title: Succinobucol, a Non-Statin Hypocholesterolemic Drug, Prevents Premotor Symptoms and Nigrostriatal Neurodegeneration in an Experimental Model of Parkinson's Disease.
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.
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP 88040-900, Florianópolis, Santa Catarina, Brazil. danubiabonfanti1@gmail.com.
authors: Danúbia Bonfanti
authors: DB
authors: Santos
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors: Dirleise
authors: D
authors: Colle
authors: Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors: Eduardo Luiz Gasnhar
authors: EL
authors: Moreira
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors: Mariana Appel
authors: MA
authors: Hort
authors: Escola de Química e Alimentos, Universidade Federal de Rio Grande, Campus Santo Antônio da Patrulha, Rio Grande do Sul, Brazil.
authors: Marcelo
authors: M
authors: Godoi
authors: Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors: Gael
authors: G
authors: Le Douaron
authors: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors: Antonio Luiz
authors: AL
authors: Braga
authors: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors: Jamil
authors: J
authors: Assreuy
authors: Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors: Patrick Pierre
authors: PP
authors: Michel
authors: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors: Rui Daniel
authors: RD
authors: Prediger
authors: Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors: Rita
authors: R
authors: Raisman-Vozari
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP 88040-900, Florianópolis, Santa Catarina, Brazil. marcelo.farina@ufsc.br.
authors: Marcelo
authors: M
authors: Farina
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012903:Smell / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000924:Anticholesteremic Agents; C471047:succinobucol; D011341:Probucol
keywords: Intranasal MPTP; Neurodegeneration; Parkinson’s disease; Succinobucol