Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice. (22nd January 2015)

• Record Type: Journal Article
• Authors: Santos, D.B.; Colle, D.; Moreira, E.L.G.; Peres, K.C.; Ribeiro, R.P.; dos Santos, A.A.; de Oliveira, J.; Hort, M.A.; de Bem, A.F.; Farina, M.
• Is Part Of: Neuroscience. Volume 284(2015)
• Page Start: 590
• Page End: 600
• Publication Date: 2015-01-22
• Subjects: AChE acetylcholinesterase -- aCSF artificial cerebral spinal fluid -- AD Alzheimer's disease -- APP amyloid precursor protein -- ANOVA analysis of variance -- BACE β-secretase -- CAT catalase -- CSF cerebral spinal fluid -- DTNB 5, 5′-Dithiobis(2-nitrobenzoic acid) -- EDTA ethylenediaminetetraacetic acid -- GPx glutathione peroxidase -- GR glutathione reductase -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- NADPH β-Nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate -- NPSH non-protein thiol -- SOD superoxide dismutase -- STZ streptozotocin; probucol -- streptozotocin -- cognitive impairment; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2014.10.019
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: i.c.v. STZ increased hippocampal BACE levels, AChE activity and oxidative stress. i.c.v. STZ caused cognitive impairment in mice. Probucol prevented STZ-induced cognitive impairment and hippocampal oxidative stress. Probucol protection was independent of modulatory effects on hippocampal BACE levels. 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.