Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease
Graphical abstract
Section snippets
Alzheimer's disease – a global burden
Alzheimer's disease (AD) is a complex and heterogeneous progressive disorder of the central nervous system (CNS) (Fang et al., 2013, Singh and Guthikonda, 1997). The incidence of AD is about 35 million people worldwide that accounts for 10–15% of people aged 65 or older, and 35% of those 85 years and older. With increased life expectancies and an aging population, it is estimated that this figure will triple in the next 40 years, ensuing in increased healthcare costs worldwide.
Low grade, chronic neuroinflammation in Alzheimer's disease
Pro-inflammatory activation of astroglia and microglia has been observed in many neurodegenerative diseases such as Parkinson's and Alzheimer's disease, and even autism-spectrum and obsessive-compulsive disorders. Neurofibrillary tangles (composed of hyper-phosphorylated tau) and senile plaques (composed of beta-amyloid, Aβ) are major pathological hallmarks of AD, which is also characterized by a cholinergic deficit, thus current treatments primarily focus on enhancement of cholinergic
Neuroinflammation as a therapeutic target in Alzheimer's disease
In recent years, studies have focused on different nutritional approaches to benefit AD patients (Fig. 2). More specifically, foods rich in n-3 fatty acids, vitamins, and diverse groups of polyphenolic plant secondary metabolites have been shown to be effective against several AD pathologies (Stevenson and Hurst, 2007, Willis et al., 2010). For example, in a cross-sectional study, the association between adherence to a Mediterranean diet (MeDi) and risk for Alzheimer's disease (AD) and mild
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Curcumin, a diarylheptanoid polyphenol isolated from the rhizomes of Curcuma longa L. (Zingiberaceae, common name: turmeric) is a food spice used extensively in the Indian cuisine and Ayurvedic medicine (Ringman et al., 2005).
Pharmacokinetics
Curcumin penetrates into the CNS (Yang et al., 2005) and exerts a broad range of anti-inflammatory effects. In a study conducted in mice by Pan et al., oral administration of a large dose of curcumin (1000 mg/kg) produced only plasma levels as low as 0.13 μg/mL after
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Apigenin (4′,5,7-trihydroxyflavone) is a flavonoid particularly abundant in the ligulate flowers of the chamomile plant (68% apigenin of total flavonoids) (McKay and Blumberg, 2006) and also found in other sources such as celery (4.61 mg/100 g), parsley (302 mg/100 g), peppermint (8.71 mg/100 g) (Shukla and Gupta, 2010).
Pharmacokinetics
Apigenin crosses the BBB, and concentrations in the cerebellar granule brain cells of the rat have reached 1.2 μM after daily i.p. administration of 20 mg/kg of apigenin
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Unfermented teas (Green and White) are derived from the steamed and dried leaves of the Camellia sinensis plant. Polyphenols from green tea have been shown to be powerful hydrogen-donating antioxidants, free radical scavengers of ROS and RNS in vitro (Mandel et al., 2004). Among the green tea polyphenols, a subclass termed catechins has received the greatest attention, of which green tea is one of the best-known dietary sources. Of the four major tea catechins in fresh tea leaves, (-)
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Docosahexaenoic acid is an essential omega-3 (n-3) polyunsaturated fatty acid (PUFA) that is found abundantly in marine fish. DHA is known to be the most important n-3 PUFA in the brain, accounting for roughly 15% of total fatty acids in grey matter, where it is enriched at synapses (Salem et al., 2001). Epidemiological data indicate that a low dietary intake of n-3 PUFA is a risk factor for AD (Lim et al., 2005), while people who ingest higher levels of DHA are less likely to develop cognition
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α-lipoic acid (ALA) is chemically synthesized, but can be considered a natural compound as it is a naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (Maczurek et al., 2008, Münch et al., 2010).
Pharmacokinetics
ALA is a low molecular weight compound which easily penetrates the BBB (Biewenga et al., 1997). After crossing the BBB, ALA is absorbed into cells and tissues, which is then reduced to dihydrolipoate
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Resveratrol (3, 5, 4’ –trihydroxystilbene) is a polyphenolic phytoalexin, produced in response to damage in grapevines, pines and legumes, such as peanuts. It is also found in the “Itadori plant” (Polygonum cuspidatum) and tea (Burns et al., 2002, Langcake and Pryce, 1977, Soleas et al., 1997).
Pharmacokinetics
Resveratrol is poorly absorbed, and enhanced absorption is only seen with methylated analogs and piperine supplements (Kapetanovic et al., 2011). When resveratrol administered at a dose of 25 mg, the
Conclusion
This review provides a comprehensive overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective and cognition-enhancing effects of curcumin, apigenin, EGCG, n-3 fatty acids, α-lipoic acid and resveratrol. These compounds have been examined in numerous in vitro and in vivo studies and many of their cellular targets identified. However, despite encouraging animal data, the percentage of positive human trials in AD is surprisingly low (as with many other drugs like
Acknowledgements
We thank Ralph Martins, Julian Castillo, Lezanne Ooi, Alejandra Rangel, Klaus Hager, Marlene Kenklies and Klaus Wessel for support and inspiration. We thank the National Health and Medical Research Council of Australia for funding (# 480102, to GM and MJS).
References (146)
- et al.
Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages
Pharmacol. Res. Off. J. Italian Pharmacol. Soc.
(1999) - et al.
Microglia, amyloid and dementia in alzheimer disease. A correlative study
Neurobiol. Aging
(2000) - et al.
The pharmacology of the antioxidant lipoic acid
General Pharmacol.
(1997) - et al.
Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model
Neuron
(2004) - et al.
The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study
Prog. Neuro Psychopharmacol. Biol. Psychiatry
(2008) - et al.
Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis
Neurochem. Int.
(2010) - et al.
Effects of C-glycosylation on anti-diabetic, anti-Alzheimer's disease and anti-inflammatory potential of apigenin
Food Chem. Toxicol.
(2014) - et al.
The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons
Life Sci.
(2001) - et al.
Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer's disease
Alzheimer's Dementia J. Alzheimer's Assoc.
(2012) - et al.
New insights into mechanism for the effect of resveratrol preconditioning against cerebral ischemic stroke: possible role of matrix metalloprotease-9
Med. Hypotheses
(2008)