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Effects of Aging and Tocotrienol-Rich Fraction Supplementation on Brain Arginine Metabolism in Rats

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Effects of Aging and Tocotrienol-Rich Fraction Supplementation on Brain Arginine Metabolism in Rats Hindawi Oxidative Medicine and Cellular Longevity Volume 2017, Article ID 6019796, 13 pages https://doi.org/10.1155/2017/6019796 Research Article Effects of Aging and Tocotrienol-Rich Fraction Supplementation on Brain Arginine Metabolism in Rats 1 2 2 3 Musalmah Mazlan, Hamizah Shahirah Hamezah, Nursiati Mohd Taridi, Yu Jing, 3 4 2 2 Ping Liu, Hu Zhang, Wan Zurinah Wan Ngah, and Hanafi Ahmad Damanhuri 1Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Sungai Buloh, Malaysia 2Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 3Department of Anatomy, University of Otago, Dunedin, New Zealand 4School of Pharmacy, University of Otago, Dunedin, New Zealand Correspondence should be addressed to Hanafi Ahmad Damanhuri; hanafi[email protected] Received 21 July 2017; Revised 4 October 2017; Accepted 9 October 2017; Published 19 November 2017 Academic Editor: Anna M. Giudetti Copyright © 2017 Musalmah Mazlan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Accumulating evidence suggests that altered arginine metabolism is involved in the aging and neurodegenerative processes. This study sought to determine the effects of age and vitamin E supplementation in the form of tocotrienol-rich fraction (TRF) on brain arginine metabolism. Male Wistar rats at ages of 3 and 21 months were supplemented with TRF orally for 3 months prior to the dissection of tissue from five brain regions. The tissue concentrations of L-arginine and its nine downstream metabolites were quantified using high-performance liquid chromatography and liquid chromatography tandem mass spectrometry. We found age-related alterations in L-arginine metabolites in the chemical- and region-specific manners. Moreover, TRF supplementation reversed age-associated changes in arginine metabolites in the entorhinal cortex and cerebellum. Multiple regression analysis revealed a number of significant neurochemical-behavioral correlations, indicating the beneficial effects of TRF supplementation on memory and motor function. 1. Introduction precursor of the polyamines putrescine, spermidine, and spermine [5], which are required for optimal cell growth Declined cognitive and motor functions occur during aging and function [8], including neurogenesis [9]. L-Ornithine even in the absence of neurodegenerative diseases. While var- can also be converted to L-glutamyl-c-semialdehyde that is ious mechanisms, such as cellular communication, oxidative further metabolized to glutamate by P5C dehydrogenase stress, and inflammation, have been suggested to be involved [5]. Glutamate can also be synthesized by glutaminase using in age-related cognitive and motor deficits [1], a growing glutamine as a precursor [10] and can be converted to body of evidence indicates the role of altered arginine metab- gamma-aminobutyric acid (GABA) by glutamate decarbox- olism in the aging and neurodegenerative processes [2–4]. ylase (GAD) [5]. Agmatine, decarboxylated arginine, is a L-Arginine is a semiessential amino acid that can be novel putative neurotransmitter and directly participates metabolized by nitric oxide synthase (NOS) to produce nitric in learning and memory processing [11–13]. It also plays oxide (NO) and L-citrulline, by arginase to form L-ornithine an important role in regulating the production of NO and and urea, and by arginine decarboxylase (ADC) to generate polyamines [14]. agmatine and carbon dioxide [5]. NO plays an important role Given the physiological roles of L-arginine metabolites, a in maintaining physiological function of the nervous system considerable number of studies have investigated how brain [6]. However, it can be neurotoxic when present in excess arginine metabolism is affected by aging. Earlier research due to its free radical property [7]. L-Ornithine is the main has demonstrated age-related changes in the L-arginine 2 Oxidative Medicine and Cellular Longevity metabolic profiles in the brain, particularly in the brain were randomly divided into two groups: young and old (3 regions involved in learning and memory, in a region- and 21 months, resp.). Rats in both groups were given either specific manner, and the associations of neurochemical TRF (200 mg/kg body weight, oral gavage) or control (equal changes with animals’ behavioral performance in various volume of olive oil, oral gavage) (n =9per group) daily, for learning and memory tasks [2, 3, 15, 16]. It has been well doc- 3 months. At the end of the treatment period, the rat’s behav- − umented that NO reacts with O and H O to form ior was tested by the open-field test and Morris water maze − 2 2 2 ONOO , and the accumulation of these free radicals may task (see Taridi et al. [25]). lead to neuronal death and learning and memory impair- Evaluation on the locomotor activity, exploration, and ments in the aged. To this end, pharmacological manipula- anxiety of the rat in the open-field test was conducted by tions of brain L-arginine metabolism during aging may be a placing the rat into an open-field chamber (60 × 60 × potential preventive or treatment strategy for age-related 20 cm3). The floor of the open-field chamber was divided into cognitive decline. 36 equal-sized square-shape cells (10 × 10 cm2). The rat’s Neurodegeneration and cognitive decline can be modu- behavior was recorded within the 5 min exploration time. lated by dietary components rich in antioxidants such as veg- Then, the number of fecal boli, the number and duration of etables and fruits and ascorbic acid [17–20]. Research has wall-supported rearing and grooming, the number and per- shown that supplementation with vitamin E is able to pre- centage of grid squares traversed, and the number of central serve cognitive function and general well-being in the elderly squares crossed were analyzed. [21–23]. This is in accordance with the report that low To investigate spatial learning and memory, the Morris plasma tocopherol and tocotrienol levels are associated with water maze (MWM) task was carried out in a black circular increased risks of mild cognitive impairment (MCI) and Alz- galvanized pool (140 cm diameter), filled with 30 cm water heimer’s disease (AD) [24]. Further investigation from our depth. The pool was divided into four equal quadrants, and laboratory [25] provides additional evidence which showed a platform (13 × 13 cm) was placed in a target quadrant (the 3-month daily supplementation of TRF able to reverse center of one of the quadrants), 2 cm below the water surface. behavioral impairment in aged rats. In the study of Mangia- This test was conducted within 10 consecutive days: place lasche et al. [26], elevated serum tocopherol and tocotrienol navigation (days 1 to 6), probe test (day 7), cued navigation levels appear to be associated with reduced risk of cognitive (day 8), and working memory task (days 9 and 10). During impairment in older adults. Moreover, cell culture studies the place navigation test, the rat was trained to find the fixed have demonstrated the neuroprotective effects of vitamin hidden platform. The parameters measured in this place nav- E, with tocotrienol being more potent than tocopherol igation test were escape latency, swim path, and swim speed. [27–29]. The mechanisms of action of tocotrienol includes On the next day after the completion of the place navigation but not limited to free radical scavenging and modulation test, the platform was removed and the rat was tested to find of arachidonic acid metabolism [28, 30–32], kainic acid the platform location. This test was repeated twice for each metabolism [33], homocysteic acid metabolism [34], and rat. The percentage of time the rat spent in the target mitochondrial metabolism [35]. quadrant and the number of platform crossings in probe 1 The present study was therefore designed to further (the first time the rat was tested without a platform) and investigate how brain arginine metabolism was affected by probe 2 (the second time the rat was tested without a plat- age and to elucidate how the long-term supplementation of form) were measured. Meanwhile, during the cued naviga- TRF affected brain arginine metabolism in both young and tion test, the platform was shifted to another quadrant and aged rats. The findings of this study demonstrated altered raised 2 cm above the water surface. In order to make the brain arginine metabolism in the aged rats in the chemical- platform more visible, the edge of the platform was marked and region-specific manners and the neuroprotective effect by a masking tape. Then, the rat was allowed to find the vis- of vitamin E in the form of TRF via the modulation of brain ible platform within 60 s. Cued navigation is a control test to L-arginine metabolism. ensure that the rat used in this study has an intact vision. Escape latency was measured in this test. 2. Materials and Methods On the next two days of Morris water maze, the working memory test was carried out. In this test, the rat was given 2.1. Animals. Thirty-six male Wistar rats were fed with stan- two trials per day (each trial consisted of a sample phase dard rat chow (Gold Coin, Malaysia) and tap water ad libi- and a test phase), with the hidden platform location changed tum. Animals were housed one animal per cage at room between each trial. The sample phase involved in each trial temperature under a 12 h dark : light cycle. This study was the first time that the rat was placed in the pool. The rats were approved by the Universiti Kebangsaan Malaysia Animal rested for 1 min and 1 hour before they were retested in the Ethics Committee (protocol nos. UKMAECFP/BIOK/2008/ test phase. The parameters measured in this test were the MUSALMAH/13-FEB/215-FEB-2008-OCT-2010).
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