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Succinobucol, a Non-Statin Hypocholesterolemic Drug, Prevents Premotor Symptoms and Nigrostriatal Neurodegeneration in an Experimental Model of Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by non-motor and motor disabilities. This study investigated whether succinobucol (SUC) could mitigate nigrostriatal injury caused by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. Moreover, the effects of SUC against MPTP-induced behavioral impairments and neurochemical changes were also evaluated. The quantification of tyrosine hydroxylase-positive (TH+) cells was also performed in primary mesencephalic cultures to evaluate the effects of SUC against 1-methyl-4-phenylpyridinium (MPP+) toxicity in vitro. C57BL/6 mice were treated with SUC (10 mg/kg/day, intragastric (i.g.)) for 30 days, and thereafter, animals received MPTP infusion (1 mg/nostril) and SUC treatment continued for additional 15 days. MPTP-infused animals displayed significant non-motor symptoms including olfactory and short-term memory deficits evaluated in the olfactory discrimination, social recognition, and water maze tasks. These behavioral impairments were accompanied by inhibition of mitochondrial NADH dehydrogenase activity (complex I), as well as significant decrease of TH and dopamine transporter (DAT) immunoreactivity in the substantia nigra pars compacta and striatum. Although SUC treatment did not rescue NADH dehydrogenase activity inhibition, it was able to blunt MPTP-induced behavioral impairments and prevented the decrease in TH and DAT immunoreactivities in substantia nigra (SN) and striatum. SUC also suppressed striatal astroglial activation and increased interleukin-6 levels in MPTP-intoxicated mice. Furthermore, SUC significantly prevented the loss of TH+ neurons induced by MPP+ in primary mesencephalic cultures. These results provide new evidence that SUC treatment counteracts early non-motor symptoms and neurodegeneration/neuroinflammation in the nigrostriatal pathway induced by intranasal MPTP administration in mice by modulating events downstream to the mitochondrial NADH dehydrogenase inhibition.

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Acknowledgments

The authors gratefully thank the financial support and grants provided by the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and CAPES-COFECUB (France/Brazil; 681/2010). RRV and PPM were supported by program Investissements d’avenir ANR-10-IAIHU-06.

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Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP 88040-900, Florianópolis, Santa Catarina, Brazil

    Danúbia Bonfanti Santos, Dirleise Colle, Mariana Appel Hort & Marcelo Farina

  2. Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil

    Eduardo Luiz Gasnhar Moreira

  3. Escola de Química e Alimentos, Universidade Federal de Rio Grande, Campus Santo Antônio da Patrulha, Rio Grande do Sul, Brazil

    Marcelo Godoi

  4. Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France

    Gael Le Douaron, Patrick Pierre Michel & Rita Raisman-Vozari

  5. Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil

    Antonio Luiz Braga

  6. Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil

    Jamil Assreuy & Rui Daniel Prediger

Authors
  1. Danúbia Bonfanti Santos
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  2. Dirleise Colle
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  3. Eduardo Luiz Gasnhar Moreira
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  4. Mariana Appel Hort
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  5. Marcelo Godoi
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  6. Gael Le Douaron
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  7. Antonio Luiz Braga
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  9. Patrick Pierre Michel
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  11. Rita Raisman-Vozari
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  12. Marcelo Farina
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Corresponding authors

Correspondence to Danúbia Bonfanti Santos or Marcelo Farina.

Ethics declarations

The procedures used in the present study were approved by the Committee of Ethics for the Use of Animals—Universidade Federal de Santa Catarina (CEUA/UFSC; PP00546). Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996), European Directive 86/609, and the National Institutes of Health (NIH) publication “Principles of Laboratory Animal Care.”

Conflict of Interest

The authors have no financial or personal conflict of interest related to this study.

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Supplemental Figure 1

Scheme of in vivo experimental protocols. A) Experimental protocol 1; B) Experimental protocol 2 and C) Experimental protocol 3. (GIF 24 kb)

High resolution image (TIF 5270 kb)

Supplemental Figure 2

Effects of succinobucol and/or MPTP treatment on tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum. (A) Representative images of TH immunostaining in the striatum (scale bar = 2 mm). (B) Relative quantification of the optical density TH in striatum of mice. (C) TH protein content measured by Western Blot analysis. (D) Representative images of DAT immunostaining in the striatum (scale bar = 500 μm). (E) Relative quantification of the optical density DAT neurons in striatum of mice. Values represent the mean ± SEM (n = 5 animals/group). *p < 0.05; ***p < 0.001 compared to the control group; #p < 0.05; ###p < 0.001 compared to the MPTP group (two-way ANOVA followed by Newman- Keuls test). (GIF 8 kb)

High resolution image (TIF 4688 kb)

Supplemental Figure 3

Effects of succinobucol (10 mg/kg/day, i.g.; during 45 consecutive days) on glial fibrillary acidic protein (GFAP) in the striatum evaluated through immunohistochemistry 15 days after i.n. infusion of control (saline) or MPTP (1 mg/nostril). (A) Representative images of GFAP immunostaining in the striatum (scale bar = 2 mm). (B) Relatives quantifications of the GFAP optical densities in striatum. Values represent the mean ± SEM (n = 5 animals/group). ***p < 0.001 compared to the control group; ##p < 0.01, compared to the MPTP group (two-way ANOVA followed by Newman- Keuls test). (GIF 2 kb)

High resolution image (TIF 1038 kb)

Supplementary table 1

Succinobucol (SUC) reduces plasma cholesterol levels in mice. Animals were treated with SUC and/or MPTP according to Supplemental Figure 1. Plasma cholesterol levels are expressed as mg/dL and presented as mean ± S.E.M. (n = 6-7 mice/group). **p < 0.01 compared to the control group; ##p < 0.01, compared to the MPTP group (two-way ANOVA followed by Newman- Keuls test). (DOCX 14 kb)

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Santos, D.B., Colle, D., Moreira, E.L.G. et al. Succinobucol, a Non-Statin Hypocholesterolemic Drug, Prevents Premotor Symptoms and Nigrostriatal Neurodegeneration in an Experimental Model of Parkinson’s Disease. Mol Neurobiol 54, 1513–1530 (2017). https://doi.org/10.1007/s12035-016-9747-z

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