Hesperidin Ameliorates Anxiety-Depressive-Like Behavior in 6-OHDA Model of Parkinson’s Disease by Regulating Striatal Cytokine and Neurotrophic Factors Levels and Dopaminergic Innervation Loss in the Striatum of Mice


The mechanisms underlying the neuroprotective effects of hesperidin in a murine model of PD are not fully elucidated. The current study was carried out to investigate the ability of hesperidin in modulating proinflammatory cytokines, neurotrophic factors, and neuronal recovery in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic neuronal loss. Adult male C57BL/6 mice were randomly assigned into four groups: (I) sham/vehicle, (II) sham/hesperidin, (III) 6-OHDA/vehicle, and (IV) 6-OHDA/hesperidin. Mice received a unilateral intrastriatal injection of 6-OHDA and treated with hesperidin (50 mg/kg; per oral) for 28 days. After hesperidin treatment, mice were submitted to behavioral tests and had the striatum removed for neurochemical assays. Our results demonstrated that oral treatment with hesperidin ameliorated the anxiety-related and depressive-like behaviors in 6-OHDA-lesioned mice (p < 0.05). It also attenuated the striatal levels of proinflammatory cytokines tumor necrosis factor-α, interferon-gamma, interleukin-1β, interleukin-2, and interleukin-6 and increased the levels of neurotrophic factors, including neurotrophin-3, brain-derived neurotrophic factor, and nerve growth factor in the striatum of 6-OHDA mice (p < 0.05). Hesperidin treatment was also capable to increase striatal levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid and protects against the impairment of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (p < 0.05). In conclusion, this study indicated that hesperidin exerts anxiolytic-like and antidepressant-like effect against 6-OHDA-induced neurotoxicity through the modulation of cytokine production, neurotrophic factors levels, and dopaminergic innervation in the striatum.

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Brain-derived neurotrophic factor




3,4-dihydroxyphenylacetic acid


Elevated plus-maze test


Glial cell-derived neurotrophic factor


Homovanillic acid












Nerve growth factor




Open field test


Parkinson’s disease


Tyrosine hydroxylase


Tumor necrosis factor-alpha


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The authors are grateful for the financial support by FAPERGS, CNPQ, and CAPES. LCS is recipient by CNPq fellowship (150560/2019-2) and VCB, MRPS, and SMA are recipient by CAPES fellowship (Finance code 001). We would like to thank Professor Cristiano Ricardo Jesse for the study design, interpretation of the data, and for providing their thoughts and his contribution to the development of the experiments.


This study was financial supported by FAPERGS Research Grants No.16/2551-0000526-5 (PRONUPEQ) and No. 16/2251-0000183-9 (ARD/PPP).

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MSA carried out the experiments and wrote the manuscript. FVLL, AABLL and ALM carried out the experiments. VCB, MRPS and SMA performed behavioral studies and carried out experiments. LCS, participated in the design of the study and experiments, wrote and reviewed the manuscript. MP, CWN and SPB conceived of and participated in the design of the study and reviewed the manuscript. All authors read and approved of the final manuscript.

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Correspondence to Leandro Cattelan Souza.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Specifically, all experiments in the present study were approved by Ethical Committee for Animal Use (CEUA protocol No. 001/2013) of the Federal University of Pampa, Brazil.

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Antunes, M.S., Cattelan Souza, L., Ladd, F.V.L. et al. Hesperidin Ameliorates Anxiety-Depressive-Like Behavior in 6-OHDA Model of Parkinson’s Disease by Regulating Striatal Cytokine and Neurotrophic Factors Levels and Dopaminergic Innervation Loss in the Striatum of Mice. Mol Neurobiol 57, 3027–3041 (2020). https://doi.org/10.1007/s12035-020-01940-3

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  • Dopamine
  • Flavonoid
  • Inflammation, neurodegeneration
  • Neurotrophins