Protective effect of xanthohumol against age-related brain damage,☆☆

https://doi.org/10.1016/j.jnutbio.2017.07.011Get rights and content

Abstract

It has been recently shown that xanthohumol, a flavonoid present in hops, possesses antioxidant, anti-inflammatory and chemopreventive properties. However, its role in the aging brain has not been addressed so far. Therefore, this study aimed to investigate the possible neuroprotective activity of xanthohumol against age-related inflammatory and apoptotic brain damage in male senescence-accelerated prone mice (SAMP8). Animals were divided into 4 groups: Untreated young mice, untreated old mice and old mice treated either with 1 mg kg−1 day−1 or 5 mg kg−1 day−1 xanthohumol. Young and old senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and their brains were collected and immediately frozen in liquid nitrogen. mRNA (GFAP, TNF-α, IL-1β, AIF, BAD, BAX, XIAP, NAIP and Bcl-2) and protein (GFAP, TNF-α, IL-1β, AIF, BAD, BAX, BDNF, synaptophysin and synapsin) expressions were measured by RT-PCR and Western blotting, respectively. Significant increased levels of pro-inflammatory (TNF-α, IL-1β) and pro-apoptotic (AIF, BAD, BAX) markers were observed in both SAMP8 and SAMR1 old mice compared to young animals (P<.05) and also in SAMP8 untreated old mice compared to SAMR1 (P<.05). These alterations were significantly less evident in animals treated with both doses of xanthohumol (P<.05). Also, a reduced expression of synaptic markers was observed in old mice compared to young ones (P<.05) but it significantly recovered with 5 mg kg−1 day−1 xanthohumol treatment (P<.05). In conclusion, xanthohumol treatment modulated the inflammation and apoptosis of aged brains, exerting a protective effect on damage induced by aging.

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.

References (52)

  • T. Takeda

    Senescence-accelerated mouse (SAM): a biogerontological resource in aging research

    Neurobiol Aging

    (1999)
  • A. Puig et al.

    Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model

    Exp Gerontol

    (2016)
  • P. Chomczynski et al.

    Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction

    Anal Biochem

    (1987)
  • K.J. Livak et al.

    Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method

    Methods

    (2001)
  • S. Albrecht et al.

    Activation of caspase-6 in aging and mild cognitive impairment

    Am J Pathol

    (2007)
  • I.S. Lee et al.

    Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells

    Neurochem Int

    (2011)
  • M. Reale et al.

    Peripheral cytokines profile in Parkinson's disease

    Brain Behav Immun

    (2009)
  • M. Mogi et al.

    p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain

    Neurosci Lett

    (2007)
  • F.C. Kischkel et al.

    Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8

    J Biol Chem

    (2001)
  • M.K. McMillian et al.

    Brain injury in a dish: a model for reactive gliosis

    Trends Neurosci

    (1994)
  • C. Marin et al.

    Endothelial aging associated with oxidative stress can be modulated by a healthy mediterranean diet

    Int J Mol Sci

    (2013)
  • D. Delmas et al.

    Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe

    Curr Med Chem

    (2011)
  • J.M. Villalba et al.

    Sirtuin activators and inhibitors

    Biofactors

    (2012)
  • J.F. Stevens et al.

    Fate of xanthohumol and related prenylflavonoids from hops to beer

    J Agric Food Chem

    (1999)
  • C. Gerhauser et al.

    Cancer chemopreventive activity of Xanthohumol, a natural product derived from hop

    Mol Cancer Ther

    (2002)
  • E. Lupinacci et al.

    Xanthohumol from hop (Humulus lupulus L.) is an efficient inhibitor of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha release in LPS-stimulated RAW 264.7 mouse macrophages and U937 human monocytes

    J Agric Food Chem

    (2009)
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    Funding: Red de Fragilidad y Envejecimiento RETICEF (grant RD12/0043/0032) and GRUPOS UCM-BSCH (grant GR35/10-A).

    ☆☆

    Conflicts of interest: none.

    1

    Both authors contributed equally to this work.

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