The Medicinal Chemistry of Natural and Semisynthetic Compounds

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The Medicinal Chemistry of Natural and Semi-Synthetic Compounds Against Parkinson’s and Huntington’s Diseases Enrico Zanforlin, Giuseppe Zagotto, and Giovanni Ribaudo ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00283 • Publication Date (Web): 01 Sep 2017 Downloaded from http://pubs.acs.org on September 4, 2017

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ACS Chemical Neuroscience

The Medicinal Chemistry of Natural and Semi-Synthetic Compounds Against Parkinson’s and Huntington’s Diseases Enrico Zanforlina, Giuseppe Zagotto*a, Giovanni Ribaudoa a

Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; ABSTRACT: Among the diseases affecting the Central Nervous System (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of a natural origin which are currently under study against two well-defined pathologies: Parkinson’s Disease (PD) and Huntington’s Disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and, where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the aetiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

Keywords: Dementia, Parkinson’s Disease, Huntington’s Disease, CNS, Natural Products, Semi-Synthetic Compounds. INTRODUCTION “Dementia is a general term for loss of memory and other mental abilities severe enough to interfere with daily life. It is caused by physical changes in the brain”. This type of definition include a plethora of different pathologies such as: Alzheimer's disease (AD), Vascular dementia, Dementia with Lewy bodies (DLB), Mixed dementia, Parkinson's disease (PD), Frontotemporal dementia, Creutzfeldt-Jakob disease, Normal pressure hydrocephalus, Huntington's disease (HD), Wernicke-Korsakoff Syndrome.1 One of the most pressing topics in the modern world is the need of finding new strategies able to counteract the global exponential rising of dementia’s cases. This is an extremely important issue, not only for what concerns the quality of life of the patients who suffer of these pathologies and their families, who have to take care of them. The social burden on the whole society is also relevant. As a matter of fact, in 2015, the global cost for the treatment of dementias was around US$ 818 billion but in 2018 this cost is estimated to reach the threshold of US$ 1 trillion. The trend of the cost rise is also critical: it is estimated that the global spending will grow by 85% in the period from 2010 to 2030, and the increase will be more sudden in poor and underdeveloped countries.2,3 The heterogeneity of the cost growth among different countries is principally due to the fact that in the rich countries the average age is already high, and for this reason they have reached a sort of plateau of the incidence of dementias. Thus, in the poor and middle income countries the population is still growing exponentially and, consequently, average age is increasing. This event is strictly linked with the growing incidence of this type of pathologies, which in turn leads to the increase of the spending. This general trend is described in several articles and reports drafted by different organisations. Globally, there are 9.9 million new cases every year, one every 3.2 seconds. In 2015 the number of people affected by dementia worldwide was estimated to be around 47.5 million. This value is expected to double every 20 years, reaching more than 135 million patients in 2050.3 From 2015 to 2050, the number of people suffering from dementia will have doubled in Europe and north America, tripled in Asia and will have increased fourfold in south America and Africa.3

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Factors which influence the onset of different types of dementias are diverse, but those that are well accepted and documented include: low levels of education in early life, hypertension in midlife, and smoking and diabetes throughout life.4 This is not particularly true concerning HD, because this pathology is given by and inherited genetic defects and so all the factors previously mentioned are ineffective on this type of patients. Even now the treatments which are available for these pathologies are not very effective, except for certain cases such as levodopa for the treatment of Parkinson’s Disease.5 Faced with the situation where the number of patients is drastically increasing and there is a lack of suitable treatments, the development of new treatment strategies and remedies ought to be a priority. A wide range of pathologies are currently included in the class of dementias. In this review, the main focus will be on two different pathologies, which are considered representative of the dementias around the world: Parkinson’s Disease (PD) and Huntington’s Disease (HD). The aim is to give an overview of new and promising natural products and semisynthetic compounds that could represent a source of “lead compounds” for the development of new potential drugs. This in turn could provide valid therapeutic strategies for the treatment of these pathologies. PARKINSON’S DISEASE Etiology and symptoms Parkinson disease (PD) is a neurological disorder which affects approximately 2% of the population older than 65 years and the percentage raises to 5% when considering the population over 85, with 7-10 million cases worldwide.6,7 It is described as the second most frequent degenerative disorder related to aging. PD is chronic and progressive, and it is clinically identified by 4 cardinal signs (resting tremor, bradykinesia, rigidity and postural instability).8 Moreover, nonmotor symptoms which may occur at various degrees in PD patients include depression, fatigue, hyposmia, sleep disorders, automatic dysfunction, cognitive impairment and dementia.9 This neurodegenerative disease is mostly sporadic: less then 10% of the cases are reported to be inherited10 and, in general, PD is known to be caused by both genetic and environmental risk factors.9 Exposure to toxins, in particular, seems to be involved in the late-onset forms of PD, while genetic factors appear to be predominant in early-onset PD.8 Mutations affecting autosomal dominant genes such as SNCA (encoding for α-synuclein protein), LRRK2 (encoding for leucine-rich repeat kinase 2) and EIF4G1 or recessive genes such as PRKN (or PARK2 encoding for parkin), PINK1 (encoding for Pten-induced kinase 1) and DJ1 (or PARK7 encoding for Parkinson disease protein 7) have been identified in PD cases.11 PARK2 and PARK7 mutations cause a form of the disease known as autosomal recessive juvenile PD (ARJP).12 Recent genomewide association studies (GWASs) identified over 20 candidate risk genomic loci where single nucleotide polymorphisms can be connected with an increased risk of developing PD.13 Neurodegeneration: biochemical mechanisms and potential targets While damage signs are detectable in several areas of the brain, motor symptoms of PD are linked to the loss of substantia nigra (SN) dopamine (DA) neurons.14 These neurons are involved in the nigrostriatal pathway and their death results in the depletion of striatal dopamine, which is responsible for the clinical phenotype.6 From a biochemical point of view, the neurodegeneration appears to be caused by a multi-factorial chronic deregulation of cellular processes concurring to neuron death.11 The concerted cytotoxic events described to date encompasses mitochondrial impairment, oxidative stress, proteasome dysfunction, deficient membrane physiology or vesicular transport, unbalanced iron homeostasis, impaired gene transcription, protein degradation, microglia-dependent neuroinflammation, deregulation of protein translation, Ca2+ homeostasis and autophagy.8 One of the most studied pathological mechanisms focuses on the role of aggregated α-synuclein deposits in fibrillar form included in Lewy bodies (LBs), which are peculiar neuropathological features of sporadic PD found in PD brain specimens.15,16 α-synuclein is a 140 amino acids, approximately 14 kDa protein which can be found in its unfolded and monomeric form in the neuronal tissue, and in particular in the presynaptic compartment. Physiologically it exerts a protective action on nerve terminals. 17,10 It appears to be involved in vesicle dynamics and trafficking and neurotransmitter release.18 Thus, α-synuclein plays a pathological function when, due to a complex process involving hydrophobic interactions, it gives rise to oligomerization and formation of fibrils:19 aggregation of α-synuclein leads to neuronal distress and precedes neuronal cell death. These protein aggregates can be detected before the onset of neurodegenerative disease symptoms.17 Another big player in the onset of PD is oxidative stress. Dopaminergic neurons may undergo oxidative stress due to the presence of Reactive Oxygen Species (ROS)-generating enzymes such as monoamine oxidase and tyrosine hydrolase7 or environmental pollutants20.An excess of cytosolic dopamine can induce the formation of oxidized, reactive and toxic


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derivatives of dopamine itself. These species can pathologically modify proteins (such as the above mentioned αsynuclein to its cytotoxic form), induce dysfunction of mitochondria and accumulate in the nigral region.7,21,22 Current treatment Since, as described above, PD is the result of multiple mechanisms which have been only partially understood, PD therapy is symptomatical rather than preventive or curative. Currently, levodopa is the most effective pharmacological treatment for PD. Levodopa is converted to dopamine in the brain, compensating DA deficiency. It is usually combined with carbidopa or benserazide (decarboxylase inhibitors) to inhibit the peripheral metabolic activation to dopamine, limiting the side effects.23 Levodopa is effective on motor symptoms, although with adverse side effects such as nausea, vomiting and delirium. Long-term treatment, however, often results in a gradual loss of efficacy together with motor fluctuations and dyskinesia (LID, levodopa-induced dyskinesia).24 Therapeutic Targets for PD, and Natural and Semi-Synthetic Compounds Active on Them Non-pharmacological, complementary and alternative therapies are currently being studied to overcome these limitations and also target nonmotor symptoms.9 In this regard, we focused our attention on the potential use of molecules of a natural origin for the treatment of PD. We have taken into account the most recent, quality research paper reporting advances on natural compounds with well-described molecular targets and mechanisms against PD models, also considering polypharmacology-based multi-target strategies. Moreover, we dedicated particular attention to papers reporting pre-clinical and clinical data, where available, to provide the most updated and realistic alternatives to the current, limited available treatments.

Figure 1. Extract components undergoing clinical studies for PD. Interference with α-synuclein fibrillation Preclinical data show that herbal medicines may be effective against PD animal models, both as single molecules and in combination. It has been previously reported, for example, that tea consumption shows an inverse association with PD onset risk in case-control and cohort studies.25–27 More recently, the molecular components which are responsible for this effect have been highlighted. Polyphenols contained in tea are known to express antioxidant and antineuroinflammation properties (please refer to the relative paragraph for the potential role of natural antioxidants in PD), but some of the major components from this chemical class, such as epigallocatechin-3-gallate (EGCG) and theaflavins, may directly inhibit α-synuclein aggregation, remodeling fibrils and, as a consequence, reducing cellular toxicity.28,29 These molecular effects, which turn out in reduced dopaminergic neuronal injury and alleviated motor impairment, were observed in animal models13 and EGCG reached phase II trials.9 Coffee consumption has been related to a reduced risk of developing PD. J. Kardani et al. recently reported that caffeine, besides the action on A2A receptors (Adenosine Receptors A2A), influences α-synuclein aggregation in vitro, diminishing the toxicity of oligomers and aggregates in PD models.30 The flavonoid baicalein has been shown to inhibit the formation of α-synuclein aggregates and to promote the disruption of existing fibrils-31 More recently, a detailed mechanistic study has been published by Lobbens et al. concerning the activity of Geum urbanum extract, which is proposed as a fibrillation inhibitor: the ethanolic extract was investigated for its effect on hydrodynamic properties of αsynuclein also from a kinetic point of view, confirming its potential in inhibiting aggregation and, moreover,



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disintegrating performed fibrils in vitro.17 The dried root and rhizoma of Polygonum cuspidatum and its component resveratrol, which is a known neuroprotective agent in SN cells in vivo, increase degradation of α-synuclein in vitro.32,33 In addition, Cuminum cyminum essential oil and cuminaldehyde was recently reported to inhibit α-synuclein fibrillation in vitro. This effect may be due to a reaction of cuminaldehyde with Lys residues in α-synuclein, which would prevent the aggregation process.34 Monoamine oxidase (MAO) Monoamine oxidases (MAOs) are a class of enzymes that catalyze the oxidation of monoamines, which include dopamine, and exist in two isoforms, namely MAO-A and MAO-B. While MAO-A represents one of the targets in the treatment of depression and anxiety, modulation of MAO-B represents an appealing strategy against Alzheimer’s disease and PD.35 Lee et al. recently investigated the inhibitory activity on MAO-B of some components of the extracts of the roots of Sophora flavescens.36 Genistein, (-)-4-hydroxy-3-methoxy-8,9-methylenedioxypterocarpan, formononetin, (-)-maackiain, sophoraflavanone, kushenol F and kushenol E have been screened against recombinant human MAO-A and MAO-B. (-)-maackiain was found to be the most effective, reversible MAO-B inhibitor of the set (IC50 = 0.68 µM), with an outstanding selectivity index for this isoform with reference to MAO-A.36 This pterocarpan has also been described in Sophora angustifolia, Sophora japonica and Sophora subprostrata. The IC50 on MAO-B is one of the lowest reported to date among natural products. Similar mechanism of action has been previously described for 7-(6’R-hydroxy-3’,7’-dimethyl-2’E,7’octadienyloxy) coumarin and auraptene from Dictamnus albus (0.5 and 0.6 µM, respectively), gancaonin A from Cudrania tricuspidata (0.8 µM), (2E)-3-(1,3-benzodioxol-5-yl)-1-(4methylpiperidin-1-yl) prop-2-en-1-one from Piper nigrum (0.497 µM).37–39 Naturally occurring coumarins and their semi-synthetic or synthetic derivatives possess a wide spectrum of biological activities, ranging from anticancer to anti-inflammatory, recently reviewed by Sandhu et al.40 This class of compounds, and 3-phenyl coumarins in particular, are known as MAO-B inhibitors which may find application in the treatment of PD. Monankarins a-f are examples of potent MAO-B inhibitors isolated from Monaskus anka. Another class of compounds that are showing good in vitro results for the modulation of this enzyme is berberine and its semisynthetic derivatives.41 The reader interested in this topic is invited to refer to a more focused review on the role and potential applications of coumarins in CNS diseases that was very recently published by Skalicka-Wozniak et al.42 MAOs are also targeted in vitro by lapachol, its semy-synthetic derivative norlapachol and other analogues of the 1,4naphthoquinones class.43 Microglial activation Microglia are the resident immune cells in the brain and may play a role in preventing neurodegeneration. Resting microglia represents the physiological condition of the brain, with low level of inflammatory molecule expression in the immune system.44 Thus, microglial hyperactivation in the substantia nigra is one of the events connected with neuroinflammation causing the loss of dopaminergic neurons in the brains of PD patients and animal models.45,46 Prenyloxyphenylpropanoids are C-prenylated, secondary metabolites of phenylpropanoids, which are found in plants (Rutaceae, Apiaceae, and Compositae, to name a few) containing edible parts. These compounds are reported to express anticancer, anti-inflammatory and antimicrobial activities.47 Okuyama et al. studied the effects of auraptene (AUR), 7isopentenyloxycoumarin (7-IP), 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid (4′ -geranyloxyferulic acid, GOFA) on lipopolysaccharide (LPS)-induced PD-like mouse model.48 Compounds have been considered for their neuroprotective activity, laying the basis for a behavioral performance test on animals and hypothesizing the involvement of up-regulation of BDNF (brain-derived neurotrophic factor) and/or GDNF (glial cell-derived neurotrophic factor) neurotropic factors in ameliorating pathological conditions. Naringin, a flavanone glycoside found in grapefruits and citrus fruits has been recently studied by Kim et al. for neuroprotective activity in 6-hydroxydopamine(6-OHDA)-induced PD mouse model:44 naringin protected the nigrostriatal DA neurons and induced the activation of mammalian target of rapamycin complex 1 (mTORC1), a survival factor for DA neurons. This flavonoid also inhibited microglial activation in SN. Thus, naringin alone may not be enough to restore the nigrostriatal DA projection in the animal model, leading the authors to only defining the compound as a “beneficial natural product”.44 Tripchlorolide and triptolide, from Tripterygium baicalensis, were also investigated in rat and mice models and were shown to inhibit microglial activation and upregulate nerve growth factors.49,50 Akt and mitochondrial dysfunction


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Mitochondrial dysfunction and ATP loss characterize PD DA neurons. Mortiboys et al. investigated the effects of ursolic acid and some derivatives on tissues from patients showing familial PD. The ameliorating role of ursolic acid, ursocholanic acid, ursodeoxycholic acid and dehydro(11,12)ursolic acid lactone was studied on parkin (PARK2) and LRRK2G20195 mutant fibroblasts, the two most common causes of early-onset and late-onset inherited PD, respectively. An increased activity of the complexes of the mitochondrial respiratory chain and mitochondrial membrane potential was observed. The rescued mitochondrial dysfunction has been reported to be connected with the activation of a glucocorticoid receptor with increased phosphorylation of Akt (Protein kinase B (PKB)), leading to normalized intracellular ATP levels and survival. Thus, ursolic acid itself is known for its protective effect against muscular cellular atrophy depending on an increased phosphorylation of Akt at Ser473.51 Akt survival signaling has been recently invoked as a possible mechanism of action of another class of natural compounds: dibenzocyclooctadiene lignans from Schisandra chinensis.52 These compounds, and schisantherin A in particular, have been reported to be effective against PD models in vitro and in vivo. Multi-target compounds and dopaminergic modulation Multiple drug therapy, consisting in the use of a combination of molecules with potentially different mechanisms of action in the treatment of one pathological condition, is one of the recent trends in medicinal chemistry to overcome the limitations (tolerance, side effects, drug resistance) of conventional treatments. Moreover, in the case of PD, therapies involving multiple components of a natural source, from a single plant or a combination, represent attracting polypharmacology-based strategies that may help in targeting some symptoms, as the nonmotor ones which are not ameliorated by current treatments. In this regard, Zhang et al. studied two polyphenols from Alpinia oxyphylla, namely protocatechuic acid (PCA) and chrysin.53 PCA and chrysin have been tested in vitro promoting, in 6-OHDA-treated PC12 cells, a decrease in the release of lactate dehydrogenase (LDH), which is involved in the neuroinflammation process. Moreover, reduced dopaminergic neuron loss have been observed in zebrafish and mice models with a therapeutic effect comparable to that of selegiline. PCA and chrysin showed synergistic neuroprotective effects through different mechanisms, such as upregulation of nuclear factor-erythroid 2-related factor 2 (NRF2) expression and transcriptional activity and modulation of cellular redox status through upregulation of expression of antioxidant enzymes (heme oxygenase-1, superoxide dismutase, catalase). NRF2, a trigger for a cascade of antioxidative responses in the cell, has also been reported to be targeted by oxyphylla A from A. oxyphylla. This natural compound has been screened in vitro and in vivo, ameliorating DA neuron loss and behavioral impairment in zebrafish and mice models.54 Protocatechuic acid and chrysin also seem to ameliorate nucleolin deficiency: the expression of nucleolin, which is a protein involved in the post-transcriptional regulation of the amyloid precursor protein mRNA in PD and other neurodegenerative diseases, is lowered in PD patients and PD cellular models.53,55 Ginseng is a plant well known for its anti-inflammatory properties and for its beneficial effects on fatigue and cognition. Some components of its extracts, namely Rb1, Rg1, Rd, Re, notoginsenoside R2 and pseudoginsenoside-F11, were studied for their effects in PD animal models.56,9 As for other molecules described in this section, the neuroprotective action of these compounds seems to be exploited throughout multiple mechanisms. In particular, decreased nigral iron levels together with decreased apoptosis, regulation of N-methyl-D-aspartate (NMDA) receptor and, a reduced neuroinflammation may contribute in the final amelioration of the pathological condition.56–58 Over 20 kinds of ginsenosides contained in American Ginseng were shown to improve impairments in movement and loss of neurons.7 Another group of molecules, of various origins and from different chemical classes, exploit anti PD actions directly by rebalancing dopamine levels in neurons. Mucuna pruriens and Vicia faba beans, for example, are rich in levodopa itself and have neuroprotective effects in the SN, reducing dyskinesia.59,60 M. pruriens has also been evaluated in a clinical trial for levodopa pharmacokinetics and clinical efficacy.61 Ergot alkaloids show dopaminomimetic activity, together with a broad range of pharmacological effects. Natural compounds and synthetic derivatives (pergolide, bromocriptine and lisuride) exploit their action by stimulating D1 and D2 receptors (Dopamine receptors). Other compounds act through different mechanisms but promote a similar effect: Ginkgo biloba extract EGb 761, rich in flavonoids and ginkgolides, increases extracellular dopamine concentration in prefrontal cortex in rat models, and its effect has also been evaluated in a clinical study.62,63 Similarly, tetramethylpyrazine from Ligusticum chuanxiong have been demonstrated to modulate dopamine metabolism in rat striatum. Furthermore, another mechanism reported for some natural anti-PD remedies is the stimulation of adenosine receptors. This mechanism is the one reported, for example, for paeoniflorin from Paeonia lactiflora, which activity has been demonstrated in rodent models.7,64



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Oxidative stress The class of natural compounds interfering with cellular oxidative stress is surely, to date, the most widely represented, given the high number of molecules of a natural origin endowed with redox properties and the notable relevance of this phenomenon in PD onset and progression. Thus, anti-ROS therapeutic approaches may not be defined as selective strategies, and have already been proposed, with a variety of outcomes, in other pathologies such as atherosclerosis, cancer, diabetes and neurological diseases. Redox properties are often claimed by combinations of natural molecules (often polyphenols and flavonoids) from a single or multiple sources, which have been studied as a de facto polypharmacological approach. This mechanism of action is expressed by the components of a traditional chinese decotion named San-Huang-Xie-Xin-Tang containing Coptidis rhizoma, Scutellariae radix and Rhei rhizoma which have been reported to ameliorate PD conditions in vitro and in vivo.65 Focusing on the molecular level, Sarrafchi et al. published very recently a review on herbal antioxidants that are currently being studied in vitro or in vivo for their potential application in the treatment of PD.7 As a consequence, this topic will be only briefly discussed in this review, even though antioxidant mechanism concur in the action of molecules or extracts that are discussed in other sections. Thus, we here aim to provide a quick update, which may be of interest to the reader, on these compounds or extracts that are being investigated at least at a preclinical level. It has to be pointed out that the antioxidants reported in this sections often act through various combinations of biochemical mechanisms, involving radical scavenging, modulation/inhibition of enzyme activity and expression or modulation of the ROS pathways at different levels. These compounds and extracts may also exploit their action through other mechanisms described elsewhere in this review. Coenzyme Q10, an antioxidant involved in the mitochondrial function the levels of which are lowered in PD patients, was evaluated in a randomized placebo-controlled trial in combination with tocopherol, resulting in a slower progression of the disease.66 In addition, resveratrol, a known polyphenol from grape skin, has been shown to protect DA neurons from oxidative stress in vivo in mice.67 Acanthopanax senticosus extract exploits neuroprotective effects on DA neurons in rat models, raising the concentration of dopamine and noradrenaline. Moreover, its component sesamin have been reported to be a modulator of a set of ROS-related enzymes in cell such as catalase and superoxide dismutase.68,69 In connection with contrasting oxidative distress in neurons, echinacoside from Cistanche salsa and whole plant ethanol extract of Gymnostemma pentaphyllum showed neuroprotective effects on 6-OHDA-induced PD in rat and mice models.70 Moreover, A. oxyphylla extracts, in addition to the mechanisms described in other paragraphs of this review, are also reported to interfere with redox balance in similar models.71 Green tea catechins from Camelia sinensis, together with the other mechanisms reported here, protect neurons by inhibiting ROS-nitrogen monoxide (NO) pathway in rat models. Epigallocatechin-3-gallate (EGCG) have been shown to be the most effective component of the class in vitro, regulating dopamine transporter via protein kinase C modulation.72,73 Hypericum perforatum, and in particular its methanol extract, decreases oxidative stress in vivo in rats by enhancing the gene expression of antioxidant enzymes. Its component hyperoside was also shown to contrast peroxide-induced cytotoxicity in vitro.74 The mediterranean diet has been associated with reduced risk of developing degenerative diseases such as PD. Polyphenols, and hydroxytyrosol from natural olive oil in particular, are believed to be responsible for the antioxidant role. These compound scavenge free radicals and regulate antioxidant enzyme activity. Gallardo et al. very recently studied the antioxidant properties of hydroxytyrosol in vitro, preparing some semi-synthetic nitro- and alkyl-derivatives and building preliminary structure-activity relationship data.75 Glucosinolates (GLs) and their breakdown products isothiocyanates (ITCs) represent a class of natural compounds that are receiving growing interest in the recent years because of their potential activity against carcinogenesis and neurodegenerative diseases.76 ITCs are released after cell damage by the action of myriosinase on the GL and express their biochemical activities through a combination of mechanisms, recently reviewed by Giacoppo et al., including antioxidant activity, induction of the Keap1/Nrf2/ARE pathway and the modulation of some metabolic enzymes.76 These compounds have been described in Brassicaceae and Moringaceae: glucomoringin, from Moringa oleifera, provides the glycosylated isothiocyanate moringin after myriosinase-induced hydrolysis. Moringin, in particular, showed neuroprotective effects against neurodegenerative disorders. R-sulphoraphane (R-SFN), released by glucoraphanin, preserves DA neurons from substantia nigra in mouse models. Multiple mechanisms, reviewed by Giacoppo et al., have been proposed for the observed effect, involving redox scavenging, modulation of glutathione and of Nrf2 levels.76 Similarly, glucoraphanin, from Brassica oleracea and bioactivated by myriosinase has been


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demonstrated to be effective against secondary events triggered by PD, such as deficits in movement coordination and tremors, in mouse models. Stimulation of neurotropic growth factors (GAP-43) appear to be involved.77

Figure 2. Natural compounds in advanced study (preclinical models) for PD.

Considerations Biochemical processes leading to PD start in patients before the manifestation of its clinical symptoms. Moreover, current treatments are temporary, not disease modifying and often do not take into account nonmotor symptoms. The search for novel strategies against PD, together with preventing agents and compounds with lower side effects, is wide open and natural molecules may play a role. Herbal medicines may have a great potential in providing promising compounds against PD, but clinical data and a detailed characterization of bioactive components and their mechanisms of action must be provided.

Table 1. Table of the natural compounds and extracts that are under study for the treatment of Parkinson’s Disease. Compound

Source

Mechanism of action

Model of the study

Referenc e

alaternin

Cassia obtusifolia, Cassia semen, cassia tora

anti-inflammatory

preclinical

78

astragaloside IV

Astragalus membranaceus

redox

in vitro

71

auraptene

Dictamnus albus

inhibition of MAO, modulation of microglial activation

in vitro, preclinical

Chrysanthemum morifolium, Chrysantemum indicum

Chrysanthemum morifolium, Chrysantemum indicum

redox



37,38,48

79


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chrysin/protocatechuic acid (PCA) combination

Alpinia oxyphylla

upregulation of NRF2, upregulation of antioxidant enzymes, expression of nucleolin, reduction of oxidative stress (extract)

7-(6’R-hydroxy-3’,7’dimethyl2’E,7’octadienyloxy) coumarin

Dictamnus albus

inhibition of MAO

in vitro

37,38

7isopentenyloxycoumarin (7-IP)

Rutaceae, Apiaceae, and Compositae

modulation of microglial activation

preclinical

48

baicalein

Scutellaria baicalensis, Oroxylum indicum

inhibition of α-synuclein aggregation

in vitro

31

coumarins

Apiaceae, Rutaceae

redox, inhibition of MAO

in vitro

40,42

cuminaldehyde

Cuminum cyminum


in vitro

34

epigallocatechin-3-gallate (EGCG), theaflavins, polyphenols

Camelia sinensis

inhibition of α-synuclein aggregation, reduction of oxidative stress, modulation of protein kinase C

in vitro, preclinical, clinical

fraxetin, liriodendrin, esculin

Fraxinus rhynchophylla, Fraxinus chinensis, Fraxinus szaboana, Fraxinus sielboldiana

redox

in vitro

80

gancaonin A

Cudrania tricuspidata

inhibition of MAO

in vitro

37,38,48

Geum urbanum (ethanolic extract)

Geum urbanum


in vitro

17

Ginkgo biloba extract EGb 761

Ginkgo biloba

dopaminergic activity

preclinical, clinical

decrease of nigral iron, regulation of N-methylD-aspartate receptor, modulation of inflammation


Brassica oleracea

stimulation of neurotrophioc growth factors

preclinical

77

olive oil

redox

in vitro

75

Hypericum perforatum

reduction of oxidative stress


inhibition of MAO

in vitro

43

Sophora flavescens

inhibition of MAO

in vitro

36

Monascus anka

inhibition of MAO

in vitro

42

Ginseng (Rb1, Rg1, Rd, Re, notoginsenoside R2, pseudoginsenoside-F11)

glucoraphanin hydroxytyrosol (and nitro, alkyl derivatives) Hypericum perforatum (methanol extract), hyperoside lapachol, norlapachol (semi-synthetic) (-)-maackiain monankarins a-f



53,71

28,29,72

9,62,63

7,9,56–58

74

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Mucuna pruriens (extract)

Mucuna pruriens

levodopa

clinical

59

naringin

grapefruit, citrus


preclinical

44

oxyphylla A

Alpinia oxyphylla

upregulation of NRF2


paeoniflorin

Paeonia lactiflora

modulation of adenosine receptors

preclinical

7,64

Rutaceae, Apiaceae, and Compositae


preclinical

48

Piper nigrum

inhibition of MAO

in vitro

39

resveratrol

Polygonum cuspidatum, grape skin

degradation of αsynuclein, reduction of oxidative stress

preclinical

32,33

San-Huang-Xie-XinTang (chinese decotion)

Coptidis rhizoma, Scutellariae radix, Rhei rhizoma



schisanterin A

Schisandra chinensis

Akt pathway


sesamin

Acanthopanax senticosus


preclinical

68,69

R-sulphorane

Brassicaceae

increase of glutathione and Nrf2 levels, redox

preclinical

76

tenuigenin

Polygala tenuifolia, Polygala sibirica

redox

in vitro

81


clinical

66


preclinical

49,50

Akt-mediated modulation of motochondrial function

in vitro (ex vivo)

levodopa

preclinical

3-(4′-geranyloxy-3′methoxyphenyl)-2-trans propenoic acid (4′ geranyloxyferulic acid, GOFA) (2E)-3-(1,3-benzodioxol5-yl)-1-(4methylpiperidin-1-yl) prop-2-en-1-one

tocopherol tripchlorolide and triptolide

Triptergyum baicalensis

ursolic acid

Vicia faba beans

Vicia faba

54

65

52

82

60

HUNTINGTON’S DISEASE Etiology and symptoms Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease.83,84 This pathology has a different prevalence all over the world, with significant differences between all the continents.85 In Asia, for example, there is an incidence of 0.4 people affected per 100.000 considered persons, and this data is significantly lower if it is compared with that of North America, where 7.33 Americans per 100.000 suffer of this pathology. On average, for the whole worldwide population, the incidence is 5 cases per 100.000 people. From a statistical analysis conducted by Michael D. Rawlins and co-workers, the incidence of this pathology grows about of 15% for each decade.85 This pathology affects males and females in the same way, with no gender differences. The median age of diagnosis is



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around 40 years, with a wide range in age of onset. The expectancy of life after the diagnosis is around 15 to 20 years.86,87 Unlike the other neurodegenerative pathology which has been previously discussed in this review, HD is the only one that presents a precise and defined cause that leads to the onset of this pathology. HD is generated by a genetic mutation of the gene (HTT), situated on chromosome 4, that encoded for the huntingtin (Htt) protein.83,87 The pathological gene present an abnormal number of CAG repeats, that leads to the production of a protein that presents an excessively long polyglutamine stretch near the N-terminus.83,87 This pathology is characterised by different clinical signs, such as progressive motor, behavioural and cognitive declines. The earliest manifestation of the pathology is usually a general impairment of the motor capacity following the appearance of chorea.83,84 This gradually evolves in a general rigidity and bradykinesia in late stages. This may be different for those patients who suffer of juvenile HD.86,87 Usually these young patients do not exhibit chorea at the beginning of the pathology, but they manifest directly rigidity and bradykinesia. Generally, in concomitance with this motor degeneration, there is a slow but appreciable change of the behaviour of the patient who suffers of HD.84,88 Most of these changes appear before the diagnosis, but they are so subtle and progressive that they can be appreciated and defined as a consequence of the pathology only after a certain period. The consequence of these modifications is the instauration of a psychiatric disorder that leads in the late stages to the manifestation of depression, obsessive compulsive behaviours, irritability and outburst.84 The last aspect of this pathology is the gradual and irreversible cognitive impairment. Unlike AD dementia, HD dementia is largely subcortical, marked by slow thought processes and executive dysfunction, and problems with attention and sequencing.88 All these transformations, and the sequence with they appear, are strictly linked with the types of neuronal circuits that are progressively altered by the advancement of the pathology. Neurodegeneration: biochemical mechanisms and potential targets HD is morphologically characterised by a massive striatum degeneration and atrophy.83 This event starts before the diagnosis of the pathology and in the last stages of the disease the atrophy interests not only the striatum but all the CNS, in particular it involves the white matter.84 From a biochemical point of view all the macroscopic manifestations are referable and attributable to a single gene mutation. The responsible of HD is the HTT gene which presents an abnormal number of CAG repeats.83,87 In a healthy subject, the number of repeats are on an average 17 to 20. If the repeats are present in a range between 27 to 35, usually the pathology does not manifest, but those people who present these alterations result more prone to pass an augmented number of repeats to the offspring, and this is due to the higher genetic instability of these subjects. With 36 to 39 repeats there is an incomplete penetrance, but with 40 or more repeats, the penetrance is 100%.87 Usually the diagnosis of HD is done around the fourth and fifth decade of life.84,87 The age of onset is strictly linked with the number of repeats: the higher the number, the earlier the onset of the pathology. In juvenile cases of HD, where the onset is before 20 years old, the number of repeats is usually higher than 60.88 Due to the instability of the genetic heritage and the propensity to increase the number of CAG repeats, the offspring of the patients who suffer from HD presents an earlier onset.87 This mechanism is called anticipation and is quite common in this type of disorders. As previously mentioned, the mutated gene HTT encodes for a protein called huntingtin. This protein, in its mutated form, presents an exaggerated number of glutamine amino-acids in its N-terminus.86 This alteration renders the protein less active and more prone to form oligomers and then aggregates. Still today there is a heated debate about which are the biochemical mechanisms that lead to the onset of HD after the mutation of HTT, and about why striatum is most stricken with respect to all the other structures of the CNS. Concerning the first question, the most accepted theory describes the mutation of HTT as an event that leads to the formation of a protein which has gained certain toxic functions and, at the same time, that has lost certain other physiologic functions.87,88 The gaining of function is referred to the ability of the mutated protein to exert a toxic behaviour. All the toxic features that are expressed by the new Htt are derived from the excessive polyglutamine stretch. This mono-aminoacidic tail is toxic when it is part of the whole Htt or also by itself alone. In fact, the polyglutamine stretch can be enzymatically cleaved by the caspase 6.87,88 This mutated protein, considered together with the polyglutamine chain, has a widespread mode of action. It is able to alter the energetic metabolism of the neuronal cell, to affect the gene expression, to downregulate the clearance of the aggregates of misfolded proteins inducing the instauration of a vicious circle.86 The resulting mutated Htt is also characterised by a loss of function. In particular, this alteration leads to a reduced synthesis of the brain-derived neurotrophic factor (BDNF) and to a deep alteration of the microtubular transport of vesicles among the neural cell.87 Htt is one of the players involved in the process of transduction of the BDNF gene. In


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its wild type form it is able to interact with REST (RE1-Silencing Transcription factor), a negative modulator of the gene transduction, Sequestering it and avoiding it to enter within the nucleus, Htt is able to promote the synthesis of BDNF. Furthermore, Htt exerts its major activity as a modulator of the vesicular traffic of the neural cell. Htt is a protein adaptor that permits the right interaction between those proteins present on the vesicular surface and those ones that are present on the cytoskeleton structure, in particular with microtubules and actin filaments.87 After the drastic mutation, Htt is no more able to modulate this aspect of the neural cell life and this is one of the most deleterious events that leads to the cell death. With the aim of understanding the reason why the striatum is more sensitive to this type of mutation, several theories were proposed. One of the most accredited is that one that finds its fundaments on the excitotoxicity mediated by the glutamic acid with the NMDA (N-Methyl-D-Aspartate) receptors.83 In fact, medium sized spiny neurons (MSNs), that are the most sensitive cells within the striatum in the HD, have an augmented number of NMDA receptors compared with other types of cells. In particular, they present an increased number of NMDA receptor subtype NR2B/NR2A, and this leads to an increased sensitivity to excitotoxicity. Current treatment The actual treatments for HD are only based on the attenuation of all the symptomatic effects of the pathology. No therapies counteracting the onset of the pathology, or at least slowing the progression of the disease are available to date. The diverse aspects of HD are currently treated separately: motor symptoms, behavioural and cognitive disorders. These clinical signs are due by the degeneration of different areas of the brain. Each one of these areas alters a particular neural circuit and this leads to the onset of all the symptoms. In the HD there is a deep and general loss of the homeostasis of certain neurotransmitters, in particular: dopamine, glutamate and γ-aminobutyric acid are considered the most affected ones.86 For these reasons, all the therapies used for this pathology aim at restoring the physiological levels of these neurotransmitters. Chorea is one of the most precocious and debilitating signs, that can avoid to the patient to lead a normal lifestyle. Tetrabenazine is the only US Food and Drug Administration approved drug for HD, approved for the treatment of chorea.86 Its mechanism of action is based on the presynaptic depletion of the catecholamine neurotransmitters, in particular dopamine, reversibly inhibiting the Vesicular Monoamine Transporter Type 2 (VMAT2). A treatment with 12.5 mg/die to a maximum of 100 mg/day of tetrabenazine is really efficient to reduce this particular symptom. This drug is not without adverse effects, one of the most spread and subtle is the induction of a depressive state, that, if not diagnosed, could lead to suicide. Another drug that is used to reduce chorea is the NMDA antagonist amantadine, currently used for the treatment of AD.86 A therapy based on the administration of 400 mg/die of amantadine is efficient in the treatment of HD patients. Considering a typical manifestation of this pathology, the so-called parkinsonism, which is typical of late stages of the disease or in the cases of juvenile HD, other therapeutic options have to be considered. In these cases, the aim of the therapeutic intervention is to increase the dopaminergic tone, using remedies that are used in the treatment of PD such as levodopa.86 For what concerns the behavioural and psychiatric disturbance, several common strategies are adopted, that are not specific for HD. There are several and contrasting opinions about the efficacy and the appropriateness of the usage of Selective Serotonin Reuptake Inhibitors (SSRIs) or other antidepressant and antipsychotics agents in the management of HD.86 This is due by the complex and wide spread alteration of the majority of the neural circuits and for this reason there are more difficulties in the finding of the optimal drug and dosage for these patients. Another element that is extremely important, is the maintaining of the body weight, avoiding a sudden depletion of the energy reserves of the organism. For this reason, the use of high-calories aliments is desirable.86 Considering the actual opportunities of treatment and the fact that none of these are really effective on the aetio-pathologic mechanism of HD, seems to be urgent the development of new pharmacological strategies able to block the progression of this pathology should be considered. Therapeutic Targets for HD, and Natural and Semi-Synthetic Compounds Active on Them Interference with protein aggregation While macromolecule, and in particular protein, self-assembly is a biomolecular process which is fundamental for the life of a cell, it is now clear that aberrant misfoldings may lead to non-native and toxic aggregates responsible for several neurodegenerative disorders. These insoluble aggregates are generally defined “amyloid”. They are insoluble, protease-resistant and predominantly structured in beta-sheets. These agglomerates are a shared characteristic in different neurodegenerative diseases such as Alzheimer’s and Huntington’s disease. Usually they are considered the



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factor that leads to the onset of the pathology. Currently, with the aim to interfere with all the processes that lead to the misfolding of the protein, several approaches are under studies. The most promising are: stabilization of the native conformation of the proteins, inhibition of the fibrillation, enhancement of the clearance of toxic aggregates. A. Sgarbossa reviewed the natural compounds, mostly polyphenols, that are claimed to counteract amyloidogenesis in neurodegenerations. 89 Natural phenolic compounds, such as (EGCG), curcumin and resveratrol, are reported to interact with peptides and proteins, modifying their structural properties and influencing their activity. Thus, the author herself points out the fact that many efficient inhibitors of aggregation in vitro often fail as therapeutic agents in vivo. More recently Zeng et al. investigated the effect of xyloketal B from marine mangrove fungi and some synthetic derivatives in a Caenorhabditis elegans model of HD. 90 The natural compound and the synthesized analogues, which contained simplified molecules and derivatives bearing amides, thioesters and carboxylic acids, showed a protective effect interfering with the huntingtin aggregates, attenuating their formation. According to the proposed in silico models, the interaction of the compounds with the aminoacidic residues GLN393 and GLN36 appears crucial.90 Autophagy Autophagy consists in a cellular event that involves the lysosomal degradation of superfluous cellular biochemical matter to recycle constituents and nutrients which are fundamental for the life of the cell. This process involves the formation of a membrane, the inclusion of the substances and organelles in an autophagosome and the lysosomial degradation. While this mechanism is normally active at low basal levels, its dysregulation and defective functioning have been associated with neurodegenerative disorders, including HD. Wong et al. recently reported that neferine, a bisbenzylisoquinoline from Nelumbo nucifera, can act as an autophagy-inducer which may help in removing the neurotoxic aggregates.91 The proposed mechanism, at a cellular level, appears to be dependent on ATG-7 (Autophagy Related 7) gene. Moreover, it has been shown that neferine induces autophagy via activation of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) kinase signaling pathway. This pathway acts as an energy sensor in the cell, maintaining cellular metabolism and homeostasis. In periods of starvation this cascade is activated and this leads to an increased autophagic activity. Neferine is able to stimulate this pathway and as a consequence to increase the clearance of Htt through an autophagic mechanism.91 The same research group previously reported that the ethanol extracts of Radix Poligalae, and onjisaponin B in particular, are able to induce huntingtin removal via autophagy through AMPK-mTOR signaling pathway.92 Natural compounds interfering with other target proteins It has been reported that the overexpression or the stimulation of molecular chaperones, such as Hsp70 and Hsp90 (Heat Shock Proteins), may suppress the aggregation of elongated PoyQ fragments in cellular and animal models.93 In particular, a methanolic extract containing actinomycin D from Papua New Guinea marine sediment has been shown to influence the Hsp-mediated stress response in S. cerevisae, with a decrease of polyQ aggregates in the PC12 cell model. Interestingly, 4-100 ng/mL concentrations were found to be active in suppressing the aggregation, while higher and lower concentrations were inactive.93 In the field of the protein-mediated mechanisms, Khan et al. recently proposed the class of caspases as a potential target in the treatment of HD. Caspases are a class of protease which are divided in inflammatory and apoptotic, and caspase-1 and -3, in particular, have been reported to be involved in the progression of neurodegenerations. These enzymes were found to be highly active in HD animal and in vitro models.94 Thus, the known inhibitors are generally of a peptidic nature, which is usually considered not desirable for a novel drug candidate. While this field is rather new and unexplored, the same are investigating a set of small natural molecules (rosmarinic acid, curcumin, luteolin, huperzine A) as potential caspase inhibitors through a set of in silico tools (Molecular Docking). SIRT3, a member of sirtuin family, is considered another potential target in the treatment of HD. This protein is present in mitochondria and is related to the control of energy metabolism. Fu et al. reported that mutant Htt induces the depletion of SIRT3 with negative effects on mitochondrial membrane potential and, eventually, cell life.95 The authors investigated a set of 22 natural resveratrol analogues from Vitis spp. in cellular models, demonstrating that viniferin, in particular, activates AMP-activated kinase (AMPK), has a protective effect against SIRT3 depletion and preserves mitochondrial function reducing reactive oxygen species (ROS). Sun et al. recently reviewed the neuroprotective effects of natural saponins against several neurodegenerations.96 While the authors propose a number of mechanism by which saponins may interfere with these pathologies, such as modulation of neurotransmitters, anti-apoptosis, modulation of neurotrophic factors and inhibition of tau phosphorylation, they claim that the modulation of intracellular calcium levels appears to be the most relevant process promoted by ginsenosides in animal HD models.


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Figure 3. Natural compounds currently under study for HD.

Considerations Currently very little is known about the potential application of natural compounds against HD. To the best of our knowledge, preliminary in silico and in vitro observations were mainly reported to date. Thus, the targets described above appear to be promising and the need to explore these mechanisms by screening the investigated natural molecules. CONCLUSIONS This review has shown what are or at least could be the possibilities furnished by a natural approach for the development of new chemical entities able to modulate the progression of two different types of neurological disorders. Nature gives us the possibility to experiment with different structures that have a degree of complexity and heterogeneity which are difficult to obtain with a pure synthetic approach. For this reason, the use of natural compounds or natural derived molecules can lay the foundation for a new pharmacological approach for the treatment of these pathologies. This is particularly true because this kind of new chemical entities are often not only able to modulate a single effector of the pathology, but they may be active also on other targets which have a fundamental to block the progression of the disease. Furthermore, it is important to remember that usually these compounds of natural origin are more easily accepted by the patients, and the society in general, because they are considered healthier and more sustainable with respect to the synthetic analogues. All these considerations are particularly noticeable considering the fact that neither PD nor HD, until today, have a therapeutic option that is able to counteract the progression of the pathology.

CONFLICT OF INTEREST The authors declare no conflict of interest.



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AUTHOR CONTRIBUTIONS Mr. Zanforlin Enrico wrote the abstract, the introduction, the three first paragraphs of Huntington’s Disease and the conclusions; -

Professor Zagotto Giuseppe made the bibliographic research and he revised the manuscript;

Dr. Ribaudo Giovanni wrote the whole paragraph on Parkinson’s Disease and the remaining part of Huntington’s Disease.

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Natural Compounds

Synthetic Compounds

Synthetic Compound usually exploit few “handhold” with a strong interaction with the aim to reach a therapeutic effect. On the other side, Natural Compound use a lot of different and weaker interactions and in this way they can obtain success also in such therapeutic fields where a “Classical” approach has failed. ACS Paragon Plus Environment

The Medicinal Chemistry of Natural and Semisynthetic Compounds

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