Hesperidin protects against behavioral alterations and loss of dopaminergic neurons in 6-OHDA-lesioned mice: the role of
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ORIGINAL ARTICLE
Hesperidin protects against behavioral alterations and loss of dopaminergic neurons in 6-OHDA-lesioned mice: the role of mitochondrial dysfunction and apoptosis Michelle S. Antunes 1 & Fernando Vagner Lobo Ladd 2 & Aliny Antunes Barbosa Lobo Ladd 3 & Amanda Lopez Moreira 3 & Silvana Peterini Boeira 1 & Leandro Cattelan Souza 1 Received: 7 April 2020 / Accepted: 14 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Hesperidin is a flavonoid glycoside that is frequently found in citrus fruits. Our group have demonstrated that hesperidin has neuroprotective effect in 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD), mainly by antioxidant mechanisms. Although the pathophysiology of PD remains uncertain, a large body of evidence has demonstrated that mitochondrial dysfunction and apoptosis play a critical role in dopaminergic nigrostriatal degeneration. However, the ability of hesperidin in modulating these mechanisms has not yet been investigated. In the present study, we examined the potential of a 28-day hesperidin treatment (50 mg/kg/day, p.o.) in preventing behavioral alterations induced by 6-OHDA injection via regulating mitochondrial dysfunction, apoptosis and dopaminergic neurons in the substantia nigra pars compacta (SNpc) in C57BL/6 mice. Our results demonstrated that hesperidin treatment improved motor, olfactory and spatial memory impairments elicited by 6-OHDA injection. Moreover, hesperidin treatment attenuated the loss of dopaminergic neurons (TH+ cells) in the SNpc and the depletion of dopamine (DA) and its metabolities 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of 6-OHDA-lesioned mice. Hesperidin also protected against the inhibition of mitochondrial respiratory chain complex-I, -IV and V, the decrease of Na + -K + ATPase activity and the increase of caspase-3 and -9 activity in the striatum. Taken together, our findings indicate that hesperidin mitigates the degeneration of dopaminergic neurons in the SNpc by preventing mitochondrial dysfunction and modulating apoptotic pathways in the striatum of 6-OHDA-treated mice, thus improving behavioral alterations. These results provide new insights on neuroprotective mechanisms of hesperidin in a relevant preclinical model of PD. Keywords Apoptosis . Dopaminergic neurons . Flavonoid . Mitochondrial dysfunction . Parkinson’s disease
Introduction Parkinson’s disease (PD) is the second most common agerelated neurodegenerative disorder, after Alzheimer’s disease. PD is characterized by a progressive degeneration of * Leandro Cattelan Souza [email protected] 1
Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, RS CEP 97650-000, Brazil
2
Department of Morphology/Laboratory of Neuroanatom, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
3
Laboratory of Stochastic Stereology and Chemical Anatomy, Department of Surgery, College of Ve
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