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Cinnamon, a promising prospect towards Alzheimer’s disease

https://www.sciencedirect.com/science/article/abs/pii/S1043661817311659

Cinnamon, a promising prospect towards Alzheimer’s disease

Cinnamon, a promising prospect towards Alzheimer’s disease

Author links open overlay panelSaeideh Momtaz b a, Shokoufeh Hassani a c, Fazlullah Khan a c d, Mojtaba Ziaee b e, Mohammad Abdollahi a c d

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Abstract

Over the last decades, an exponential increase of efforts concerning the treatment of Alzheimer’s disease (AD) has been practiced. Phytochemicals preparations have a millenary background to combat various pathological conditions. Various cinnamon species and their biologically active ingredients have renewed the interest towards the treatment of patients with mild-to-moderate AD through the inhibition of tau protein aggregation and prevention of the formation and accumulation of amyloid-β peptides into the neurotoxic oligomeric inclusions, both of which are considered to be the AD trademarks. In this review, we presented comprehensive data on the interactions of a number of cinnamon polyphenols (PPs) with oxidative stress and pro-inflammatory signaling pathways in the brain. In addition, we discussed the potential association between AD and diabetes mellitus (DM), vis-à-vis the effluence of cinnamon PPs. Further, an upcoming prospect of AD epigenetic pathophysiological conditions and cinnamon has been sighted. Data was retrieved from the scientific databases such as PubMed database of the National Library of Medicine, Scopus and Google Scholar without any time limitation. The extract of cinnamon efficiently inhibits tau accumulations, Aβ aggregation and toxicity in vivo and in vitro models. Indeed, cinnamon possesses neuroprotective effects interfering multiple oxidative stress and pro-inflammatory pathways. Besides, cinnamon modulates endothelial functions and attenuates the vascular cell adhesion molecules. Cinnamon PPs may induce AD epigenetic modifications. Cinnamon and in particular, cinnamaldehyde seem to be effective and safe approaches for treatment and prevention of AD onset and/or progression. However, further molecular and translational research studies as well as prolonged clinical trials are required to establish the therapeutic safety and efficacy in different cinnamon spp.

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Introduction

According to statistics, there were 46.8 million people worldwide encountering dementia in 2015 and this number will ascend to 131.5 million in 2050 [205]. Observational data strongly support the association between genetic and human lifestyle to develop such conditions. Many clinical trials have shown that early intervention and treatment are the only way to slow or maybe reverse the progression of the disease, since the current therapies mostly possess symptomatic properties with surplus side effects and insufficient effectiveness. Concurrently, dietary components were found to impress the incidence, severity and management of many health issues such as chronic diseases, DM and cognitive impairments [73]. Alzheimer’s disease (AD) is characterized as a subgroup of a progressive age-related neurodegenerative disorders and as the most preval‎ent type of dementia. In a simple definition, AD is triggered by the distinct protein inclusions that presumably can confer synaptic/neuronal dysfunctions [65]. In the brain of patients with AD, in addition to atrophy, nerve and synapse loss, deposition of the extracellular amyloid/senile plaques and formation of an excessive level of hyperphosphorylated intracellular neurofibrillary tangles (NFTs) containing microtubule-associated tau protein, are perceived. Rather than amyloid plaques, NFTs and by some classification hippocampal acetylcholine (ACh) decline, several other structural and functional modifications such as inflammatory responses and oxidative stresses seize critical impressions on pathological alterations in AD [[53], [207]].

Basically, amyloid plaques have been structured of amyloid-beta (Aβ) containing 39–42 amino-acid peptides that results from the sequential cleavage of the amyloid precursor protein (APP) by three proteases including α-, β- and γ-secretase. Aβ is capable of self-aggregation, and at high concentration forms very toxic monomeric and oligomeric structures. The Aβ42/Aβ40 ratio manipulates the formation of amyloid plaques, particularly by increasing the production of the toxic plaque-promoting Aβ42 peptide and this ratio can be amplified by mutations/changes in three different genes such as APP on chromosome 21, presenilin-1 (PS1) on chromosome 14 and PS2 on chromosome 1, which are mainly involved in AD [65]. To defeat AD, up to date, Aβ inhibitors are either targeting Aβ generation or oligomerization and are supposed as the focal potential treatments. Therefore, therapeutic strategies should mainly focus to restrain either β- or γ-secretase that lessen Aβ production or aggregation, or by factors that increase its removal as by some means AD was described as a result of an imbalance between Aβ production and Aβ clearance [[103], [169]]. In this process, the enzyme acetylcholine esterase (AChE) plays a key role and facilitates the synthesis, deposition and aggregation of toxic Aβ. Accordingly, AChE interacts with Aβ and interrupts cholinergic transmission at the cholinergic synapses by rapid hydrolysis of ACh, leading to the cognitive impairment in AD. Thus, inhibition of AChE presumes as a strategy for AD management, because of an enhancement in cholinergic function in the brain regions and a decrease in deposition of Aβ [[66], [132]].

Besides Aβ and AChE, tau or axonal protein (also found in somatodendritic compartments and oligodendrocytes) plays crucial in AD development. Under normal conditions, the stabilization, regulation, function and assembly of microtubules in neural cells (central and peripheral nervous system) is correlated with tau. Broadly, these microtubules facilitate the transportation of the proteins and neurotransmitters that have been synthesized within the cell towards the synapses; those are mainly correlated with cognitive functions. The balance between assembly and disassembly of these microtubules is synchronized by tau, so in this way the stability and the integrity of neurons is regularly maintained. Thus, the abnormal activity of tau is linked with AD progression and also to the activity of enzymes that have been implicated in tau hyperphosphorylation such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 (GSK3). Both Aβ and tau induce toxicity in AD via the procedures that are fully regulated by different kinases and phosphatases [26].

Once tau is hyperphosphorylated, detaches from microtubules, accumulates in the somatodendritic compartment of neurons, in which modifies normal neuronal functions, morphology and viability. Subsequently, tau proteins are aggregated and eventually form NFTs and neuropil threads [76]. Regularly, these tangles are formed in the late stages of AD in association with amyloid formation [151]. The amount of NFTs has also been linked to the severity of dementia in AD [11]. It has been proposed that hyperphosphorylated tau may contribute in neuronal dysfunction even before its deposition [178]. On the other hand, tau is known to regulate neuronal excitability and hyperphosphorylated tau suppresses pre-synaptic protein expression‎ and causes dysfunctional regulation of neuronal signaling and synaptic function that contribute to AD [[131], [23]]. Plethora studies have pointed out that phosphorylated tau is essential for Aβ-induced neurotoxicity and cognitive decline [[6], [168]]. In 2011, Ittner and Götz proposed that the augmentation in the concentration of tau within the dendrites, increased the chance of neurons to be more susceptible to the damages caused by Aβ in the postsynaptic dendrites. Therefore, combinatorial approaches, which target both tau and Aβ proteins, emerge prudent.

As yet, plant-derived bioactive phytochemicals have been speculated to perform various neuroprotective and neuroregenerative actions. Table 1 indicates a comprehensive list of the plant species capable to ameliorate AD and brain conditions, those trap tau or Aβ proteins from aggregation and also AChE inhibitors. More to the point, the evidence supports the nutritional interventions for AD. To explain, the level of oxidative stress is implicated to the diet regimen, and also oxidative stress is known as a potential cause of AD. Further, dietary restriction may extend the resistance of neuronal dysfunction [125]. With respect to AD, in this review we have intended to highlight the neuroprotectivity posture of cinnamon and its bioactive derivatives to modulate the upstream contributing mediators of AD. Also, the bioavailability and clinical application of cinnamon and its ingredients along with the promising prospect of the possible interactions between cinnamon, AD, and related epigenetic mechanisms, is discussed.

Section snippetsCinnamon

The genus Cinnamomum belongs to the Lauraceae family with nearly 250 species, several are known as spices. Cinnamon is a globally well-known plant that applies as a generic term and mainly covers 2 plant species; Cinnamomum verum J.S. Presl (C. zeylanicum Nees/Ceylon cinnamon/true cinnamon/Mexican cinnamon) and C. cassium Blume (C. aromaticum Nees/Chinese cinnamon/cassia) [28]. Similarly, some other species appealed commercial interests, for example; C. burmannii (Indonesian cassia), C. tamala

Cinnamon and neurocognitive function

There are certain compounds that have been reported in many studies those have the potential to inhibit the formation of Aβ plaques. It has been stated that cinnamon extract can interact with Aβ peptide at the initial stage of self-aggregation via polyphenol entity in order to inhibit its aggregation, therefore reduces Aβ toxicity [55]. Cinnamon inhibited the formation, accumulation and toxic effects of Aβ plaques in PC12 neuronal cells. PC12 cell viability was reported about 100% along with a

Brain localization of cinnamon

When cinnamon is ingested in the body, it undergoes extensive metabolism both in the small and large intestine and in the liver as well, which results in the production of various derivatives, and these metabolites are different from those of parent compounds which can be found in foods [[121], [204]]. The ability of cinnamon to affect the nervous system will mostly depend on their metabolites ability to cross the BBB through the process of diffusion across the membrane and eventually enter the 

Cinnamon and oxidative impairments

Cinnamon PPs exhibit neuroprotective effects in AD models through various intracellular mechanisms. The free radical theory of aging along with the fact that aging is the prime stressor of AD merits the implication of oxidative stress in the clinical progression of Behl, 1997; [175]. In AD, oxidative impairments usually originate from mitochondrial dysfunction (formation of ROS and oxidative stress), from Aβ42 toxicity (production of ROS in the presence of metal ions; Fe 2+ and Cu 2+) and from

Cinnamon, AD and endothelial functions

Vascular defects, neural and vascular inflammation and brain endothelial dysfunction are frequently diagnosed in AD. Aβ peptides are scavenged from the brain through different mechanisms such as passage to the cerebrospinal fluid (CSF) with subsequent re-absorption into the venous circulation, and direct conduction across the BBB [222]. Aβ peptides are transported by receptors for advanced glycation endproducts (RAGE) to the perivascular space. It was shown that RAGE expression‎ was elevated

Cinnamon; bioavailability and clinical application in neurodegenerative disorders

In case of natural compounds, their pharmacokinetics, bioavailability, bioactivity and metabolism within the human body have attained serious concerns as they extensively differ from one compound to another. Their biological profile, availability and absorption rate widely depends on their chemical structures [181]. This matters more when it comes to the brain area by means of whether these compounds are capable to reach the brain in adequate quantity and are they still biologically active?

Cinnamon, AD and epigenetics, a promising prospect

Epigenetic means the stable and heritable changes in the chromatin structure that may influence gene expression‎ [119]. Epigenetic modifications are typically classified as DNA methylation, histone post-translational changes and microRNAs (miRNAs). Irregular regulation of epigenetic mechanisms has been linked to AD and other neuronal dysfunctions [69]. A great body of evidence testifies that patients with AD have an aberrant DNA methylation profile in both early and late stages of the disease [19

Conclusion

Altogether, there is an emerging prerequisite to commence a systematic and comprehensive exploration of different species of the genus cinnamomum regarding their exquisite therapeutic values. Precise and well controlled clinical trials should be constructed to escalate the credibility and safety profiles of various cinnamon spp. Interestingly, cinnamon has been profited from the advantages of an extended variety of phytochemicals known as procyanidins, catechins, coumarins, flavonoids,

Conflict of interest statement

The authors indicate no conflict of interest with the subject matter of this review.

Acknowledgments

Authors wish to thank the Iran National Science Foundation (INSF) and to acknowledge Mr Eqbal Jasemi for graphical design.

References (250)

• G. Amadoro et al.Endogenous Aβ causes cell death via early tau hyperphosphorylation

  Neurobiol. Aging

  (2011)

• P. Anand et al.A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease

  Bioorg. Med. Chem. Lett.

  (2012)

• P. Anand et al.Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and GLUT4 translocation in experimental diabetic rats

  Chem. Biol. Interact.

  (2010)

• J. Bekir et al.Assessment of antioxidant, anti-inflammatory, anti-cholinesterase and cytotoxic activities of pomegranate (Punica granatum) leaves

  Food Chem. Toxicol.

  (2013)

• M. Bradley-Whitman et al.Epigenetic changes in the progression of Alzheimer’s disease

  Mech. Ageing Dev.

  (2013)

• H. Cao et al.Cinnamon extract and polyphenols affect the expression‎ of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes

  Arch. Biochem. Biophys.

  (2007)

• A.M. Cárdenas et al.Role of tau protein in neuronal damage in Alzheimer’s disease and Down syndrome

  Arch. Med. Res.

  (2012)

• N.B. ChauhanEffect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576

  J. Ethnopharmacol.

  (2006)

• N.B. ChauhanEffect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576

  J. Ethnopharmacol.

  (2006)

• S.-W. Choi et al.Epigenetics: a new bridge between nutrition and health

  ADV Nute Res.

  (2010)

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