in mice. J Pharm Pharmacol. 1999; 51(1): 97–103, indexed in Pubmed: 10197425.
  • 22. Lee S, Park S, Won J, et al. The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury. Int J Mol Sci. 2015; 16(8): 19657–19670, doi: 10.3390/ijms160819657, indexed in Pubmed: 26295390.
  • 23. Lenzlinger PM, Saatman KE, Hoover RC, et al. Inhibition of vascular endothelial growth factor receptor (VEGFR) signaling by BSF476921 attenuates regional cerebral edema following traumatic brain injury in rats. Restor Neurol Neurosci. 2004; 22(2): 73–79, indexed in Pubmed: 15272142.
  • 24. Lim SW, Wang CC, Wang YH, et al. Microglial activation induced by traumatic brain injury is suppressed by postin jury treatment with hyperbaric oxygen therapy. J Surg Res. 2013; 184(2): 1076–1084, doi: 10.1016/j.jss.2013.04.070, indexed in Pubmed: 23726237.
  • 25. Lin JW, Chen JT, Hong CY, et al. Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway. Neuro Oncol. 2012; 14(3): 302–314, doi: 10.1093/neuonc/nor217, indexed in Pubmed: 22259050.
  • 26. Lin YR, Chen HH, Lin YC, et al. Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain. J Biomed Sci. 2009; 16: 94, doi: 10.1186/1423-0127-16-94.
  • 27. Liou KT, Lin SM, Huang SS, et al. Honokiol ameliorates cerebral infarction from ischemia-reperfusion injury in rats. Planta Med. 2003; 69(2): 130–134, doi: 10.1055/s2003-37707, indexed in Pubmed: 12624817.
  • 28. Liou KT, Shen YC, Chen CF, et al. Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain Res. 2003; 992(2): 159–166, doi: 10.1016/j.brainres.2003.08.026, indexed in Pubmed: 14625055.
  • 29. Liou KT, Shen YC, Chen CF, et al. The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. Eur J Pharmacol. 2003; 475(1-3): 19–27, doi: 10.1016/s0014-2999(03)02121-6, indexed in Pubmed: 12954355.
  • 30. Lo YC, Teng CM, Chen CF, et al. Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochem Pharmacol. 1994; 47(3): 549–553, doi: 10.1016/0006-2952(94)90187-2, indexed in Pubmed: 8117323.
  • 31. Marmarou A, Foda MA, van den Brink W, et al. A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg. 1994; 80(2): 291–300, doi: 10.3171/jns.1994.80.2.0291, indexed in Pubmed: 8283269.
  • 32. Missler U, Wiesmann M, Wittmann G, et al. Measurement of glial fibrillary acidic protein in human blood: analytical method and preliminary clinical results. Clin Chem. 1999; 45(1): 138–141, indexed in Pubmed: 9895354.
  • 33. Munroe ME, Arbiser JL, Bishop GA. Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis. J Immunol. 2007; 179(2): 753–763, doi: 10.4049/jimmunol.179.2.753, indexed in Pubmed: 17617564.
  • 34. Nag S, Takahashi JL, Kilty DW. Role of vascular endothelial growth factor in blood-brain barrier breakdown and angiogenesis in brain trauma. J Neuropathol Exp Neurol. 1997; 56(8): 912–921, doi: 10.1097/00005072-199708000-00009, indexed in Pubmed: 9258261.
  • 35. Nakano N, Matsuda S, Ichimura M, et al. PI3K/AKT signaling mediated by G protein‑coupled receptors is involved in neurodegenerative Parkinson’s disease (Review). Int J Mol Med. 2017; 39(2): 253–260, doi: 10.3892/ijmm.2016.2833, indexed in Pubmed: 28000847.
  • 36. Ou HC, Chou FP, Lin TM, et al. Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells. Chem Biol Interact. 2006; 161(1): 1–13, doi: 10.1016/j.cbi.2006.02.006, indexed in Pubmed: 16580656.
  • 37. Özevren H, Irtegün S, Deveci E, et al. Neuroprotective effects of Potentilla fulgens on traumatic brain injury in rats. Anal Quant Cytol Histol. 2017; 39: 35–44.
  • 38. Preston GW, Phillips DH. Quantification of a peptide standard using the intrinsic fluorescence of tyrosine. Anal Bioanal Chem. 2016; 408(9): 2187–2193, doi: 10.1007/s00216-016-9334-1, indexed in Pubmed: 26879647.
  • 39. Scheff SW, Price DA, Hicks RR, et al. Synaptogenesis in the hippocampal CA1 field following traumatic brain injury. J Neurotrauma. 2005; 22(7): 719–732, doi: 10.1089/neu.2005.22.719, indexed in Pubmed: 16004576.
  • 40. Shultz SR, McDonald SJ, Vonder Haar C, et al. The potential for animal models to provide insight into mild traumatic brain injury: Translational challenges and strategies. Neurosci Biobehav Rev. 2017; 76(Pt B): 396–414, doi: 10.1016/j.neubiorev.2016.09.014, indexed in Pubmed: 27659125.
  • 41. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010; 119(1): 7–35, doi: 10.1007/s00401-009-0619-8, indexed in Pubmed: 20012068.
  • 42. Sohrab G, Angoorani P, Tohidi M, et al. Pomegranate (Punicagranatum) juice decreases lipid peroxidation, but has no effect on plasma advanced glycated end-products in adults with type 2 diabetes: a randomized double-blind clinical trial. Food Nutr Res. 2015; 59: 28551, doi: 10.3402/fnr.v59.28551, indexed in Pubmed: 26355954.
  • 43. Stroop R, Thomale UW, Päuser S, et al. Magnetic resonance imaging studies with cluster algorithm for characterization of brain edema after controlled cortical impact injury (CCII). Acta Neurochir Suppl. 1998; 71: 303–305, indexed in Pubmed: 9779214.
  • 44. Sulakhiya K, Kumar P, Gurjar SS, et al. Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice. Pharmacol Biochem Behav. 2015; 132: 79–87, doi: 10.1016/j.pbb.2015.02.015, indexed in Pubmed: 25725264.
  • 45. Talarek S, Listos J, Barreca D, et al. Neuroprotective effects of honokiol: from chemistry to medicine. Biofactors. 2017; 43(6): 760–769, doi: 10.1002/biof.1385, indexed in Pubmed: 28817221.
  • 46. Ucar T, Tanriover G, Gurer I, et al. Modified experimental mild traumatic brain injury model. J Trauma. 2006; 60(3): 558–565, doi: 10.1097/01.ta.0000209172.75637.db, indexed in Pubmed: 16531854.
  • 47. Wang H, Liao Z, Sun X, et al. Intravenous administration of Honokiol provides neuroprotection and improves functional recovery after traumatic brain injury through cell cycle inhibition. Neuropharmacology. 2014; 86: 9–21, doi: 10.1016/j.neuropharm.2014.06.018, indexed in Pubmed: 24973706.
  • 48. Wang X, Duan X, Yang G, et al. Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One. 2011; 6(4): e18490, doi: 10.1371/journal.pone.0018490, indexed in Pubmed: 21559510.
  • 49. Xu Q, Yi LT, Pan Y, et al. Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(3): 715–725, doi: 10.1016/j.pnpbp.2007.11.020, indexed in Pubmed: 18093712.
  • 50. Yuan TM, Yu HM, Gu WZ, et al. Expression of glial fibrillary acidic protein in developing rat brain after intrauterine infection. Neuropathology. 2004; 24(2): 136–143, indexed in Pubmed: 15139591.
  • 51. Zhang Le, Deng M, Zhou S. Tetramethylpyrazine inhibits hypoxia-induced pulmonary vascular leakage in rats via the ROS-HIF-VEGF pathway. Pharmacology. 2011; 87(5-6): 265–273, doi: 10.1159/000326082, indexed in Pubmed: 21494058.
  • 52. Zhang P, Liu X, Zhu Y, et al. Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-kB activation and cytokine production of glial cells. Neurosci Lett. 2013; 534: 123–127, doi: 10.1016/j.neulet.2012.11.052, indexed in Pubmed: 23262090.
  • 53. Zhou PH, Hu W, Zhang XB, et al. Protective Effect of Adrenomedullin on Rat Leydig Cells from Lipopolysaccharide-Induced Inflammation and Apoptosis via the PI3K/Akt Signaling Pathway ADM on Rat Leydig Cells from Inflammation and Apoptosis. Mediators Inflamm. 2016; 2016: 7201549, doi: 10.1155/2016/7201549, indexed in Pubmed: 27212810.

Typ dokumentu



Identyfikator YADDA

JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.