Skip to main content

Advertisement

SpringerLink
Log in

Cerebroprotective Potential of Hesperidin Nanoparticles Against Bilateral Common Carotid Artery Occlusion Reperfusion Injury in Rats and In silico Approaches

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Cerebral ischemia-reperfusion (C I/R) accelerates neuronal injury through the overproduction of reactive oxygen species due to mitochondrial dysfunction. Hesperidin has cerebroprotective effects due to its antioxidant and anti-apoptotic nature against oxidative damage caused by C I/R. The blood-brain barrier also limits the hesperidin passage into the cerebral region due to its poor bioavailability. Current research included analysis of binding energy, hesperidin inhibitory constant on inflammatory cytokines (TNF α, IL 6) and apoptotic protein (caspase 3), hesperidin nanoparticles prepared, and investigation of their defense against C I/R rats. Binding energy and IC50 of hesperidin on pathological proteins using AutoDoc. 1.5.6 and PyRx in silico tools were compared with thalidomide. The fabrication method was engaged in the preparing of nano-hesperidin, characterized by SEM assessment. Bilateral common carotid artery occlusion technique has been used in experimental rats to cause C I/R. Nano-hesperidin cerebroprotective activity was assessed by differing infarction magnitude, oxidative stress parameters, TNF α and IL 6, and hippocampal histopathology with rats treated with unformulated hesperidin. Hesperidin found stronger binding strength and IC50 was relative to thalidomide on TNF α, IL 6, and caspase 3. Nano-hesperidin with a size of 100–500 nm was shown in a uniform nano-size and spherical form. Nano-hesperidin-treated rats showed significantly increased glutathione (p < 0.00***), catalase (p < 0.01**), and total protein (p < 0.001***), and decreased cerebral infarction size, TNF α (p < 0.01**), IL 6 (p < 0.01**), and malondialdehyde (p < 0.05*), compared with hesperidin-treated ischemic rats. Therefore, hesperidin nanoparticles may confer protection to the neurons against ischemic injury compared with hesperidin treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ali SH, Sulaiman GM, Al-Halbosiy MM, Jabir MS, Hameed AH (2019) Fabrication of hesperidin nanoparticles loaded by poly lactic co-glycolic acid for improved therapeutic efficiency and cytotoxicity. Artif Cell Nanomed Biotechnol 47(1):378–394

    CAS  Google Scholar 

  • Aydogmus E, Gul S, Bahadir B (2019) Neuroprotective effects of hesperidin on cerebral vasospasm after experimental subarachnoid hemorrhage in rats: biochemical, pathologic, and histomorphometric analysis. World Neurosurg 122:e1332–e1337

    PubMed  Google Scholar 

  • Bederson JB, Pitts LH, Tsuji M (1996) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17(3):472–476

    Google Scholar 

  • Cao W, Carney JM, Duchon A, Floyd RA, Chevion M (1988) Oxygen free radical involvement in ischemia and reperfusion injury to brain. Neurosci Lett 88(2):233–238

    CAS  PubMed  Google Scholar 

  • Castigli E, Arcuri C, Giovagnoli L (2000) Interleukin-1β induces apoptosis in GL15 glioblastoma derived human cell line. Am J Phys Cell Phys 279(6):C2043–C2049

    CAS  Google Scholar 

  • Chamorro A, Dirnagl U, Urra X, Planas AM (2016) Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15(8):869–881

    CAS  PubMed  Google Scholar 

  • Chandrashekhar VM, Ranpariya VL, Ganapaty S, Parashar A, Muchandi AA (2010) Neuroprotective activity of Matricaria recutita Linn against global model of ischemia in rats. J Ethnopharmacol 127(3):645–651

    CAS  PubMed  Google Scholar 

  • Cho J (2006) Antioxidant and neuroprotective effects of hesperidin and its aglycone hesperetin. Arch Pharm Res 29(8):699–706

    CAS  PubMed  Google Scholar 

  • Coyle P, Panzenbeck MJ (1990) Collateral development after carotid artery occlusion in Fischer 344 rats. Stroke 21(2):316–321

    CAS  PubMed  Google Scholar 

  • Dokoumetzidis A, Macheras PA (2006) Century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. Int J Pharm 32(1–2):1–1

    Google Scholar 

  • Doyle KP, Simon RP, Stenzel-Poore MP (2008) Mechanisms of ischemic brain damage. Neuropharmacology 55(3):310–318

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82(1):70–77

    CAS  Google Scholar 

  • Garg A, Garg S, Zaneveld LJ, Singla AK (2001) Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 15(8):655–669

    CAS  PubMed  Google Scholar 

  • Greenwald RA (2018) Handbook methods for oxygen radical research. Boca Raton

  • Gupta R, Ghosh S (2017) Putative roles of mitochondrial voltage-dependent anion channel, Bcl-2 family proteins and c-Jun N-terminal kinases in ischemic stroke associated apoptosis. Biochim Open 4:47–55

    PubMed  PubMed Central  Google Scholar 

  • Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K (2014) Cell based in vitro blood–brain barrier model can rapidly evaluate nanoparticles’ brain permeability in association with particle size and surface modification. Int J Mol Sci 15(2):1812–1825

    PubMed  PubMed Central  Google Scholar 

  • Hartings JA, Tortella FC, Rolli ML (2006) AC electrocorticographic correlates of peri infarct depolarizations during transient focal ischemia and reperfusion. J Cereb Blood Flow Metab 26(5):696–707

    PubMed  Google Scholar 

  • Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM (2017) Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr Neurosci 20(6):360–368

    CAS  PubMed  Google Scholar 

  • Kakkar V, Muppu SK, Chopra K, Kaur IP (2013) Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biopharm 85(3):339–345

    CAS  PubMed  Google Scholar 

  • Kakran M, Sahoo GN, Li L (2015) Fabrication of nanoparticles of silymarin, hesperetin and glibenclamide by evaporative precipitation of nanosuspension for fast dissolution. Pharm Anal Acta 6(1):2

    Google Scholar 

  • Kesisoglou F, Panmai S, Wu Y (2007) Nanosizing oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 59(7):631–644

    CAS  PubMed  Google Scholar 

  • Khoshnam SE, Winlow W, Farzaneh M (2017a) The interplay of MicroRNAs in the inflammatory mechanisms following ischemic stroke. J Neuropathol Exp Neurol 76(7):548–561

    CAS  PubMed  Google Scholar 

  • Khoshnam SE, Winlow W, Farbood Y, Moghaddam HF, Farzaneh M (2017b) Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents. J Stroke 19(2):166–187

    PubMed  PubMed Central  Google Scholar 

  • Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF (2017c) Pathogenic mechanisms following ischemic stroke. Neurol Sci 38(7):1167–1186

    PubMed  Google Scholar 

  • Li C, Zug C, Qu H, Schluesener H, Zhang Z (2015) Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice. Behav Brain Res 281:32–42

    CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  • Maekawa S, Sato K, Fujita K, Daigaku R, Tawarayama H, Murayama N, Moritoh S, Yabana T, Shiga Y, Omodaka K, Maruyama K (2017) The neuroprotective effect of hesperidin in NMDA-induced retinal injury acts by suppressing oxidative stress and excessive calpain activation. Sci Rep 7(1):6885

    PubMed  PubMed Central  Google Scholar 

  • Mahato SB, Kundu AP (1994) 13C NMR spectra of pentacyclic triterpenoids a compilation and some salient features. Phytochemistry 37(6):1517–1575

    CAS  Google Scholar 

  • Majumdar S, Srirangam R (2009) Solubility, stability, physicochemical characteristics and in vitro ocular tissue permeability of hesperidin: a natural bioflavonoid. Pharm Res 26(5):1217–1225

    CAS  PubMed  Google Scholar 

  • Moghaddam AH, Zare M (2018) Neuroprotective effect of hesperetin and nano hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer’s disease. Biomed Pharmacother 97:1096–1101

    Google Scholar 

  • Monforte MT, Trovato A, Kirjavainen S, Forestieri AM, Galati EM, Lo RC (1995) Biological effects of hesperidin, a Citrus flavonoid.(note II): hypolipidemic activity on experimental hypercholesterolemia in rat. Farmaco 50(9):595–599

    CAS  PubMed  Google Scholar 

  • Morimoto T, Globus MY, Busto R, Martinez E, Ginsberg MD (1996) Simultaneous measurement of salicylate hydroxylation and glutamate release in the penumbral cortex following transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 16(1):92–99

    CAS  PubMed  Google Scholar 

  • Nagy Z, Nardai S (2017) Cerebral ischemia/reperfusion injury: from bench space to bedside. Brain Res Bull 134:30–37

    CAS  PubMed  Google Scholar 

  • Nakashima M, Niwa M, Iwai T, Uematsu T (1999) Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat. Free Radic Biol Med 26(5–6):722–729

    CAS  PubMed  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    CAS  Google Scholar 

  • Quartu M, Serra MP, Boi M, Pillolla G, Melis T, Poddighe L, Del Fiacco M, Falconieri D, Carta G, Murru E, Cordeddu L (2012) Effect of acute administration of Pistacia lentiscus L. essential oil on rat cerebral cortex following transient bilateral common carotid artery occlusion. Lipids Health Dis 11(1):8

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raza SS, Khan MM, Ahmad A, Ashafaq M, Khuwaja G, Tabassum R, Javed H, Siddiqui MS, Safhi MM, Islam F (2011) Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res 1420:93–105

    CAS  PubMed  Google Scholar 

  • Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L (2016) Nanoparticle mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release 235:34–47

    CAS  PubMed  Google Scholar 

  • Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, Albers GW, Cognard C, Cohen DJ, Hacke W, Jansen O (2015) Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 372(24):2285–2295

    CAS  PubMed  Google Scholar 

  • Spuch C, Saida O, Navarro C (2012) Advances in the treatment of neurodegenerative disorders employing nanoparticles. Recent Pat Drug Deliv Formul 6(1):2–18

    CAS  PubMed  Google Scholar 

  • Sun AY, Chen YM (1998) Oxidative stress and neurodegenerative disorders. J Biomed Sci 5(6):401–414

    CAS  PubMed  Google Scholar 

  • Sun W, Depping R, Jelkmann W (2014) Interleukin-1β promotes hypoxia-induced apoptosis of glioblastoma cells by inhibiting hypoxia-inducible factor-1 mediated adrenomedullin production. Cell Death Dis 5(1):1020

    Google Scholar 

  • Tamilselvam K, Braidy N, Manivasagam T, Essa MM, Prasad NR, Karthikeyan S, Thenmozhi AJ, Selvaraju S, Guillemin GJ (2013) Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson’s disease. Oxidative Med Cell Longev 2013:11

    Google Scholar 

  • Thenmozhi AJ, Raja TR, Janakiraman U, Manivasagam T (2015) Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neuro Chem Res 40(4):767–776

    CAS  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuchiya M, Sako K, Yura S, Yonemasu Y (1993) Local cerebral glucose utilisation following acute and chronic bilateral carotid artery ligation in Wistar rats: relation to changes in local cerebral blood flow. Exp Brain Res 95(1):1–7

    CAS  PubMed  Google Scholar 

  • Viglino P, Scarpa M, Rotilio G, Rigo A (1988) A kinetic study of the reactions between H2O2 and Cu, Zn superoxide dismutase; evidence for an electrostatic control of the reaction rate. Biochtm Biophys Acta 952:77–82

    CAS  Google Scholar 

  • Yang JL, Mukda S, Chen SD (2018) Diverse roles of mitochondria in ischemic stroke. Redox Biol 16:263–275

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yanpallewar SU, Hota D, Rai S, Kumar M, Acharya SB (2004) Nimodipine attenuates biochemical, behavioral and histopathological alterations induced by acute transient and long-term bilateral common carotid occlusion in rats. Pharmacol Res 49(2):143–150

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to the DST Purse, Andhra University, Andhra, Pradesh, India, for SEM analysis.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Creative Educational Society’s College of Pharmacy, Kurnool, Andhra Pradesh, India

    P. Praveen Kumar, M. Kavya Nainita, A. Sai Tarun, B. G. Raghu Ramudu, K. Deepika, A. Pramoda & C. Yasmeen

  2. Shri Vishnu College of Pharmacy, Bhimavaram, Andhra Pradesh, India

    K. T. Sunil kumar

Authors
  1. P. Praveen Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. T. Sunil kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Kavya Nainita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Sai Tarun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. G. Raghu Ramudu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Deepika
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Pramoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Yasmeen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Praveen Kumar.

Ethics declarations

Experimental protocols were carried out with the approval of the Proposal Number of the Institutional Animal Ethics Committee: IAEC/CESCOP/AUG-18-05.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Praveen Kumar, P., Sunil kumar, K.T., Kavya Nainita, M. et al. Cerebroprotective Potential of Hesperidin Nanoparticles Against Bilateral Common Carotid Artery Occlusion Reperfusion Injury in Rats and In silico Approaches. Neurotox Res 37, 264–274 (2020). https://doi.org/10.1007/s12640-019-00098-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-019-00098-8

Keywords

Search

Navigation