Silybin Attenuates Neurobehavioural Impairments and Secondary Brain Damage Following Traumatic Brain Injury in Mice
Abstract
Background/Aim: Traumatic brain injury (TBI) is a neurodegenerative disorder resulting in temporary or permanent impairment of cognitive, physical and psychosocial functions. Presently no treatment is available to overcome TBI. Flavonoids can be utilised for treatment of TBI due to their anti-oxidant and anti-inflammatory potential. Aim of this study was to investigate the neuroprotective potential of silybin against secondary cascade of TBI.
Methods: TBI induced by weight drop model of trauma has been utilised to assess the neuroprotective effect of silybin at the doses 50 mg/kg and 100 mg/kg in mice. After 30 min of injury, silybin was administered. The effect of silybin was observed on neurobehaviour (Morris’s water maze test, beam walk and beam balance), blood brain barrier permeability (BBB), brain oedema and mitochondrial dysfunction after 24 h and 21 days of drug administration. The study of interaction of silybin with N-methyl-D-aspartate receptors (NMDARs) by using PDB: 3QEL was evaluated by molecular docking.
Results: Silybin significantly improved the neurological behaviours such as motor coordination and learning and memory. Silybin significantly decreased the BBB permeability, brain oedema and mitochondrial dysfunction. Molecular docking studies showed the significant interactions of silybin with target residues MET 207, THR174, TYR175, PHE 176, PRO177, GLU236,THR233, GLU106, ALA107, GLN110, ASP136, ALA135, MET134 of PDB: 3QEL.
Conclusion: Silybin provides novel insights into the neuroprotective and therapeutic potential for TBI.
References
Johnston AJ, Gupta AK. Advanced monitoring in the neurology intensive care unit: microdialysis. Curr Opin Crit Care. 2002;8:121-7. doi: 10.1097/00075198-200204000-00006.
Arciniegas DB, Anderson CA, Topkoff J, McAllister TW. Mild traumatic brain injury: a neuropsychiatric approach to diagnosis, evaluation, and treatment. Neuropsychiatr Dis Treat. 2005;1(4):311-27. PMID:18568112.
Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci. 2010;31(12):596-604. doi: 10.1016/j.tips.2010.09.005.
Yakovlev AG, Ota K, Wang G, Movsesyan V, Bao WL, Yoshihara K, Faden AI. Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury. J Neurosci. 2001;21(19):7439-46. doi: 10.1523/JNEUROSCI.21-19-07439.2001.
Liu P, Wang C, Chen W, Kang Y, Liu W, Qiu Z, et al. Inhibition of GluN2B pathway is involved in the neuroprotective effect of silibinin on streptozotocin-induced Alzheimer's disease models. Phytomedicine. 2023;109:154594. doi: 10.1016/j.phymed.2022.154594.
El Fadili M, Er-rajy M, Imtara H, Kara M, Zarougui S, Altwaijry N, et al. 3D-QSAR, ADME Tox in silico prediction and molecular docking studies for modeling the analgesic activity against neuropathic pain of novel NR2B-selective NMDA receptor antagonists. Processes. 2022;10(8):1462. doi: 10.1016/j.heliyon.2023.e13706.
Liu X, Liu W, Wang C, Chen Y, Liu P, Hayashi T, et al. Silibinin attenuates motor dysfunction in a mouse model of Parkinson's disease by suppression of oxidative stress and neuroinflammation along with promotion of mitophagy. Physiol Behav. 2021;239:113510. doi: 10.1016/j.physbeh.2021.113510.
Ranjan S, Gautam A. Pharmaceutical prospects of silymarin for the treatment of neurological patients: an updated insight. Front Neurosci. 2023;17:1159806. doi: 10.3389/fnins.2023.1159806.
Xu X, Yu J, Cao X, Zhu Y. Formulation of silibinin with high efficacy & prolonged action & preparation method. US patent 9,023,388 B2. 2015 May 5.
Amoabediny G, Ochi MM, Ochi SM, Rezayat SM, Akbarzadeh A, Ebrahimi B. Targeted nano-liposome co-entraping anti-cancer drugs. US patent 9,855,216 B2. 2018 Jan 2.
Liu CH, Jassey A, Hsu HY, Lin LT. Antiviral activities of silymarin and derivatives. Molecules. 2019;24(8):1552. doi: 10.3390/molecules24081552.
Shukla S, Sharma S, Vasudeva N, Hooda T. Ameliorative effect of cichoric acid against diabetes associated cognitive decline with emphasis on neurobehavioral activity, Aβ and AChE. Indian J Pharm Educ Res. 2024;58(2):595-602. doi: 10.5530/ijper.58.2.66.
Desai A, Chen H, Kim HY. Multiple mild traumatic brain injuries lead to visual dysfunction in a mouse model. J Neurotrauma. 2020;37(2):286-94. doi: 10.1089/neu.2019.6602.
Chen C, Hou J, Lu J, Zhu Z, Yang Y, Peng W, et al. A novel simple traumatic brain injury mouse model. Chin Neurosurg J. 2022;8(3):151-9. doi: 10.1186/s41016-022-00273-5.
Oufi HG, Al Shawi NN. The effects of different doses of silibinin in combination with methotrexate on testicular tissue of mice. Eur J Pharmacol. 2014;730:36-40. doi: 10.1016/j.ejphar.2014.02.010.
Marmarou CR, Prieto R, Taya K, Young HF, Marmarou A. Marmarou weight drop injury model. In: Animal Models of Acute Neurological Injuries. 2009:393-407. doi: 10.1007/978-1-60327-185-1_34.
Zhao L, Wang JL, Liu R, Li XX, Li JF, Zhang L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules. 2013;18(8):9949-65. doi: 10.3390/molecules18089949.
Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid haemorrhage rat model. J Neurosci Methods. 2008;167:327-34. doi: 10.1016/j.jneumeth.2007.08.004.
Wang C, Wang Z, Zhang X, Zhang X, Dong L, Xing Y, et al. Protection by silibinin against experimental ischemic stroke: up-regulated pAkt, pmTOR, HIF 1α and Bcl 2, down regulated Bax, NF κB expression. Neurosci Lett. 2012;529(1):45-50. doi: 10.1016/j.neulet.2012.08.078.
Manaenko A, Chen H, Kammer J, Zhang JH, Tang J. Comparison Evans blue injection routes: intravenous versus intraperitoneal, for measurement of blood–brain barrier in a mice hemorrhage model. J Neurosci Methods. 2011;195(2):206-10. doi: 10.1016/j.jneumeth.2010.12.013.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8. doi: 10.1016/0003-2697(79)90738-3.
Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47(2):389-94. doi: 10.1016/0003-2697(72)90132-7.
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70-7. doi: 10.1016/0003-9861(59)90090-6.
Berman SB, Hastings TG. Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem. 1999;73:1127-1137. doi: 10.1046/j.1471-4159.1999.0731127.x.
King TE, Howard RL. Preparations and properties of soluble NADH dehydrogenases from cardiac muscle. Methods Enzymol. 1967;10:275-94. doi: 10.1016/0076-6879(67)10055-4.
King TE. Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. Methods Enzymol. 1967;10:322-31. doi: 10.1016/0076-6879(67)10061-X.
Sottocasa GL, Kuylenstierna B, Ernster L, Bergstrand A. An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol. 1967;32:415-38. doi: 10.1083/jcb.32.2.415.
Kom HH, Nageshwar M, Srilatha K, Reddy KP. Protective effect of quercetin on weight drop injury model induced neuroinflammation alterations in brain of mice. J Appl Pharm Sci. 2019;9(4):96-103. doi: 10.7324/JAPS.2019.90412.
Hemlata, Sharma S, Vasudeva N, Hooda T. Neuroprotective effects of oleanolic acid against secondary cascades of traumatic brain injury in mice. Brain Disord. 2024;16:100173. doi: 10.1016/j.dscb.2024.100173.
Parvesh, Kumar S, Singh G, Khatri R, Sharma S, Lather A, et al. Neuroprotective role of ranolazine: ESR1 and NMDA receptor agonist in traumatic brain injury in Drosophila melanogaster, in silico and in vivo correlation. Indian J Neurotrauma. 2024;22(1). doi: 10.1055/s-0044-1795153.
Shukla S, Sharma S, Vasudeva N, Hooda T. Danshensu attenuates diabetes associated cognitive dysfunction by markedly reversing oxidative stress, Aβ and AChE activity. Indian J Pharm Educ Res. 2024;58(2):503-9. doi: 10.5530/ijper.58.2.56.
Hooda T, Sharma S, Vasudeva N. In silico designing, synthesis, SAR and microbiological evaluation of novel amide derivatives of 2-(3-methylbenzo[b]thiophen-6-yl)-1-(3 nitrophenyl)-1H benzo[d]imidazole 5 carboxylic acid. Indian J Pharm Educ Res. 2019;53(3 Suppl 2):s437-s450. doi: 10.5530/ijper.53.3s.117.
Hooda T, Sharma S, Goyal N. Synthesis, in silico designing, microbiological evaluation and structure activity relationship of novel amide derivatives of 1-(2,4 dinitrophenyl)-2-(3 methylbenzo[b]thiophen-6 yl)-1H benzo[d]imidazole 5 carboxylic acid. Polycyclic Aromat Comp. 2022;42(6):3361-76. doi: 10.1080/10406638.2020.1869793.
Hooda T, Sharma S, Goyal N. Synthesis, in silico designing, SAR and microbiological evaluation of novel amide derivatives of 1-(4 nitrophenyl)-2-(3 methylbenzo[b]thiophen-6 yl)-1H benzo[d]imidazole 5 carboxylic acid. Indian J Pharm Educ Res. 2020;54(2):471-83. doi: 10.5530/ijper.54.2.54.
Bhardwaj A, Nayan V, Sharma P, Kumar S, Pal Y, Singh J. Molecular characterization, modeling, in silico analysis of equine pituitary gonadotropin alpha subunit and docking interaction studies with ganirelix. In Silico Pharmacol. 2017;6:1-3. doi: 10.1007/s40203-017-0025-1.
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