Elsevier

Brain Research Bulletin

Volume 119, Part A, October 2015, Pages 1-11
Brain Research Bulletin

Review
Luteolin as an anti-inflammatory and neuroprotective agent: A brief review

https://doi.org/10.1016/j.brainresbull.2015.09.002 Get rights and content

Highlights

  • Neurodegenerative diseases are leading causes of age related-morbidity and mortality.

  • Extensive research suggests the therapeutic role of dietary phytochemicals for the treatment of neurological disorders.

  • Luteolin suppresses inflammation and regulates different cell signaling pathways.

  • Improved formulations may overcome issues with bioavailability, metabolism, and toxicity.

Abstract

According to the World Health Organization, two billion people will be aged 60 years or older by 2050. Aging is a major risk factor for a number of neurodegenerative disorders. These age-related disorders currently represent one of the most important and challenging health problems worldwide. Therefore, much attention has been directed towards the design and development of neuroprotective agents derived from natural sources. These phytochemicals have demonstrated high efficacy and low adverse effects in multiple in vitro and in vivo studies. Among these phytochemicals, dietary flavonoids are an important and common chemical class of bioactive products, found in several fruits and vegetables. Luteolin is an important flavone, which is found in several plant products, including broccoli, pepper, thyme, and celery. Numerous studies have shown that luteolin possesses beneficial neuroprotective effects both in vitro and in vivo. Despite this, an overview of the neuroprotective effects of luteolin has not yet been accomplished. Therefore, the aim of this paper is to provide a review of the available literature regarding the neuroprotective effects of luteolin and its molecular mechanisms of action. Herein, we also review the available literature regarding the chemistry of luteolin, its herbal sources, and bioavailability as a pharmacological agent for the treatment and management of age-related neurodegenerative disorders.

Introduction

According to World Health Organization reports, the number of elderly people (>60 years old) will significantly increase over the next 40 years (Fries, 2002, Wancata et al., 2003). Worldwide, the increase in the number of elderly people is associated with the rapidly growing incidence of morbidity and mortality due to age-related diseases (Carranza et al., 2013, de Lau and Breteler, 2006, Hendrie, 1998, Sosa-Ortiz et al., 2012, Nabavi et al., 2012a, Nabavi et al., 2013a, Nabavi et al., 2013b). In the last two decades, scientific research has focused on the discovery and design of novel neuroprotective agents with high efficacy and low adverse effects (Guttmacher et al., 2003, Matteo and Esposito, 2003, Youdim and Buccafusco, 2005). Although the pathophysiology of Alzheimer’s disease and Parkinson’s disease remains unclear, it is well known that neuronal dysfunction is associated with neuroinflammation, glutamatergic excitotoxicity, and redox active metals, which play an important role in the initiation and progression of these neurocognitive and locomotor disorders (Ahmed et al., 2015, Guttmacher et al., 2003, Matteo and Esposito, 2003, Renaud et al., 2015, Youdim and Buccafusco, 2005). In addition, abundant scientific evidence shows that oxidative stress plays a crucial role in the neurodegeneration that underlies these diseases. Therefore, much attention has been focused on the beneficial role of natural neuroprotective substances with potent antioxidant and anti-inflammatory effects (Ahmed et al., 2015, Orhan et al., 2015, Renaud et al., 2015).

Phytochemicals are plant-derived bioactive chemical constituents, which are responsible for the pharmacological effects of medicinal plant extracts (Nabavi et al., 2014a, Nabavi et al., 2012b, Nabavi et al., 2015a). Among them, polyphenolic compounds, in particular flavonoids, are one of the most effective chemical classes which possess a wide range of health-promoting activities and pharmacological effects, such as antioxidant, anti-inflammatory, anticancer, neuroprotective, and cardioprotective effects. (Daglia et al., 2014, Donato et al., 2014, Nabavi et al., 2014b, Nabavi et al., 2012c, Nabavi et al., 2015b, Middleton et al., 2000, Xue et al., 2014). To date, there are more than 8000 flavonoids which are classified into different sub-groups, such as chalcones, flavones, flavonols, flavanones, flavanols, anthocyanins, and isoflavones (Corcoran et al., 2012, Orhan et al., 2015).

Luteolin (3′,4′,5,7-tetrahydroxy flavone, Fig. 1) is an important flavone, which is naturally found in several plant species (Kim et al., 2000a, Peters et al., 1986). Chemically, it has a C6-C3-C6 structure that contains two benzene rings and one oxygen-containing ring with a C2-C3 carbon double bond (Fig. 1) (Bravo, 1998, Lin et al., 2008). Structure-activity studies have shown that the presence of hydroxyl moieties at carbons 5, 7, 3′ and 4′ positions of the luteolin structure and the presence of the 2–3 double bond are responsible for its multiple pharmacological effects (Lin et al., 2008). Luteolin, which is naturally found as a glycosylated form, is present in different fruits and vegetables, including broccoli, pepper, thyme, and celery (Lopez-Lazaro, 2009, Shimoi et al., 1998). A growing body of literature shows that luteolin possesses antioxidant, anticancer, anti-inflammatory, and neuroprotective effects (Chen et al., 2008, Cheng et al., 2010, Dirscherl et al., 2010, Kang et al., 2004, Lin et al., 2008, Pandurangan and Esa, 2014, Qiao et al., 2012, Theoharides et al., 2015, Zhang et al., 2013); however, a coherent review of the scientific literature regarding its neuroprotective effects is still lacking. Therefore, the aim of the the present paper is to review existing literature, evaluating the neuroprotective effects of luteolin. In addition, in the following sections the natural sources, chemistry, and bioavailability of luteolin will be discussed, providing a more comprehensive assessment of the beneficial effects of this important compound.

Section snippets

Sources of luteolin

Luteolin is one of the most common flavonoids present in edible plants. For example, it has been found in carrots (Daucus carota L.), peppers (Capsicum annuum L.), celery (Apium graveolens L.), olive oil (Olea europaea L.), peppermint (Mentha piperita L.), thyme (Thymus vulgaris L.), rosemary (Rosmarinus officinalis L.), oregano (Origanum vulgare L.), lettuce (Lactuca sativa L.), perilla leaves (Perilla frutescens (L.) Britton), pomegranate (Punica granatum L.), artichoke (Cynara scolymus L.),

Isolation from natural sources

Luteolin and its derivatives have been isolated from a wide variety of natural sources, which possess several pharmacological activities.

Synthesis of luteolin derivatives

In discussing the synthesis of luteolin and its bioactive derivatives, it is necessary to mention the variety of methodologies applied by researchers, especially from Asian countries, where the study of the biochemistry of natural products is very advanced. Contributions about the importance of luteolin and the experimental procedures for obtaining several derivatives will be discussed below. Earlier studies, from the 1980s, were limited to the synthetic field; therefore, this review will only

Bioavailability and oral absorption

It was previously thought that the oral bioavailability of flavonoids is very low. However, one study recently investigated the bioavailability of luteolin in peanut hull extracts (PHE) (Zhou et al., 2008). More specifically, the study showed that the effective permeability (Peff) and absorption rate constant (ka) of pure luteolin (5.0 μg/mL) were not significantly different in the duodenum and jejunum, but significantly greater in the colon and ileum. The Peff and ka of PHE were significantly

Mechanism of action of luteolin in the central nervous system

Luteolin exerts a variety of pharmacological activities and anti-oxidant properties associated with its capacity to scavenge oxygen and nitrogen species. Luteolin has been shown to inhibit cytokine expression, nuclear factor kappa B (NFkB) signaling, and TLR4 signalling at micromolar concentrations in immune cells, including mast cells (Kim and Jobin, 2005, Lee et al., 2009, Weng et al., 2015). As well, luteolin has been shown to attenuate microglial activation and mediate BDNF-like behavior

Epilepsy

The plant extract obtained from Eclipta alba, which contains small quantities of luteolin, has been traditionally used in Ayruvedic medicine for the treatment of epilepsy. E. alba has demonstrated anticonvulsant properties in a maximal electroshock rat model (Shaikh and Sathaye, 2011). Acute luteolin administration has also been shown to attenuate oxidative stress in neuroblastoma cells (Zhou et al., 2011). Anxiolytic-like effects of luteolin have been reported following oral and

Conclusion and recommendations

Recent epidemiological studies have shown that the elderly is the fasted growing population in the developed world. Accurate estimates of the prevalence of neurodegenerative diseases are important for optimal healthcare planning. The growing burden on public health of neurological deficits is not helped by the failure of synthetic agents to slow down or to prevent the progression of these diseases and related morbidities. This suggests that naturally occurring protective agents may provide

Conflict of interest

There is no conflict of interest.

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