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Potential antiparkinsonian agents derived from South African medicinal plants
Accepted Manuscript Title: Potential antiparkinsonian agents derived from South African medicinal plants Authors: Adaze Bijou Enogieru, Sylvester Ifeanyi Omoruyi, Donavon Charles Hiss, Okobi Eko Ekpo PII: DOI: Reference:
S2210-8033(18)30031-9 https://doi.org/10.1016/j.hermed.2018.06.001 HERMED 222
To appear in: Received date: Revised date: Accepted date:
10-10-2017 24-5-2018 11-6-2018
Please cite this article as: Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE, Potential antiparkinsonian agents derived from South African medicinal plants, Journal of Herbal Medicine (2018), https://doi.org/10.1016/j.hermed.2018.06.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Potential antiparkinsonian agents derived from South African medicinal plants Authors: Adaze Bijou Enogieru a, Sylvester Ifeanyi Omoruyi a, Donavon Charles Hiss a, Okobi Eko Ekpo a* a
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Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, SOUTH AFRICA Corresponding author: * Dr. Okobi Ekpo, Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, SOUTH AFRICA. Fax: +27-21959-3125; E-mail: [email protected]. Abstract
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Many natural products and medicinal plants have been tested experimentally for validation of their reported folkloric efficacies. South Africa has abundant plant biodiversity and medicinal plants are still widely used in most parts of the country for the treatment of common neurodegenerative disorders (NDDs). However, very few studies have reported on the validation of South African medicinal plants (SAMPs) used in traditional, complementary and alternative medicine (TCAM) for the treatment of NDDs. Extensive testing provides the basis for clinical trials which progressively lead to the development of affordable indigenous and readily available products for preventing or treating NDD including Parkinson's disease (PD), one of the most common central nervous system (CNS) disorders among the elderly often characterized by the progressive loss of dopaminergic neurons (DNs) or dopamine-producing cells in the substantia nigra of the midbrain. In this study, several databases were searched to identify active compounds in SAMPs known to potentially protect neurons from progressive damage as seen in most NDDs. Our search results showed many commonly used SAMPs and their possible mechanisms of action including prevention of neuronal death by inhibition of Caspase-3 activation, MAO-B enzyme inhibition as well as restoration of glutathione content in cells. Most of the observed effects relate to the protection of DNs from degeneration, indicating the potential use of these compounds as antiparkinsonian agents. This review article therefore identifies and presents research gaps on how indigenous SAMPs could be studied more extensively for their chemical constituents and bioactivity against age-related NDDs such as PD.
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Keywords: Dopaminergic; Naringenin; Neuroprotection; Parkinson's disease; Rutin; Traditional medicine.
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Introduction Epidemiology and pharmacology of PD Models of PD Methodology Studies on South African plants with antiparkinsonian activity 1
Rutin as an active compound in South African Medicinal Plants Mechanisms of action of Rutin in PD models Naringenin as an active compound in South African Medicinal Plants Mechanisms of action of Naringenin in PD models Conclusion and Future Perspectives
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Introduction
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South Africa's large cultural diversity is complemented by an exceptionally rich plant diversity of about 30,000 flowering plant species which is about a tenth of the world's plant population (Stafford et al., 2007). Most traditional herbal medicines used in South Africa are derived from as many as 1020 plant species sources (Fennell et al., 2004; Mander et al, 2007), using local expertise and extensive indigenous knowledge systems which date back as far as 1000 BC (Street et al., 2008). Hitherto, the practice of traditional and Western medicine co-exist in South Africa (Stafford et al., 2008) and the majority of the low-income population utilize the over-burdened public healthcare facilities (Morris, 2001; Eastman, 2005) and in most cases, concurrently with the relatively accessible and affordable traditional medicines (Marais et al, 2015; Audet et al., 2017). Recently, the misleading reports that 80% of South Africans use traditional medicines for their primary healthcare needs have been controverted (Nxumalo et al., 2011 and Oyebode, et al., 2016), although it is common knowledge that the practice of traditional medicine remains active especially among rural communities in South Africa.
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Renewed interests in traditional pharmacopoeias over the years indicate that scientists are interested not only in the determination of the scientific rationale for plant use, but also with the discovery of novel compounds of pharmaceutical value (Fennell et al., 2004). Traditional knowledge provides the basis for guided scientific study of plants that may be medicinally useful as against random screening procedures (Cox, 1994). Thus, more than 122 pharmaceutical compounds from 94 plant species have been discovered through guided ethnobotanical screening (Fabricant, 2001), using different assays to test for biological activity, firstly in vitro and later, in vivo for promising compounds (Fennell et al., 2004).
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Many neurodegenerative and psychiatric conditions in South Africa have been treated for centuries with traditional herbal medicines (Gqaleni et al, 2007) and PD is one such condition, often characterized by four major motor symptoms - rigidity, bradykinesia, tremor, and postural instability (Savitt et al., 2006). In PD, there is progressive loss of dopaminergic neurons in the substantia nigra of the midbrain and acetylcholine activity is increased due to dopamine deficiency, leading to an imbalance of many functions (Zhu et al., 2008). The two major pathological findings in PD patients include the presence of Lewy bodies in the substantia nigra, and loss of neurons in portions of its ventral part (Calne, 2001). Available pharmacotherapeutic strategies for PD include oral administration of levodopa (LDOPA), dopamine receptor agonists and monoamine oxidase-B (MAO-B) inhibitors (Sarkar et al., 2016). Deep brain stimulation of the subthalamic nucleus and globus pallidus by surgically implanted electrodes as well as stem cell transplantation into the striatum are other well-known treatment modalities (Fu et al., 2013; Buzhor et al., 2014; Fu et al., 2015). Protective treatments have also been proposed to suppress the possible causes of dopaminergic neuron apoptosis such 2
as age-dependent mitochondrial dysfunction, oxidative stress, disturbances of calcium homeostasis, neurotoxicity, decrease in levels of neurotrophic factors, excitotoxicity, immunological imbalances as well as infections (Naoi M and W, 2001). Increased oxidative stress in nigral dopaminergic neurons has been attributed to dopamine oxidation leading to the generation of reactive oxygen species (ROS) and the cytotoxic dopamine quinone, increased iron deposition as well as reduced antioxidant capacity (Götz and Freyberger, 1990; Morais et al., 2002).
Epidemiology and pharmacology of PD
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A number of traditional South African medicinal plants (SAMPs) have been reported to contain such potent neuroprotective compounds as Rutin (Afshar and Delazar, 1994) and Naringerin (Olsen et al., 2008) which have been shown to prevent the loss of dopaminergic neurons via inhibition MAO-B activity in both in-vitro and in-vivo models. There is currently a dearth of published information on potent SAMPs with neuroprotective properties for NDDs, including PD. This review therefore aims to provide information on different SAMPs and their extracted bioactive compounds used for the treatment of PD, as part of the search for affordable, safe and effective antiparkisonian traditional medicines capable to slowing down or preventing the progression of the disease.
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Parkinson’s disease (PD), one of the many common neurological conditions, is second to Alzheimer’s disease in prevalence worldwide (De Rijk, 2000) and is a progressive neurodegenerative disorder which affects one in every 100 people over the age of 65 years, increasing to 4% in individuals aged >80 years (De Lau and Breteler, 2006; Chesselet and Richter, 2011; Hirsch et al., 2016). The ageing population (≥60 years) in sub-Saharan Africa (SSA) is growing faster than the rest of the world and it is expected to double by the year 2030 and double again in 2050 (Velkoff and Kowal, 2007; Cleland and Machiyama, 2017). Only fewer PD cases are reported in Africa compared to Europe or North America (Okubadejo et al., 2006) due to a combination of factors (Okubadejo et al., 2008). The lowest was prevalence reported in countries of the Western sub-region (Ghana, Liberia, Nigeria) as well as the Eastern sub-region (Ethiopia, Kenya, Somalia, Tanzania, Uganda) respectively, which are countries in which life expectancy is usually below 57 years, with less than 4% of the population aged ≥60 years (Okubadejo et al., 2006). The specific prevalence of PD in South Africa is not clearly documented (Carr et al., 2009).
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PD remains an incurable disease but symptoms can be managed with drugs that mimic the effects of dopamine or boost its levels in the brain thereby offering only symptomatic relief to patients (Stafford et al., 2008). In PD patients, dopamine is preferentially deaminated by the enzyme MAOB in the human brain; hence treatment with MAO-B inhibitors such as Selegiline often increases the basal central dopamine levels (Knoll 1999; Stafford et al., 2008) but also leads to a mild antidepressant effect (Finberg and Rabey, 2016). The oxidation step catalyzed by MAO-B is known to yield reactive hydrogen peroxide as a by-product of amine turnover, which together with other ROS may cause neuronal death or lead to deterioration in neuronal function (Stafford et al., 2008). The search for new MAO-B inhibitors is therefore valid as currently used ones have many known side effects (Vlok et al., 2006). 1.2
Models of PD
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Methodology
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Research into the pathogenesis, progression and treatment of PD is mostly done using both in vitro and in vivo chemical and genetic models which have been developed and optimized over the years to depict the pathophysiology of the human disease in many ways. Neurotoxic compounds such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), paraquat, rotenone and reserpine remain the preferred and most widely used chemical agents for inducing both reversible and irreversible chemical models in animals (in vivo) and cells (in vitro) (Blesa et al., 2012). Cellular models are mostly useful for exploring single pathogenetic mechanisms involved in disease conditions and are very reproducible as they mostly target exact molecular pathways responsible for the progression of the disease (Dawson et al., 2010). On the other hand, laboratory animals have been used to model various aspects of the PD phenotype and to study disease development and possible treatment mechanisms, thus contributing immensely to the understanding of PD pathophysiology (Jagmag et al., 2016). Common cellular models use dopaminergic and catecholaminergic cells such as the differentiated human neuroblastoma cell line SH-SY5Y and the rat pheochromocytoma cell line PC12 (Falkenburger et al., 2016).
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The authors searched different electronic databases, namely Pubmed, Science Direct, Google scholar and Scopus from January 1980 until January 2018 for research articles published on potential antiparkinson agents derived from South African medicinal plants. The keywords for the search included South Africa, traditional medicine, Parkinson’s disease, neuroprotection, mode of action, mechanism and monoamine Oxidase-B, searched either individually or in combinations. Some of the authors extracted data independently, while others assessed the titles and abstracts of each article for duplication and inclusion criteria. Only research articles published in the English language with focus on potential neuroprotective activity of indigenous South African plants were included while articles that only focus on ethnobotanical information of SAMPs without experimental validation data were excluded. This search revealed that there are very few review articles available in the literature on the use of South African medicinal plants for the treatment of neurodegenerative conditions including PD, which is a justification for the current study. Thus, this review focuses on available studies on different South African medicinal plants and their extracted bioactive compounds used as neuroprotective agents in PD. Studies on South African plants with antiparkinsonian activity
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In one study, four plants traditionally used to treat neurological disorders namely Scadoxus Puniceus, Lannea schweinfurthii, Zanthoxylum capense, Crinum bulbispermum (Table 1) were investigated for their neuroprotective activity using an in vitro rotenone-induced model of PD in SH-SY5Y neuroblastoma cells. All extracts from these plants were found to inhibit activation of apoptosis and restore intracellular glutathione (GSH) content (Seoposengwe et al., 2013), possibly indicative of potent antiparkinsonian properties. Pre-treatment with two of these plants - S. puniceus and C. bulbispermum extracts was found to reverse the effects of rotenone on intracellular ROS levels and to modulate rotenone-induced decrease in intracellular glutathione (GSH) levels. In addition, mitochondrial membrane potential (MMP) was neutralized by pre-treatment with the ethyl acetate extracts C. bulbispermum. In another study, the traditionally used SAMPs Gomphocarpus physocarpus, Leonotis leonurus, Mentha aquatic and Ruta graveolens were screened by Stafford et al., (2007) for MAO inhibition 4
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and specific MAO-B inhibition activity (Table 1). A photometric peroxidase-linked assay was used to determine the inhibition of the oxidative deamination of tyramine by MAO isolated from rat liver (Stafford et al., 2007). Ruta graveolens was found to exhibit the best MAO inhibitory IC50 activity (aqueous leaf extract = 267 ± 262 ug/ml; ethanol leaf extract = 18.5 ± 1.5 μg/ml; ethyl acetate leaf extract = 5 ± 1μg/ml; petroleum ether extract = 3 ± 1 μg/ml) and specific MAO-B inhibition (aqueous leaf extract= 1436 ± 909 μg/ml; ethanol leaf extract = 35 ± 56 μg/ml; ethyl acetate leaf extract = 7 ± 6 μg/ml; petroleum ether extract = 3 ± 1 μg/ml). Mentha aquatica also exhibited remarkable MAO inhibition activity (aqueous leaf extract = 23 ± 5 μg/ml; ethanol leaf extract = 24 ± 36ug/ml) and MAO-B activity (aqueous leaf extract = 101 ± 21 μg/ml; ethanol leaf extract = 68 ± 42 ug/ml). Findings from the study tend to support the use of traditional plants as potent MAO-B inhibitors (Stafford et al., 2007).
Rutin as an active compound in South African Medicinal Plants
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Rutin is a bioflavonoid also called vitamin P (Khan et al., 2012) and is composed of quercetin and the disaccharide rutinose (rhamnose and glucose). Its common name is derived from Ruta graveolens, a plant that contains high amounts of the compound although other names like rutoside, quercetin-3-O-rutinoside or sophorin have also been used for this compound (Dawidowicz et al., 2016). Rutin is widely found in citrus fruits, rinds of grapes and lime as well as in cranberries, mulberries, buckwheat and asparagus. Rutin-rich plants have been used in traditional medicine for centuries in the form of beverages or foods and due to its versatile properties, rutin is today a well-known constituent of over 130 registered medicinal preparations (Chua, 2013). The first isolation of rutin from the leaves of Ruta graveolens was done by Pathak et al., (2003) and has since then been reported to exhibit many significant benefits including antioxidant, anti-inflammatory, antiallergenic, antiviral, anticarcinogenic and superoxide radical scavenging potentials (Perk et al., 2014; Al-Dhabi et al., 2015). Intake of rutin from natural food sources, such as groats or ‘soba’ noodles has been reported to be potentially effective in protecting against neuron loss in Alzheimer’s disease (Koda et al., 2008; Pu et al., 2004).
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The chemical structure of rutin (Figure 1) resembles that of quercetin (Figure 2), with the exception that the hydrogen atom on the right side in the quercetin structure is replaced by the disaccharide rutinose molecule (Magalingam et al., 2013). However, rutin has disaccharide sugar molecules as its side chain which may confer improved antioxidant properties as well as greater bioavailability potential compared to quercetin (Hollman and Katan, 1998; Magalingam et al., 2013). In the human body, rutin binds to the iron ion (Fe2+), preventing it from binding to hydrogen peroxide, which could lead to generation of highly reactive free radicals capable of damaging body cells (Afanas' ev et al., 1989). Although many studies have reported the neuroprotective role of quercetin, there are very few studies on rutin. 3.3
Mechanisms of action of Rutin in PD models
Antioxidant compounds are reducing agents that scavenge free radicals and protect cells from undergoing degeneration. Plant-derived antioxidants supplement endogenous antioxidants to maintain equilibrium between cellular ROS production and internal defense against oxidative stress (Uslu et al., 2003; Magalingam et al., 2013). The potential antioxidant properties of rutin have been investigated in both in-vitro and in-vivo models and at least three mechanisms of action 5
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have been elucidated. Firstly, rutin directly scavenges ROS to stop the progression of the deteriorating chain reaction (Hanasaki et al., 1994). Secondly, rutin inhibits the ROS-generating enzyme xanthine oxidase (Kostić et al., 2015). Thirdly, rutin increases the production of GSH and increases the activity of many antioxidant enzymes such as superoxide dismutase (SOD) or catalase (Ahmed and Zaki, 2009; Kandemir et al., 2015). There is growing evidence on the therapeutic potential of rutin especially in conditions with oxidative stress as a major underlying cause, e.g., neurodegenerative diseases (Magalingam et al., 2013; Park et al., 2014; Wang et al., 2015). The potential neuroprotective effects of rutin on ischaemia/reperfusion injury has also been investigated and reported (Khan et al., 2009).
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The neuroprotective and antioxidant effects of rutin in 6-OHDA induced toxicity was investigated using PC-12 neuronal cells as an in-vitro model (Magalingam et al., 2013). Cells were pre-treated with rutin and significant cytoprotection was observed in a dose-dependent manner. There was also marked activation of antioxidant enzymes including SOD, Catalase, Glutathione Peroxidase (GPx), and GSH when compared to cells incubated with 6-OHDA alone and lipid peroxidation was also significantly reduced. The authors concluded that rutin inhibited 6-OHDA-induced neurotoxicity in PC-12 cells by improving antioxidant enzyme levels and inhibiting lipid peroxidation.
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Another study by Khan et al., (2012), found that rutin pre-treatment could confer neuroprotection on 6-OHDA-induced PD in Wistar rats. Most of the animals experienced increased rotations, deficits in locomotor activity, poor motor coordination, decrease in antioxidant levels, reduced dopamine content/metabolites as well as significant increase in the number of striatal dopaminergic D2 receptors. The results from this study were further supported by histopathological and immunohistochemical improvements in the substantia nigra, leading to the conclusion that the observed neuroprotection was as a result of the powerful antioxidant and antiinflammatory properties of rutin as corroborated by previous studies (Bishnoi et al., 2007; Khan et al., 2009; Koda et al., 2009). MAO-B enzyme activity has been implicated in PD (Alper et al., 1999; Cohen and Kesler, 1999) and a study by Lee et al., (2001) showed that rutin exhibited inhibitory effects on MAO-B at an IC50 value of 3.89 µM as well as free radical scavenging activities, both of which are potentially beneficial in preventing neurodegenerative diseases.
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Despite exciting findings on the bioactivity of rutin, there is currently very little research geared towards evaluating its neuroprotective activities in additional models of PD. There is therefore need for further research in this area. 3.4
Naringenin as an active compound in South African Medicinal Plants
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Naringenin is a plant bioflavonoid classified as flavonone (Jain and Mittal, 2012) with a chemical name of 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one (Figure 3) and a molecular weight of 272.26 (C15H12O5) (Wilcox et al., 1999). Naringenin is insoluble in water but soluble in organic solvents such as alcohol and its main sources include citrus fruits and tomatoes (Kawaii et al., 1999). In the grapefruit, it is principally present in the form of the glycosidic compound naringenin-7-rhamnoglucoside (naringin) (Ortuno et al., 1995). Natural sources of naringenin are very limited and this appears to hinder further studies on its pharmacological actions (Erlund, 2004). However, naringin is abundant in natural 6
sources and because of the close structural relationship between these two compounds, naringenin could be obtained by enzymatic hydrolysis of naringin (Ribeiro and Ribeiro, 2008); (Fig. 4).
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Mechanisms of action of Naringenin in PD models
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Naringenin is reported to have tyrosinase inhibitory activity (Yamauchi et al., 2011), antiviral activity (Ahmad et al., 2014), anti-carcinogenic activity (Badary et al., 2005), anti-oxidative as well as anti-hyperlipidemic activities (Mulvihill et al., 2009). Dietary intake of 1-3% of naringenin was found to improve insulin resistance (Mulvihill et al., 2009) and inhibit hyperglycaemia partly due to its inhibition of renal glucose uptake and reabsorption (Li et al., 2006). Other studies have also suggested that naringenin could have anti-inflammatory and anti-fibrotic effects (Liu et al., 2006; Lin and Lin, 2010). Since naringenin has been reported to cross the blood-brain barrier (Youdim et al., 2004), it could have effects on CNS function.
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Naringenin has previously been reported to significantly attenuate the loss of dopaminergic neurons in the substantia nigra and also increase striatal dopamine concentrations in 6-OHDAinduced PD model, possibly due to the presence of the 2, 3-double bond in conjugation with a 4oxo group which is believed to be responsible for its antioxidant activity (Zbarsky et al., 2005). In a different study, oral administration of naringenin (10 mg/kg) was found to inhibit apoptosis and promote neuronal survival in a rotenone-induced animal model of PD (Sonia Angeline et al., 2013). In that study, naringenin effectively restored the levels of the protective proteins parkin, PARK 7 protein (DJ1), tyrosine hydroxylase (TH) and C terminus Hsp70 interacting protein (CHIP), while reducing ubiquitin levels, inhibiting caspase activation and reducing cell death in several sites in the brain. In addition, differential expression of heat shock proteins 60, 70 and 90 was observed. The authors concluded that the mechanism of neuroprotection by naringenin was through its ability to reduce caspase activation while upregulating the heat shock proteins.
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Lou et al., (2014) appeared to support a ROS scavenging effect for naringenin in a 6-OHDA model of PD, which occurs through the stimulation of nuclear factor E2-related factor 2 (Nrf2) transcription and its downstream antioxidant pathways in both in-vivo and in-vitro models. The study also showed that naringenin protected SH-SY5Y cells against 6-OHDA toxicity. Olsen et al., (2008) studied the MAO inhibition effects of naringenin isolated from a 70% ethanol extract of Mentha aquatic, a plant indigenous to Africa and Europe, using the peroxidase-linked photometric assay. The IC50 values for MAO inhibition by this naringenin was found to be 342 ± 33 µM for the rat liver mitochondrial fraction, 955 ± 129 µM for MAO-A and 288±18 µM for MAO-B.
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It is likely that the content of naringenin in Mentha aquatica might explain its use as a potent traditional medicine for depression-like conditions and its inhibition of MAO-B might further validate its use as a protective agent for PD. 4.0
Conclusion and Future Perspectives
Due to the increasing prevalence of PD worldwide, there is pressing need for improved and affordable treatment options in order to alleviate the burden of this disease especially in subSaharan Africa. The prognosis of PD remains poor due to many emerging comorbid conditions, all contributing to the lack of an effective treatment. This review is significant because it provides summarized information on eight SAMPs with potential neuroprotection-like mechanisms of 7
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action (inhibition of MAO-B, inhibition of Caspase 3 activation, restoration of GSH content), giving pharmacognosists and neuroscience researchers the rationale for further interdisciplinary studies in the form of extensive screening, testing and validation of the antiparkinsonian effects of these extracts and their identified compounds using in vitro, in vivo and genetic PD models. Findings from such screening studies could also lead to the establishment of libraries of purified extracts, fractions and pure compounds which are potential developmental candidates for newer safe and effective antiparkinsonian drugs compared with current therapy. In addition, postscreened promising compounds could be used as ingredients for the formulation of antiparkinsonian remedies by TCAM practitioners. In South Africa, the promotion and regulation of indigenous healthcare knowledge systems as well as bioprospecting beneficiation by host communities are supported by policy; hence a study such as this helps to provide relevant information that will generate the desired value chain both in the pharmaceutical industry and the traditional healthcare sector.
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Figure 1: Chemical structure of Rutin
Figure 2: Chemical structure of Quercetin
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Figure 3: Chemical structure of Naringenin
Figure 4: Chemical structure of Naringin
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3.0 Table 1: South African plants tested for antiparkinsonian activity Species
Ethnobotanical, Traditional Uses
Part of plant (Extract)
Mechanism of Action
Type of Mod el
Amaryllidacea e
Scadoxus puniceus
It is known to cause CNS depression or excitation
Root/ Bulb (Ethanol, Methanol, Ethyl Acetate)
In vitro In vivo
Asclepidaceae
Gomphocarp us physocarpus
Leaf (Ethanol)
Lamiaceae
Leonotis leonurus
Lamiaceae
Mentha aquatica
Its leaves are often used to ‘strengthen body’. The powdered leaf is used as sedative This plant is reported to be mildly narcotic and its aqueous extracts are reported to have anticonvulsant activity in animal studies It is used as a stimulant and known to contain flavones. It is mixed with leaves of Tagetes minuta L., burned and then the smoke is inhaled for treating mental illness in Venda. It is also reported that its Leaf extracts exhibited Selective serotonin reuptake inhibition (SSRI) activity.
Inhibition of MAO-B, Inhibits activation of Caspase 3, Restoration of intracellular Glutathione content Inhibition of MAO-B
Active compound for Neuroprotec tion Not yet reported
References
(Seoposengwe et al., 2013; Stafford et al., 2007; Veale et al., 1992)
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Family
Not yet reported
(Stafford et al., 2007; Van Wyk and Gericke, 2000; Pujol, 1990)
In vivo
Not yet reported
(Stafford et al., 2007; Bienvenu et al., 2002; Watt and Breyer Brandwijk, 1962)
In vivo
Naringenin
(Olsen et al., 2008; Stafford et al., 2007; Nielsen et al., 2004; Williamson et al., 1988; Burzanska Hermann et al., 1978)
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In vivo
Inhibition of MAO-B
Leaf (Water, Ethanol)
Inhibition of MAO-B
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Leaf (Water)
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S2210-8033(18)30031-9 https://doi.org/10.1016/j.hermed.2018.06.001 HERMED 222
To appear in: Received date: Revised date: Accepted date:
10-10-2017 24-5-2018 11-6-2018
Please cite this article as: Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE, Potential antiparkinsonian agents derived from South African medicinal plants, Journal of Herbal Medicine (2018), https://doi.org/10.1016/j.hermed.2018.06.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Potential antiparkinsonian agents derived from South African medicinal plants Authors: Adaze Bijou Enogieru a, Sylvester Ifeanyi Omoruyi a, Donavon Charles Hiss a, Okobi Eko Ekpo a* a
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Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, SOUTH AFRICA Corresponding author: * Dr. Okobi Ekpo, Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, SOUTH AFRICA. Fax: +27-21959-3125; E-mail: [email protected]. Abstract
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Many natural products and medicinal plants have been tested experimentally for validation of their reported folkloric efficacies. South Africa has abundant plant biodiversity and medicinal plants are still widely used in most parts of the country for the treatment of common neurodegenerative disorders (NDDs). However, very few studies have reported on the validation of South African medicinal plants (SAMPs) used in traditional, complementary and alternative medicine (TCAM) for the treatment of NDDs. Extensive testing provides the basis for clinical trials which progressively lead to the development of affordable indigenous and readily available products for preventing or treating NDD including Parkinson's disease (PD), one of the most common central nervous system (CNS) disorders among the elderly often characterized by the progressive loss of dopaminergic neurons (DNs) or dopamine-producing cells in the substantia nigra of the midbrain. In this study, several databases were searched to identify active compounds in SAMPs known to potentially protect neurons from progressive damage as seen in most NDDs. Our search results showed many commonly used SAMPs and their possible mechanisms of action including prevention of neuronal death by inhibition of Caspase-3 activation, MAO-B enzyme inhibition as well as restoration of glutathione content in cells. Most of the observed effects relate to the protection of DNs from degeneration, indicating the potential use of these compounds as antiparkinsonian agents. This review article therefore identifies and presents research gaps on how indigenous SAMPs could be studied more extensively for their chemical constituents and bioactivity against age-related NDDs such as PD.
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Keywords: Dopaminergic; Naringenin; Neuroprotection; Parkinson's disease; Rutin; Traditional medicine.
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Introduction Epidemiology and pharmacology of PD Models of PD Methodology Studies on South African plants with antiparkinsonian activity 1
Rutin as an active compound in South African Medicinal Plants Mechanisms of action of Rutin in PD models Naringenin as an active compound in South African Medicinal Plants Mechanisms of action of Naringenin in PD models Conclusion and Future Perspectives
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Introduction
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South Africa's large cultural diversity is complemented by an exceptionally rich plant diversity of about 30,000 flowering plant species which is about a tenth of the world's plant population (Stafford et al., 2007). Most traditional herbal medicines used in South Africa are derived from as many as 1020 plant species sources (Fennell et al., 2004; Mander et al, 2007), using local expertise and extensive indigenous knowledge systems which date back as far as 1000 BC (Street et al., 2008). Hitherto, the practice of traditional and Western medicine co-exist in South Africa (Stafford et al., 2008) and the majority of the low-income population utilize the over-burdened public healthcare facilities (Morris, 2001; Eastman, 2005) and in most cases, concurrently with the relatively accessible and affordable traditional medicines (Marais et al, 2015; Audet et al., 2017). Recently, the misleading reports that 80% of South Africans use traditional medicines for their primary healthcare needs have been controverted (Nxumalo et al., 2011 and Oyebode, et al., 2016), although it is common knowledge that the practice of traditional medicine remains active especially among rural communities in South Africa.
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Renewed interests in traditional pharmacopoeias over the years indicate that scientists are interested not only in the determination of the scientific rationale for plant use, but also with the discovery of novel compounds of pharmaceutical value (Fennell et al., 2004). Traditional knowledge provides the basis for guided scientific study of plants that may be medicinally useful as against random screening procedures (Cox, 1994). Thus, more than 122 pharmaceutical compounds from 94 plant species have been discovered through guided ethnobotanical screening (Fabricant, 2001), using different assays to test for biological activity, firstly in vitro and later, in vivo for promising compounds (Fennell et al., 2004).
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Many neurodegenerative and psychiatric conditions in South Africa have been treated for centuries with traditional herbal medicines (Gqaleni et al, 2007) and PD is one such condition, often characterized by four major motor symptoms - rigidity, bradykinesia, tremor, and postural instability (Savitt et al., 2006). In PD, there is progressive loss of dopaminergic neurons in the substantia nigra of the midbrain and acetylcholine activity is increased due to dopamine deficiency, leading to an imbalance of many functions (Zhu et al., 2008). The two major pathological findings in PD patients include the presence of Lewy bodies in the substantia nigra, and loss of neurons in portions of its ventral part (Calne, 2001). Available pharmacotherapeutic strategies for PD include oral administration of levodopa (LDOPA), dopamine receptor agonists and monoamine oxidase-B (MAO-B) inhibitors (Sarkar et al., 2016). Deep brain stimulation of the subthalamic nucleus and globus pallidus by surgically implanted electrodes as well as stem cell transplantation into the striatum are other well-known treatment modalities (Fu et al., 2013; Buzhor et al., 2014; Fu et al., 2015). Protective treatments have also been proposed to suppress the possible causes of dopaminergic neuron apoptosis such 2
as age-dependent mitochondrial dysfunction, oxidative stress, disturbances of calcium homeostasis, neurotoxicity, decrease in levels of neurotrophic factors, excitotoxicity, immunological imbalances as well as infections (Naoi M and W, 2001). Increased oxidative stress in nigral dopaminergic neurons has been attributed to dopamine oxidation leading to the generation of reactive oxygen species (ROS) and the cytotoxic dopamine quinone, increased iron deposition as well as reduced antioxidant capacity (Götz and Freyberger, 1990; Morais et al., 2002).
Epidemiology and pharmacology of PD
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A number of traditional South African medicinal plants (SAMPs) have been reported to contain such potent neuroprotective compounds as Rutin (Afshar and Delazar, 1994) and Naringerin (Olsen et al., 2008) which have been shown to prevent the loss of dopaminergic neurons via inhibition MAO-B activity in both in-vitro and in-vivo models. There is currently a dearth of published information on potent SAMPs with neuroprotective properties for NDDs, including PD. This review therefore aims to provide information on different SAMPs and their extracted bioactive compounds used for the treatment of PD, as part of the search for affordable, safe and effective antiparkisonian traditional medicines capable to slowing down or preventing the progression of the disease.
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Parkinson’s disease (PD), one of the many common neurological conditions, is second to Alzheimer’s disease in prevalence worldwide (De Rijk, 2000) and is a progressive neurodegenerative disorder which affects one in every 100 people over the age of 65 years, increasing to 4% in individuals aged >80 years (De Lau and Breteler, 2006; Chesselet and Richter, 2011; Hirsch et al., 2016). The ageing population (≥60 years) in sub-Saharan Africa (SSA) is growing faster than the rest of the world and it is expected to double by the year 2030 and double again in 2050 (Velkoff and Kowal, 2007; Cleland and Machiyama, 2017). Only fewer PD cases are reported in Africa compared to Europe or North America (Okubadejo et al., 2006) due to a combination of factors (Okubadejo et al., 2008). The lowest was prevalence reported in countries of the Western sub-region (Ghana, Liberia, Nigeria) as well as the Eastern sub-region (Ethiopia, Kenya, Somalia, Tanzania, Uganda) respectively, which are countries in which life expectancy is usually below 57 years, with less than 4% of the population aged ≥60 years (Okubadejo et al., 2006). The specific prevalence of PD in South Africa is not clearly documented (Carr et al., 2009).
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PD remains an incurable disease but symptoms can be managed with drugs that mimic the effects of dopamine or boost its levels in the brain thereby offering only symptomatic relief to patients (Stafford et al., 2008). In PD patients, dopamine is preferentially deaminated by the enzyme MAOB in the human brain; hence treatment with MAO-B inhibitors such as Selegiline often increases the basal central dopamine levels (Knoll 1999; Stafford et al., 2008) but also leads to a mild antidepressant effect (Finberg and Rabey, 2016). The oxidation step catalyzed by MAO-B is known to yield reactive hydrogen peroxide as a by-product of amine turnover, which together with other ROS may cause neuronal death or lead to deterioration in neuronal function (Stafford et al., 2008). The search for new MAO-B inhibitors is therefore valid as currently used ones have many known side effects (Vlok et al., 2006). 1.2
Models of PD
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Research into the pathogenesis, progression and treatment of PD is mostly done using both in vitro and in vivo chemical and genetic models which have been developed and optimized over the years to depict the pathophysiology of the human disease in many ways. Neurotoxic compounds such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), paraquat, rotenone and reserpine remain the preferred and most widely used chemical agents for inducing both reversible and irreversible chemical models in animals (in vivo) and cells (in vitro) (Blesa et al., 2012). Cellular models are mostly useful for exploring single pathogenetic mechanisms involved in disease conditions and are very reproducible as they mostly target exact molecular pathways responsible for the progression of the disease (Dawson et al., 2010). On the other hand, laboratory animals have been used to model various aspects of the PD phenotype and to study disease development and possible treatment mechanisms, thus contributing immensely to the understanding of PD pathophysiology (Jagmag et al., 2016). Common cellular models use dopaminergic and catecholaminergic cells such as the differentiated human neuroblastoma cell line SH-SY5Y and the rat pheochromocytoma cell line PC12 (Falkenburger et al., 2016).
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The authors searched different electronic databases, namely Pubmed, Science Direct, Google scholar and Scopus from January 1980 until January 2018 for research articles published on potential antiparkinson agents derived from South African medicinal plants. The keywords for the search included South Africa, traditional medicine, Parkinson’s disease, neuroprotection, mode of action, mechanism and monoamine Oxidase-B, searched either individually or in combinations. Some of the authors extracted data independently, while others assessed the titles and abstracts of each article for duplication and inclusion criteria. Only research articles published in the English language with focus on potential neuroprotective activity of indigenous South African plants were included while articles that only focus on ethnobotanical information of SAMPs without experimental validation data were excluded. This search revealed that there are very few review articles available in the literature on the use of South African medicinal plants for the treatment of neurodegenerative conditions including PD, which is a justification for the current study. Thus, this review focuses on available studies on different South African medicinal plants and their extracted bioactive compounds used as neuroprotective agents in PD. Studies on South African plants with antiparkinsonian activity
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In one study, four plants traditionally used to treat neurological disorders namely Scadoxus Puniceus, Lannea schweinfurthii, Zanthoxylum capense, Crinum bulbispermum (Table 1) were investigated for their neuroprotective activity using an in vitro rotenone-induced model of PD in SH-SY5Y neuroblastoma cells. All extracts from these plants were found to inhibit activation of apoptosis and restore intracellular glutathione (GSH) content (Seoposengwe et al., 2013), possibly indicative of potent antiparkinsonian properties. Pre-treatment with two of these plants - S. puniceus and C. bulbispermum extracts was found to reverse the effects of rotenone on intracellular ROS levels and to modulate rotenone-induced decrease in intracellular glutathione (GSH) levels. In addition, mitochondrial membrane potential (MMP) was neutralized by pre-treatment with the ethyl acetate extracts C. bulbispermum. In another study, the traditionally used SAMPs Gomphocarpus physocarpus, Leonotis leonurus, Mentha aquatic and Ruta graveolens were screened by Stafford et al., (2007) for MAO inhibition 4
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and specific MAO-B inhibition activity (Table 1). A photometric peroxidase-linked assay was used to determine the inhibition of the oxidative deamination of tyramine by MAO isolated from rat liver (Stafford et al., 2007). Ruta graveolens was found to exhibit the best MAO inhibitory IC50 activity (aqueous leaf extract = 267 ± 262 ug/ml; ethanol leaf extract = 18.5 ± 1.5 μg/ml; ethyl acetate leaf extract = 5 ± 1μg/ml; petroleum ether extract = 3 ± 1 μg/ml) and specific MAO-B inhibition (aqueous leaf extract= 1436 ± 909 μg/ml; ethanol leaf extract = 35 ± 56 μg/ml; ethyl acetate leaf extract = 7 ± 6 μg/ml; petroleum ether extract = 3 ± 1 μg/ml). Mentha aquatica also exhibited remarkable MAO inhibition activity (aqueous leaf extract = 23 ± 5 μg/ml; ethanol leaf extract = 24 ± 36ug/ml) and MAO-B activity (aqueous leaf extract = 101 ± 21 μg/ml; ethanol leaf extract = 68 ± 42 ug/ml). Findings from the study tend to support the use of traditional plants as potent MAO-B inhibitors (Stafford et al., 2007).
Rutin as an active compound in South African Medicinal Plants
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Rutin is a bioflavonoid also called vitamin P (Khan et al., 2012) and is composed of quercetin and the disaccharide rutinose (rhamnose and glucose). Its common name is derived from Ruta graveolens, a plant that contains high amounts of the compound although other names like rutoside, quercetin-3-O-rutinoside or sophorin have also been used for this compound (Dawidowicz et al., 2016). Rutin is widely found in citrus fruits, rinds of grapes and lime as well as in cranberries, mulberries, buckwheat and asparagus. Rutin-rich plants have been used in traditional medicine for centuries in the form of beverages or foods and due to its versatile properties, rutin is today a well-known constituent of over 130 registered medicinal preparations (Chua, 2013). The first isolation of rutin from the leaves of Ruta graveolens was done by Pathak et al., (2003) and has since then been reported to exhibit many significant benefits including antioxidant, anti-inflammatory, antiallergenic, antiviral, anticarcinogenic and superoxide radical scavenging potentials (Perk et al., 2014; Al-Dhabi et al., 2015). Intake of rutin from natural food sources, such as groats or ‘soba’ noodles has been reported to be potentially effective in protecting against neuron loss in Alzheimer’s disease (Koda et al., 2008; Pu et al., 2004).
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The chemical structure of rutin (Figure 1) resembles that of quercetin (Figure 2), with the exception that the hydrogen atom on the right side in the quercetin structure is replaced by the disaccharide rutinose molecule (Magalingam et al., 2013). However, rutin has disaccharide sugar molecules as its side chain which may confer improved antioxidant properties as well as greater bioavailability potential compared to quercetin (Hollman and Katan, 1998; Magalingam et al., 2013). In the human body, rutin binds to the iron ion (Fe2+), preventing it from binding to hydrogen peroxide, which could lead to generation of highly reactive free radicals capable of damaging body cells (Afanas' ev et al., 1989). Although many studies have reported the neuroprotective role of quercetin, there are very few studies on rutin. 3.3
Mechanisms of action of Rutin in PD models
Antioxidant compounds are reducing agents that scavenge free radicals and protect cells from undergoing degeneration. Plant-derived antioxidants supplement endogenous antioxidants to maintain equilibrium between cellular ROS production and internal defense against oxidative stress (Uslu et al., 2003; Magalingam et al., 2013). The potential antioxidant properties of rutin have been investigated in both in-vitro and in-vivo models and at least three mechanisms of action 5
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have been elucidated. Firstly, rutin directly scavenges ROS to stop the progression of the deteriorating chain reaction (Hanasaki et al., 1994). Secondly, rutin inhibits the ROS-generating enzyme xanthine oxidase (Kostić et al., 2015). Thirdly, rutin increases the production of GSH and increases the activity of many antioxidant enzymes such as superoxide dismutase (SOD) or catalase (Ahmed and Zaki, 2009; Kandemir et al., 2015). There is growing evidence on the therapeutic potential of rutin especially in conditions with oxidative stress as a major underlying cause, e.g., neurodegenerative diseases (Magalingam et al., 2013; Park et al., 2014; Wang et al., 2015). The potential neuroprotective effects of rutin on ischaemia/reperfusion injury has also been investigated and reported (Khan et al., 2009).
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The neuroprotective and antioxidant effects of rutin in 6-OHDA induced toxicity was investigated using PC-12 neuronal cells as an in-vitro model (Magalingam et al., 2013). Cells were pre-treated with rutin and significant cytoprotection was observed in a dose-dependent manner. There was also marked activation of antioxidant enzymes including SOD, Catalase, Glutathione Peroxidase (GPx), and GSH when compared to cells incubated with 6-OHDA alone and lipid peroxidation was also significantly reduced. The authors concluded that rutin inhibited 6-OHDA-induced neurotoxicity in PC-12 cells by improving antioxidant enzyme levels and inhibiting lipid peroxidation.
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Another study by Khan et al., (2012), found that rutin pre-treatment could confer neuroprotection on 6-OHDA-induced PD in Wistar rats. Most of the animals experienced increased rotations, deficits in locomotor activity, poor motor coordination, decrease in antioxidant levels, reduced dopamine content/metabolites as well as significant increase in the number of striatal dopaminergic D2 receptors. The results from this study were further supported by histopathological and immunohistochemical improvements in the substantia nigra, leading to the conclusion that the observed neuroprotection was as a result of the powerful antioxidant and antiinflammatory properties of rutin as corroborated by previous studies (Bishnoi et al., 2007; Khan et al., 2009; Koda et al., 2009). MAO-B enzyme activity has been implicated in PD (Alper et al., 1999; Cohen and Kesler, 1999) and a study by Lee et al., (2001) showed that rutin exhibited inhibitory effects on MAO-B at an IC50 value of 3.89 µM as well as free radical scavenging activities, both of which are potentially beneficial in preventing neurodegenerative diseases.
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Despite exciting findings on the bioactivity of rutin, there is currently very little research geared towards evaluating its neuroprotective activities in additional models of PD. There is therefore need for further research in this area. 3.4
Naringenin as an active compound in South African Medicinal Plants
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Naringenin is a plant bioflavonoid classified as flavonone (Jain and Mittal, 2012) with a chemical name of 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one (Figure 3) and a molecular weight of 272.26 (C15H12O5) (Wilcox et al., 1999). Naringenin is insoluble in water but soluble in organic solvents such as alcohol and its main sources include citrus fruits and tomatoes (Kawaii et al., 1999). In the grapefruit, it is principally present in the form of the glycosidic compound naringenin-7-rhamnoglucoside (naringin) (Ortuno et al., 1995). Natural sources of naringenin are very limited and this appears to hinder further studies on its pharmacological actions (Erlund, 2004). However, naringin is abundant in natural 6
sources and because of the close structural relationship between these two compounds, naringenin could be obtained by enzymatic hydrolysis of naringin (Ribeiro and Ribeiro, 2008); (Fig. 4).
3.5
Mechanisms of action of Naringenin in PD models
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Naringenin is reported to have tyrosinase inhibitory activity (Yamauchi et al., 2011), antiviral activity (Ahmad et al., 2014), anti-carcinogenic activity (Badary et al., 2005), anti-oxidative as well as anti-hyperlipidemic activities (Mulvihill et al., 2009). Dietary intake of 1-3% of naringenin was found to improve insulin resistance (Mulvihill et al., 2009) and inhibit hyperglycaemia partly due to its inhibition of renal glucose uptake and reabsorption (Li et al., 2006). Other studies have also suggested that naringenin could have anti-inflammatory and anti-fibrotic effects (Liu et al., 2006; Lin and Lin, 2010). Since naringenin has been reported to cross the blood-brain barrier (Youdim et al., 2004), it could have effects on CNS function.
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Naringenin has previously been reported to significantly attenuate the loss of dopaminergic neurons in the substantia nigra and also increase striatal dopamine concentrations in 6-OHDAinduced PD model, possibly due to the presence of the 2, 3-double bond in conjugation with a 4oxo group which is believed to be responsible for its antioxidant activity (Zbarsky et al., 2005). In a different study, oral administration of naringenin (10 mg/kg) was found to inhibit apoptosis and promote neuronal survival in a rotenone-induced animal model of PD (Sonia Angeline et al., 2013). In that study, naringenin effectively restored the levels of the protective proteins parkin, PARK 7 protein (DJ1), tyrosine hydroxylase (TH) and C terminus Hsp70 interacting protein (CHIP), while reducing ubiquitin levels, inhibiting caspase activation and reducing cell death in several sites in the brain. In addition, differential expression of heat shock proteins 60, 70 and 90 was observed. The authors concluded that the mechanism of neuroprotection by naringenin was through its ability to reduce caspase activation while upregulating the heat shock proteins.
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Lou et al., (2014) appeared to support a ROS scavenging effect for naringenin in a 6-OHDA model of PD, which occurs through the stimulation of nuclear factor E2-related factor 2 (Nrf2) transcription and its downstream antioxidant pathways in both in-vivo and in-vitro models. The study also showed that naringenin protected SH-SY5Y cells against 6-OHDA toxicity. Olsen et al., (2008) studied the MAO inhibition effects of naringenin isolated from a 70% ethanol extract of Mentha aquatic, a plant indigenous to Africa and Europe, using the peroxidase-linked photometric assay. The IC50 values for MAO inhibition by this naringenin was found to be 342 ± 33 µM for the rat liver mitochondrial fraction, 955 ± 129 µM for MAO-A and 288±18 µM for MAO-B.
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It is likely that the content of naringenin in Mentha aquatica might explain its use as a potent traditional medicine for depression-like conditions and its inhibition of MAO-B might further validate its use as a protective agent for PD. 4.0
Conclusion and Future Perspectives
Due to the increasing prevalence of PD worldwide, there is pressing need for improved and affordable treatment options in order to alleviate the burden of this disease especially in subSaharan Africa. The prognosis of PD remains poor due to many emerging comorbid conditions, all contributing to the lack of an effective treatment. This review is significant because it provides summarized information on eight SAMPs with potential neuroprotection-like mechanisms of 7
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action (inhibition of MAO-B, inhibition of Caspase 3 activation, restoration of GSH content), giving pharmacognosists and neuroscience researchers the rationale for further interdisciplinary studies in the form of extensive screening, testing and validation of the antiparkinsonian effects of these extracts and their identified compounds using in vitro, in vivo and genetic PD models. Findings from such screening studies could also lead to the establishment of libraries of purified extracts, fractions and pure compounds which are potential developmental candidates for newer safe and effective antiparkinsonian drugs compared with current therapy. In addition, postscreened promising compounds could be used as ingredients for the formulation of antiparkinsonian remedies by TCAM practitioners. In South Africa, the promotion and regulation of indigenous healthcare knowledge systems as well as bioprospecting beneficiation by host communities are supported by policy; hence a study such as this helps to provide relevant information that will generate the desired value chain both in the pharmaceutical industry and the traditional healthcare sector.
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Van Wyk, B.-E., Oudtshoorn, B.v., and Gericke, N. (1997). Medicinal Plants of South Africa (Briza). Veale, D., Furman, K., and Oliver, D. (1992). South African traditional herbal medicines used during pregnancy and childbirth. J. Ethnopharmacol., 36: 185-191.
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Watt, J., and Breyer Brandwijk, M. (1962). Medicinal and poisonous plants of southern and eastern Africa. 2nd edn. 1457 pp. E. & S. Livingstone Ltd.: Edinburgh & London. S. & E. Africa.[At Museum.] Review article General article, Drug plants Medicinal plants Pharmacognosy Materia medica, Toxic plants Poisonous plants, geog (PMBD, 185304874).
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Wilcox, L.J., Borradaile, N.M., and Huff, M.W. (1999). Antiatherogenic Properties of Naringenin, a Citrus Flavonoid. Cardiovasc. Drug Rev., 17: 160–178.
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Williamson, E.M., Evans, F.J., and Wren, R. (1988). Potter's new cyclopaedia of botanical drugs and preparations. Saffron Walden (UK): CW Daniel Company Limited.
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Yamauchi, K., Mitsunaga, T., and Batubara, I. (2011). Isolation, identification and tyrosinase inhibitory activities of the extractives from Allamanda cathartica. Natural Resources, 2: 167.
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Zbarsky, V., Datla, K.P., Parkar, S., Rai, D.K., Aruoma, O.I., and Dexter, D.T. (2005). Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic. Res., 39: 1119-1125.
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Figure 1: Chemical structure of Rutin
Figure 2: Chemical structure of Quercetin
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Figure 3: Chemical structure of Naringenin
Figure 4: Chemical structure of Naringin
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3.0 Table 1: South African plants tested for antiparkinsonian activity Species
Ethnobotanical, Traditional Uses
Part of plant (Extract)
Mechanism of Action
Type of Mod el
Amaryllidacea e
Scadoxus puniceus
It is known to cause CNS depression or excitation
Root/ Bulb (Ethanol, Methanol, Ethyl Acetate)
In vitro In vivo
Asclepidaceae
Gomphocarp us physocarpus
Leaf (Ethanol)
Lamiaceae
Leonotis leonurus
Lamiaceae
Mentha aquatica
Its leaves are often used to ‘strengthen body’. The powdered leaf is used as sedative This plant is reported to be mildly narcotic and its aqueous extracts are reported to have anticonvulsant activity in animal studies It is used as a stimulant and known to contain flavones. It is mixed with leaves of Tagetes minuta L., burned and then the smoke is inhaled for treating mental illness in Venda. It is also reported that its Leaf extracts exhibited Selective serotonin reuptake inhibition (SSRI) activity.
Inhibition of MAO-B, Inhibits activation of Caspase 3, Restoration of intracellular Glutathione content Inhibition of MAO-B
Active compound for Neuroprotec tion Not yet reported
References
(Seoposengwe et al., 2013; Stafford et al., 2007; Veale et al., 1992)
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Family
Not yet reported
(Stafford et al., 2007; Van Wyk and Gericke, 2000; Pujol, 1990)
In vivo
Not yet reported
(Stafford et al., 2007; Bienvenu et al., 2002; Watt and Breyer Brandwijk, 1962)
In vivo
Naringenin
(Olsen et al., 2008; Stafford et al., 2007; Nielsen et al., 2004; Williamson et al., 1988; Burzanska Hermann et al., 1978)
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In vivo
Inhibition of MAO-B
Leaf (Water, Ethanol)
Inhibition of MAO-B
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Leaf (Water)
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