Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease. Behav Brain Res

ArticleinBehavioural brain research 231(1):92-6 · March 2012with26 Reads
Impact Factor: 3.03 · DOI: 10.1016/j.bbr.2012.03.004 · Source: PubMed
Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficiency of branched-chain α-keto acid dehydrogenase complex leading to branched chain amino acids (BCAA) leucine, isoleucine, and valine accumulation as well as their corresponding transaminated branched-chain α-keto acids. MSUD patients present neurological dysfunction and cognitive impairment. Here, we investigated whether acute and chronic administration of a BCAA pool causes impairment of acquisition and retention of avoidance memory in young rats. We have used two administration protocols. Acute administration consisted of three subcutaneous administrations of the BCAA pool (15.8 μL/g body weight at 1-h intervals) containing 190 mmol/L leucine, 59 mmol/L isoleucine, and 69 mmol/L valine or saline solution (0.85% NaCl; control group) in 30 days old Wistar rats. Chronic administration consisted of two subcutaneous administrations of BCAA pool for 21 days in 7 days old Wistar rats. N-acetylcysteine (NAC; 20 mg/kg) and deferoxamine (DFX; 20 mg/kg) co administration influence on behavioral parameters after chronic BCAA administration was also investigated. BCAA administration induced long-term memory impairment in the inhibitory avoidance and CMIA (continuous multiple-trials step-down inhibitory avoidance) tasks whereas with no alterations in CMIA retention memory. Inhibitory avoidance alterations were prevented by NAC and DFX. BCAA administration did not impair the neuropsychiatric state, muscle tone and strength, and autonomous function evaluated with the SHIRPA (SmithKline/Harwell/ImperialCollege/RoyalHospital/Phenotype Assessment) protocol. Taken together, our results indicate that alterations of motor activity or emotionality probably did not contribute to memory impairment after BCAA administration and NAC and DFX effects suggest that cognition impairment after BCAA administration may be caused by oxidative brain damage.

    • "...ine and L-carnitine, have already successfully been used for the treatment of MSUD patients [21,24,25]. Taken into account this body of evidences, in the present study, we have investigated whether the ..."
      Moreover , a high BCAA concentration stimulates in vitro lipid peroxidation and reduces the antioxidant defenses in cerebral homogenates from young rats [22,23]. Consistently, compounds with antioxidant effects, as N-acetylcysteine and L-carnitine, have already successfully been used for the treatment of MSUD patients [21,24,25]. Taken into account this body of evidences, in the present study, we have investigated whether the electrical properties of cortical neurons exposed to high BCAA concentrations might be associated with altered ROS production.
    [Show abstract] [Hide abstract] ABSTRACT: L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes, and involved in some inherited rare diseases such as Maple Syrup Urine Disease. This pathology is caused by an altered BCAA metabolism with accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyse both whether high BCAA concentrations in neurons induce Reactive Oxygen Species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures a high dose of valine increases ROS production and provokes neuronal hyperexcitability, because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The pre-incubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators.
    Full-text · Article · Dec 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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    • "...the treatment of MSUD. These include, but not limited to, the use of norleucine [65], antioxidants [66,67], hepatocyte transplantation [68], sodium phenylbutyrate [69] and carnitine [70] . There are limi..."
      There are new and novel therapies being examined for the treatment of MSUD. These include, but not limited to, the use of norleucine [65], antioxidants [66,67], hepatocyte transplantation [68], sodium phenylbutyrate [69] and carnitine [70] . There are limited data to indicate how these adjuvant therapies will impact or change dietary recommendations.
    [Show abstract] [Hide abstract] ABSTRACT: In an effort to increase harmonization of care and enable outcome studies, the Genetic Metabolic Dietitians International (GMDI) and the Southeast Regional Newborn Screening and Genetics Collaborative (SERC) are partnering to develop nutrition management guidelines for inherited metabolic disorders (IMD) using a model combining both evidence- and consensus-based methodology. The first guideline to be completed is for maple syrup urine disease (MSUD). This report describes the methodology used in its development: formulation of five research questions; review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; and expert input through Delphi surveys and a nominal group process. This report includes the summary statements for each research question and the nutrition management recommendations they generated. Each recommendation is followed by a standardized rating based on the strength of the evidence and consensus used. The application of technology to build the infrastructure for this project allowed transparency during development of this guideline and will be a foundation for future guidelines. Online open access of the full, published guideline allows utilization by health care providers, researchers, and collaborators who advise, advocate and care for individuals with MSUD and their families. There will be future updates as warranted by developments in research and clinical practice.
    Full-text · Article · May 2014 · Molecular Genetics and Metabolism
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    • "...es, which inhibits oxidative metabolism and decreases the release of proinflammatory molecules [25-27]. Studies have also shown that NAC prevents memory impairment in some experimental models [28]. ..."
      In this context drugs with antioxidant and antinflammatory potential could be consequently a promoting approach to neuroprotection in patients with glutaric acidemia [9,11,20,22]. This seems to be the case of NAC, an agent with antioxidant and antinflammatory properties, which inhibits oxidative metabolism and decreases the release of proinflammatory molecules [25-27]. Studies have also shown that NAC prevents memory impairment in some experimental models [28].
    [Show abstract] [Hide abstract] ABSTRACT: Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers. Rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150mg/kg/day; intragastric gavage; for the same period). LPS (2mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed. GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers. These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I.
    Full-text · Article · Oct 2013 · PLoS ONE
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