Protective effect of xanthohumol against age-related brain damage☆,☆☆
Introduction
Aging is a universal physiological state in which a progressive decrease in organ function occurs. This process is accompanied by the consequent development of age-related diseases. Numerous studies have linked aging to deregulation of biological systems that occurs in part through over-time accumulated damage [1]. Such damage is attributable, at least in part, to free radicals.
In relation to aging, it has been observed that nutritional intervention based on the consumption of vegetables, fruits, legumes, fish and olive oil and moderate intake of fermented beverages such as wine and beer improves vascular dysfunction and microcirculation and can play an important role in protecting against oxidative stress in cardiovascular diseases related to this process [2]. It has been suggested that resveratrol and xanthohumol, flavonoids present, respectively, in wine and beer, would be responsible for the protective effect observed in the body after moderate consumption of both fermented beverages. In the case of resveratrol, it is known its action as anti-aging molecule [3], [4]; however, the available information on the possible effects of xanthohumol is limited.
Xanthohumol is the main prenylated chalcone present in hops (Humulus lupulus L.), one of the basic ingredients of beer, reaching concentrations of 0.01–0.5% [5]. During brewing, xanthohumol turns to isoxanthohumol by non-enzymatic cyclization [6]. Like xanthohumol, isoxanthohumol also has antiproliferative properties and modulates inflammation. However, its activity seems attenuated with respect to xanthohumol [7]. In this regard, comparing the effect of both molecules on inducible nitric oxide synthase (iNOS), an enzyme associated with pro-oxidizing environments, it has been observed that isoxanthohumol inhibits iNOS more weakly than xanthohumol [8]. Hence, the incorporation of xanthohumol in the diet may potentially be more beneficial. This has been studied in liver, where its antioxidant and anti-inflammatory properties have been shown [9], [10], [11]. Moreover, different studies have shown that xanthohumol inhibits activation of Ito cells (central mediators of hepatic fibrogenesis), inducing an apoptotic process [12] and that it prevents DNA damage secondary to carcinogens in both liver and colon [13]. Some studies also suggest possible benefits of treatment with xanthohumol on the reproductive organs, especially in the prostate [14] and the endometrium [15]. Furthermore, xanthohumol treatment has proven to reduce certain markers of metabolic syndrome, especially weight and preprandial blood glucose level [16].
Regarding the brain, with the exception of some isolated research showing positive effects on cerebral infarction [17] and suggesting xanthohumol as a possible candidate for adjunctive therapy in glioma treatment [18], there are no data on the effects of xanthohumol in the brain. In addition, there are no studies, to our knowledge, that had taken into account the variable of aging, in order to demonstrate whether xanthohumol could contribute to a healthy aging process of the brain, alleviating and/or reversing some conditions and diseases observed in this vital stage.
Therefore, the aim of the present study was to investigate the possible protective effect of xanthohumol on the brain damage secondary to aging, in senescence-accelerated prone male mice (SAMP8) compared with senescence-accelerated resistant male mice (SAMR1) as controls.
Section snippets
Animal model and study groups
Male senescence-accelerated prone mice (SAMP8) were used in this study. The use of these animals is widely accepted for studying the process of tissue aging since it presents the advantage that the animals are considered old at 10 months of life, which greatly reduces the times of experimentation [19]. In addition, another of the great advantages of this mouse model of spontaneous senescence is that many of the common geriatric disorders that occur in the aged human population are also
Brain markers of inflammation and brain injury
Aging significantly increased GFAP mRNA (Fig. 1A) and protein (Fig. 1B) expressions in both strains of mice. The effect was greater in SAMP8 mice, being the values observed significantly higher (P<.05) in SAMP8 than in SAMR1 animals. These changes were associated with a significant increase (P<.05) in mRNA and protein expressions of proinflammatory cytokines IL-1β and TNF-α in old mice groups (Figs. 2 and 3) compared to the values observed in young mice. Treatment with xanthohumol, at both
Discussion
Aging is a complex process involving both structurally and functionally brain changes [28]. In fact, it is generally accepted that age is a major risk factor for various pathological conditions, including memory and cognitive impairments that could play an important role in the transition from normal aging to pathological conditions like Alzheimer's disease or senile dementia [29]. Several studies have suggested that the development of these diseases could be influenced by an altered expression
Acknowledgments
The authors would like to thank Medicine students Paula Corral, Bryan Hyacinthe and Mario Calvo-Soto (School of Medicine, Complutense University of Madrid, Spain) for their continued interest and co-operation in our work. The skillful technical assistance of Rocío Campón (Dept. of Physiology, School of Medicine, Complutense University of Madrid, Spain) is also gratefully acknowledged.
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Funding: Red de Fragilidad y Envejecimiento RETICEF (grant RD12/0043/0032) and GRUPOS UCM-BSCH (grant GR35/10-A).
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Conflicts of interest: none.
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Both authors contributed equally to this work.