Iridoids and Other Monoterpenes in the Alzheimer's Brain
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molecules Review Iridoids and Other Monoterpenes in the Alzheimer’s Brain: Recent Development and Future Prospects Solomon Habtemariam Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK; [email protected]; Tel.: +44-208-331-8302/8424 Received: 26 December 2017; Accepted: 5 January 2018; Published: 7 January 2018 Abstract: Iridoids are a class of monoterpenoid compounds constructed from 10-carbon skeleton of isoprene building units. These compounds in their aglycones and glycosylated forms exist in nature to contribute to mechanisms related to plant defenses and diverse plant-animal interactions. Recent studies have also shown that iridoids and other structurally related monoterpenes display a vast array of pharmacological effects that make them potential modulators of the Alzheimer’s disease (AD). This review critically evaluates the therapeutic potential of these natural products by assessing key in vitro and in vivo data published in the scientific literature. Mechanistic approach of scrutiny addressing their effects in the Alzheimer’s brain including the τ-protein phosphorylation signaling, amyloid beta (Aβ) formation, aggregation, toxicity and clearance along with various effects from antioxidant to antiinflammatory mechanisms are discussed. The drug likeness of these compounds and future prospects to consider in their development as potential leads are addressed. Keywords: monoterpenes; iridoids; Alzheimer’s disease; amyloid beta; drug likeness; multiple mechanisms 1. Introduction Alzheimer's disease (AD) is one of the most prevalent age-related diseases mostly affecting the elderly population. Of the estimated 5.5 million Americans with AD in 2017, 5.3 million comprising about 96% of the patients’ population, were 65 years of age or older [1]. The disease also accounts for up to 70% of all cases of dementia and has a global prevalence of about 47 million people in 2015 [2]. Moreover, the projected figure for dementia by the year 2050 is 131.5 million highlighting the rapid rate of increase in its importance. As life expectancy continues to increase all over the world in parallel with economic development, the risk of AD along with its cost and social burden will be felt even more in the future. The disease is characterized by progressive cognitive deficit and irreversible neuronal deterioration. To date, there is no cure for AD and the average lifespan between the manifestation of clinical symptoms and death is about 8.5 years [3]. The memory deficits in AD are also associated with behavioral changes making patient care management very challenging. The therapeutic options for AD are very limited with drug therapy mainly directed at the cholinergic system by using cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine. A limited benefit by using non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists including memantine have also been employed [4,5]. In the recent review article, the role of natural products in ameliorating the various neurodegenerative diseases has been outlined [6]. Significant advances in understanding the therapeutic potential of polyphenolic compounds such as flavonoids [7–12], caffeic acid derivatives [13] and aromatic diterpenoids [14] that benefit AD through multiple mechanisms of actions have also been presented. One class of compounds that has not received much attention as potential therapy for AD is the monoterpene class. In the present communication, a systematic review of these compounds with special emphasis on iridoids is presented. Molecules 2018, 23, 117; doi:10.3390/molecules23010117 www.mdpi.com/journal/molecules Molecules 2018, 23, 117 2 of 24 Molecules 2018, 23, 117 2 of 24 communication, a systematic review of these compounds with special emphasis on iridoids is Moleculescommunication,2018, 23, 117 a systematic review of these compounds with special emphasis on iridoids2 of 23is presented. presented. 2. Overview of Iridoids Chemistry 2. Overview of Iridoids Chemistry Iridoids are the monoterpenoid class of natural products that are constructed with 10 carbon Iridoids are the monoterpenoid class of natural products that are constructed with 10 carbon skeleton. One structural marker of this compounds is the ciscis--fusedfused cycyclopenta[c]pyranclopenta[c]pyran system that skeleton. One structural marker of this compounds is the cis-fused cyclopenta[c]pyran system that exist in nature nature as as glycosides, glycosides, aglycones, aglycones, in in the the form form of of secoiridoids secoiridoids or orbisiridoids bisiridoids forms forms (Figure (Figure 1).1 In). exist in nature as glycosides, aglycones, in the form of secoiridoids or bisiridoids forms (Figure 1). In Inthe the case case of ofsecoiridoids, secoiridoids, the the C7–C8 C7–C8 bond bond of of the the ir iridoididoid skeleton skeleton is is cleaved cleaved following following a a series of the case of secoiridoids, the C7–C8 bond of the iridoid skeleton is cleaved following a series of oxidation steps to give rise to compounds like seco secologaninloganin (Figure1 1),), whichwhich alsoalso servesserves asas aa precursorprecursor oxidation steps to give rise to compounds like secologanin (Figure 1), which also serves as a precursor to the synthesis of alkaloids. to the synthesis of alkaloids. 11 H 11 COOCH3 4 H COOCH3 H 4 O H 5 3 O 7 5 3 7 9 O O 9 O O H 1 H H O1 H O 10 O Glucose O Glucose 10 Glucose Glucose Iridoid glycoside Secologanin Iridoid glycoside Secologanin Figure 1. General structure of iridoids and secoiridoids. Figure 1. General structure of iridoids and secoiridoids. The biosynthesis pathway of terpenoids has been reviewed in the various literatures [15,16] and The biosynthesis biosynthesis pathway pathway of of terpenoids terpenoids has has been been reviewed reviewed in the in thevarious various literatures literatures [15,16] [15 and,16] involves some key biosynthetic intermediates like the mevalonic acid. Even though the starting andinvolves involves some some key keybiosynthetic biosynthetic intermediates intermediates like like the the mevalonic mevalonic acid. acid. Even Even though though the the starting primary metabolite goes as far back as a two-carbon metabolite, acetyl-CoA, the basic skeleton of all primary metabolite goes as far back as a two-carbon metabolite, acetyl-CoA, thethe basic skeleton of all terpenoids is defined by the 5-carbon isoprene units in the form of isopentenyl pyrophosphate (IPP) terpenoids isis defineddefined by by the the 5-carbon 5-carbon isoprene isoprene units units in in the the form form of isopentenylof isopentenyl pyrophosphate pyrophosphate (IPP) (IPP) and and dimethylallyl pyrophosphate (DMAPP). The precursor of all terpenoids in the further steps of dimethylallyland dimethylallyl pyrophosphate pyrophosphate (DMAPP). (DMAPP). The precursor The precur of allsor terpenoids of all terpenoids in the further in the stepsfurther of reactionsteps of reaction is the geranyl pyrophosphate (GPP) that is made from two isoprene units (Figure 2). The isreaction the geranyl is the pyrophosphate geranyl pyrophosphate (GPP) that is(GPP) made that from is twomade isoprene from two units isoprene (Figure2 ).units The (Figure sesquiterpenes 2). The sesquiterpenes (15 carbon), diterpenes (20 carbon) and triterpenes (30 carbons) are classical examples (15sesquiterpenes carbon), diterpenes (15 carbon), (20 carbon)diterpenes and (20 triterpenes carbon) and (30 triterpenes carbons) are (30 classical carbons) examples are classical of terpenoids examples of terpenoids that arise from condensation of these isoprene units through a serious of enzyme- thatof terpenoids arise from that condensation arise from of condensation these isoprene of units these through isoprene a serious units through of enzyme-catalyzed a serious of reactions.enzyme- catalyzed reactions. The GPP gives rise to a range of cyclic and acyclic monoterpenes of biological Thecatalyzed GPP gives reactions. rise to The a range GPP of gives cyclic rise and to acyclic a range monoterpenes of cyclic and of biologicalacyclic monoterpenes significance [ 17of], biological while the significance [17], while the 8-hydroxygeraniol unique pathways leads to iridoids and their 8-hydroxygeraniolsignificance [17], uniquewhile pathwaysthe 8-hydroxygeraniol leads to iridoids unique and their pathways derivatives leads (Figure to 2iridoids). The compounds and their derivatives (Figure 2). The compounds scrutinized for their potential effect in ameliorating the scrutinizedderivatives for(Figure their potential2). The compounds effect in ameliorating scrutinized the for biochemical their potential and behavioral effect in symptomsameliorating of ADthe biochemical and behavioral symptoms of AD are shown in Figure 3. arebiochemical shown in and Figure behavioral3. symptoms of AD are shown in Figure 3. OH OH HO CH HO HO HO 3 HO P OH HO P OH O CH3 O P O O P O O O O O O CoA O P O O P O H3COCoA HO O OH O P O O P O H3CO HO OH OH O OH OH Acetyl CoA Mevalonic acid IPP DMAPPOH Acetyl CoA Mevalonic acid IPP DMAPP HO OH HO P OH O P O O O Other terpenoids O P O Other terpenoids O P O GPP OH GPP OH H H OH H H O OH O OH OH O O OH O O Geraniol H H OH Geraniol H OH H IridoidOH Iridodial 8-Hydroxygeraniol Iridoid Iridodial 8-Hydroxygeraniol Figure 2. An overview of biosynthesis pathway of iridoids. Figure 2. An overview of biosynthesis pathway of iridoids. Molecules 2018, 23, 117 3 of 23 Molecules 2018, 23, 117 3 of 24 OH OH O OH α-Pinene Thymol Carvacrol Eucalyptol Linalool (1,8-Cineole) O H O O OCH3 HO H O HO O OCH3 R O H HO OH O O O Myrtenal R=H Bornane Fenchone Genipin HO R=OH Borneol R=O Camphor HO OH HO Oleuropein O OCH O OCH 3 3 HO HO H H H H3C H HO O O H HO O O O O O O H H H HO O HO O HO O OH OH H OH OH OH O O O O O HO HO HO OH OH OH HO HO HO Loganin Geniposide Catalpol Paeoniflorin Figure 3.