title: Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. Although AD is the most prevalent aging-related neurodegenerative disease, therapeutic strategies remain palliative. Recent studies have shown that probucol presents neuroprotective effects in experimental models of neurodegenerative disease. The present study aimed to investigate the potential protective effects of probucol against streptozotocin (STZ)-induced cognitive impairment and hippocampal biochemical changes (oxidative stress-related parameters, acetylcholinesterase (AChE) activity, cholesterol levels and β-secretase (BACE) protein levels) in mice. Adult Swiss mice received STZ [150 μg/bilateral, i.c.v.], and treated daily with probucol (≅10 mg/kg/day, in drinking water, for 5 weeks,). Twenty-one days after i.c.v. administrations, STZ-infused animals displayed significant deficits in cognition (evaluated in the displaced and new object recognition tasks), which were paralleled by a significant increase in hippocampal AChE activity. Moreover, STZ-infused mice showed increased levels of BACE and decreased glutathione reductase (GR) activity in the hippocampus compared with the control group. Probucol treatment significantly protected against the behavioral and hippocampal biochemical changes induced by STZ. However, it was unable to prevent STZ-induced increase of hippocampal BACE levels and did not change hippocampal cholesterol levels. It is noteworthy that probucol treatment increased the glutathione peroxidase (GPx) activity per se independent of STZ injection. The present findings are the first to show that i.c.v. STZ infusions are able to increase hippocampal BACE expression. Moreover, the results also show that probucol can counteract STZ-induced cognitive impairments and biochemical parameters independently of potential modulator effects toward BACE levels. The study is the first to report the protective effects of probucol against STZ-induced biochemical hippocampal changes and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil. Electronic address: danubiabonfanti@hotmail.com.
authors.forename: D B
authors.initials: DB
authors.lastname: Santos
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Colle
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: E L G
authors.initials: ELG
authors.lastname: Moreira
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: K C
authors.initials: KC
authors.lastname: Peres
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: R P
authors.initials: RP
authors.lastname: Ribeiro
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: A A
authors.initials: AA
authors.lastname: Dos Santos
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: de Oliveira
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Hort
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: A F
authors.initials: AF
authors.lastname: de Bem
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil. Electronic address: marcelo.farina@ufsc.br.
authors.forename: M
authors.initials: M
authors.lastname: Farina
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000284:Administration, Oral; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011341:Probucol / Q000494:pharmacology*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin
chemical_list: D000975:Antioxidants; D018697:Nootropic Agents; D013311:Streptozocin; D002784:Cholesterol; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D011341:Probucol
keywords: cognitive impairment; probucol; streptozotocin