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ORIGINAL ARTICLE
Year : 2017  |  Volume : 7  |  Issue : 4  |  Page : 101-106

Effect of Myricetin on the Oxidative Stress Markers in the Brain of Transgenic Flies Expressing Human Alpha-Synuclein


1 Human Genetics and Toxicology Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Drosophila Transgenic Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Date of Web Publication6-Nov-2017

Correspondence Address:
Yasir H Siddique
Drosophila Transgenic Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_41_17

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   Abstract 

Background: Parkinson’s disease (PD) is a neurodegenerative disorder having no permanent cure, but there has been a great deal of interest in finding the role of complementary and alternative medicines for the treatment of neurodegenerative disorders. Oxidative stress has also been implicated in the progression of PD. Objective: Since ancient time, natural plant products have been studied for their protective action. In this study, the effect of myricetin was studied on transgenic flies expressing human alpha-synuclein in the neurons. Materials and Methods: The PD flies were allowed to feed on a diet supplemented with 5, 10, and 20 μM of myricetin for 24 days. The flies with PD were then subjected to the study of oxidative stress markers. Results: The results of this study reveal that the exposure of flies with PD to myricetin showed a significant dose-dependent decrease in oxidative stress compared to unexposed flies with PD (P < 0.005). Conclusion: Myricetin is potent in reducing oxidative stress in the brain of flies with PD induced by the expression of human alpha-synuclein and the formation of Lewy bodies.

Keywords: Alpha-synuclein, myricetin, Parkinson’s disease


How to cite this article:
Ara G, Afzal M, Jyoti S, Siddique YH. Effect of Myricetin on the Oxidative Stress Markers in the Brain of Transgenic Flies Expressing Human Alpha-Synuclein. Int J Nutr Pharmacol Neurol Dis 2017;7:101-6

How to cite this URL:
Ara G, Afzal M, Jyoti S, Siddique YH. Effect of Myricetin on the Oxidative Stress Markers in the Brain of Transgenic Flies Expressing Human Alpha-Synuclein. Int J Nutr Pharmacol Neurol Dis [serial online] 2017 [cited 2020 Jan 29];7:101-6. Available from: http://www.ijnpnd.com/text.asp?2017/7/4/101/217556


   Introduction Top


Parkinson’s disease (PD) is a degenerative disorder of the central nervous system resulting due to the death of dopaminergic neurons in the substantia nigra.[1] Besides various cognitive symptoms, oxidative stress is also considered to be one of the pathological hallmarks of the disease.[2] Oxidative stress has been well documented in the transgenic strain of Drosophila due to the expression of human alpha-synuclein and the formation of Lewy bodies.[3],[4],[5] Because there is no permanent cure for the neurodegenerative disorders, hence, there is growing interest in establishing therapeutic and dietary strategies to combat oxidative stress induced damage to the central nervous system.[6] In this context, the natural antioxidants, particularly the flavonoids, are gaining much recognition because of their nutraceutical and health benefits.[7]

Myricetin is a natural flavonol present in a variety of fruits, vegetables, tea, berries, red wine, and medicinal plants. It is one of the key ingredients of various foods and beverages.[8] The compound exhibits a variety of biological activities that include anticancer, antidiabetic, antioxidant, and anti-inflammatory properties. These properties have been extensively reviewed by Semwal et al.[9] Its neuroprotective properties have not been explored till date. Hence, an attempt has been made to study the protective effect of myricetin on the transgenic flies expressing human alpha-synuclein in the brain.


   Materials and Methods Top


Fly strain

Transgenic fly lines that express wild-type human alpha-synuclein under upstream activation sequence (UAS) control in neurons “w[*];P{w[+mC]=UAS-Hsap/SNCA.F}”5B and the driver expressing GAL4 “w[*];P{w[+mC] ═GAL4-elavL}”3 were obtained from Bloomington Drosophila Stock Center (Indiana University, Bloomington, IN). When males belonging to UAS-Hsap/SNCA.F strains were crossed with virgin females of GAL4-elav.L or vice-versa, the progeny will express human alpha-synuclein in the neurons. The progeny (flies) were referred to as flies with PD.[10]

Drosophila culture and crosses

The flies were cultured on a standard Drosophila food containing agar, corn meal, sugar, and yeast at 25°C (24 ± 1). Crosses were set up as described in our earlier published work.[11] The flies with PD were exposed to 5, 10, and 20 μM of myricetin (Sigma, USA), which was mixed in their diet at final concentration. The flies with PD were also exposed to 10−3 M of L-dopamine. The UAS-Hsap/SNC.F strain acted as a control. The control flies were also separately exposed to the selected doses of myricetin. Heads of the flies from each group were isolated (50 heads/group; five replicates/group), and the homogenate was prepared in 0.1 M phosphate buffer for the biochemical parameters.

Estimation of glutathione content

Glutathione (GSH) content was studied colorimetrically using Ellman’s reagent [5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB)] as per the method described by Jollow et al.[12] The brain homogenate was precipitated with 4% sulphosalicylic acid in the ratio of 1:1. The samples were kept at 4°C for 1 h and then subjected to centrifugation at 5000 rpm for 10 min at 4°C. The assay mixture consisted of 550 μL of 0.1 M phosphate buffer, 100 μL of supernatant, and 100 μL of DTNB. The optical density (OD) was read at 412 nm, and the results were expressed as μM of GSH/gram tissue.

Estimation of glutathione-S-transferase activity

The method given by Habig et al.[13] was used to determine glutathione-S-transferase (GST) activity. The reaction mixture contained 500 μL of 0.1 M phosphate buffer, 150 μL of 10 mM 1-Chloro-2,4-dinitrobenzene (CDNB), 200 μL of 10 mM reduced GSH, and 50 μL of brain homogenate. The OD was read at 340 nm, and the enzyme activity was expressed as μM of CDNB conjugates/min/mg protein.

Lipid peroxidation assay

The assay was performed according to the method described by Ohkawa et al.[14] The reaction mixture was made by adding 5 μL of 10 mM butyl-hydroxytoluene, 200 μL of 0.6.7% thiobarbituric acid, 600 μL of 1% O-phosphoric acid, 105 μL of distilled water, and 90 μL of brain homogenate. The resultant mixture was incubated at 90°C for 45 min, and the OD was measured at 535 nm. The results were expressed as nmol of thiobarbituric acid reactive substances (TBARS) formed/h/g tissue.

Estimation of protein carbonyl content

Protein carbonyl content (PCC) was estimated according to the protocol described by Hawkins et al.[15] About 250 μL of brain homogenate was taken in separate Eppendorf centrifuge tubes. To it, 250 μL of 10 mM 2,4-dinitrophenyl hydrazine (dissolved in 2.5 M HCl) was added, vortexed, and kept in dark for 20 min. About 125 μL of 50% (w/v) trichloroacetic acid was added, mixed thoroughly, and incubated at −20°C for 15 min. The tubes were then centrifuged at 4°C for 10 min at 9000 rpm. The supernatant was discarded, and the pellet obtained was washed twice by ice-cold ethanol and ethyl acetate (1:1). Finally, the pellets were redissolved in 1 mL of 6 M guanidine hydrochloride, and the absorbance was read at 370 nm.

Estimation of monoamine oxidase

The method described by McEwen[16] was used to estimate the monoamine oxidase (MAO) activity. The assay mixture consisted of 400 μL of 0.1 M phosphate buffer (pH 7.4), 1300 μL of distilled water, 100 μL of benzylamine hydrochloride, and 200 μL of brain homogenate. The assay mixture was incubated for 30 min at room temperature, and then, 1 mL of 10% perchloric acid was added and centrifuged at 1500×g for 10 min. The OD was read at 280 nm.

Statistical analysis

The statistical analysis was performed using Statistica software (Statistica Soft Inc., USA). The mean values of various fly groups were statistically compared using Student’s t-test.


   Results Top


The results obtained for the GSH content are shown in [Figure 1]. A significant 1.69-fold decrease in the GSH content was observed in the flies with PD compared to the control flies [Figure 1]; P < 0.05]. The flies with PD exposed to 5, 10, and 20 μM of myricetin showed a significant dose-dependent increase in the GSH content as 1.28-, 1.40-, and 1.51-folds compared to the unexposed flies with PD [Figure 1]; P < 0.05]. The flies with PD exposed to 10−3 M of L-dopamine showed a significant increase of 1.16-fold in the GSH content compared to the unexposed flies with PD [Figure 1]; P < 0.05]. The control flies exposed to various doses of myricetin did not show any significant increase or decrease in the GSH content compared to the control flies [Figure 1]; P < 0.05]. The results obtained for the GST activity are shown in [Figure 2]. The flies with PD showed a significant increase of 2.20-fold in the activity of GST compared to the control flies [Figure 2]; P < 0.05]. The flies with PD exposed to 5, 10, and 20 μM of myricetin showed a significant dose-dependent decrease of 1.07-, 1.19-, and 1.47-folds in the GST activity compared to the unexposed flies with PD [Figure 2]; P < 0.05]. The flies with PD exposed to 10−3 M of L-dopamine showed a significant decrease of 1.63-fold compared to the unexposed flies with PD [Figure 2]; P < 0.05]. The control flies exposed to various doses of myricetin did not show any significant increase or decrease in the GST activity compared to the control flies [Figure 2]; P < 0.05]. The results obtained for lipid peroxidation (LPO) are shown in [Figure 3]. The flies with PD showed a significant increase of 4.57-fold compared to the control flies [Figure 3]; P < 0.05]. The flies with PD exposed to 5, 10, and 20 μM of myricetin showed a significant decrease of 1.25-, 1.48-, and 1.64-folds in the LPO compared to the unexposed flies with PD [Figure 3]; P < 0.05]. The flies with PD exposed to 10−3 M of L-dopamine showed a significant decrease by 2.0-fold compared to the unexposed flies with PD [Figure 3]; P < 0.05]. The control flies exposed to various doses of myricetin did not show any significant increase or decrease in the LPO compared to the control flies [Figure 3]; P < 0.05]. The results obtained for PCC are shown in [Figure 4]. The flies with PD showed a significant increase of 4.5-fold in the PCC compared to the control flies [Figure 4]; P < 0.05]. The flies with PD exposed to 5, 10, and 20 μM of myricetin showed a significant decrease of 1.28-, 1.74-, and 1.92-folds compared to the unexposed flies with PD [Figure 4]; P < 0.05]. The flies with PD exposed to 10−3 M of L-dopamine showed a significant decrease of 2.07-fold compared to the unexposed flies with PD [Figure 4]; P < 0.05]. The control flies exposed to various doses of myricetin did not show any significant increase or decrease in the PCC compared to the control flies [Figure 4]; P < 0.05]. The results obtained for MAO activity are shown in [Figure 5]. The flies with PD showed a significant increase of 2.93-fold in the MAO activity compared to the control flies [Figure 5]; P < 0.05]. The flies with PD exposed to 5, 10, and 20 μM of myricetin showed a significant decrease of 1.11-, 1.25-, and 1.49-folds in the activity of MAO compared to the unexposed flies with PD [Figure 5]; P < 0.05]. The flies with PD exposed to 10−3 M of L-dopamine showed a significant decrease of 1.77-fold compared to the unexposed flies with PD [Figure 5]; P < 0.05]. The control flies exposed to various doses of myricetin did not show any significant increase or decrease in the MAO activity [Figure 5]; P < 0.05].
Figure 1: Effect of myricetin on the glutathione (GSH) content measured in the brain of flies after 24 days of exposure in various treated groups. The values are the mean of five assays. The flies were allowed to feed on a diet supplemented with myricetin for 24 days and then assayed for its GSH content. (aSignificant with respect to control, P < 0.05; bSignificant with respect to PD model flies, P < 0.05; M1 = 5 μM, M2 = 10 μM, M3 = 20 μM; Dopamine = 10−3 M)

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Figure 2: Effect of myricetin on the glutathione-S-transferase (GST) activity measured in the brain of flies after 24 days of exposure in various treated groups. The values are the mean of five assays. The flies were allowed to feed on a diet supplemented with myricetin for 24 days and then assayed for GST activity. (aSignificant with respect to control, P < 0.05; bSignificant with respect to PD model flies, P < 0.05; M1 = 5 μM, M2 = 10 μM, M3 = 20 μM; Dopamine = 10−3 M)

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Figure 3: Effect of myricetin on lipid peroxidation measured in the brain of flies after 24 days of exposure in various treated groups. The values are the mean of five assays. The flies were allowed to feed on a diet supplemented with myricetin for 24 days and then assayed for lipid peroxidation assay. (aSignificant with respect to control, P < 0.05; bSignificant with respect to PD model flies, P < 0.05; M1 = 5 μM, M2 = 10 μM, M3 = 20 μM; Dopamine = 10−3 M)

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Figure 4: Effect of myricetin on the protein carbonyl content measured in the brain of flies after 24 days of exposure in various treated groups. The values are the mean of five assays. The flies were allowed to feed on a diet supplemented with myricetin for 24 days and then assayed for the protein carbonyl content. (aSignificant with respect to control, P < 0.05; bSignificant with respect to PD model flies, P < 0.05; M1 = 5 μM, M2 = 10 μM, M3 = 20 μM; Dopamine = 10−3 M)

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Figure 5: Effect of myricetin on monoamine oxidase measured in the brain of flies after 24 days of exposure in various treated groups. The values are the mean of five assays. The flies were allowed to feed on a diet supplemented with myricetin for 24 days and then assayed for monoamine oxidase activity. (aSignificant with respect to control, P < 0.05; bSignificant with respect to PD model flies, P < 0.05; M1 = 5 μM, M2 = 10 μM, M3 = 20 μM; Dopamine = 10−3 M)

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   Discussion Top


The results obtained in our study clearly demonstrate that myricetin is potent in reducing oxidative stress in the brain of flies with PD. PD is characterized by several abnormalities, including inflammation, mitochondrial dysfunction, iron accumulation, and oxidative stress. A number of pharmaceutical intervention strategies are applied to one or more of these abnormalities by focusing on the molecular pathways underlying the dysfunction and the role that these pathways may play in disease initiation and progression.[4] In this study, we have focused on the oxidative stress markers, because they have been linked to both the initiation and the progression of PD.[4] It has been postulated that the genetic mutation of alpha-synuclein, a major component of Lewy bodies in sporadic PD, may increase neuronal vulnerability to cellular oxidative stress in PD pathogenesis.[10] The formation of Lewy bodies results in the loss of dopaminergic neurons.[11] One such model expressing human alpha-synuclein in the neurons based on the UAS-GAL4 system has been widely used for studying pharmacological interventions, molecular pathways, and various gene expression.[10] In this model, both normal and mutant forms of alpha-synuclein were expressed in Drosophila, producing adult onset loss of dopaminergic neurons and filamentous intraneuronal inclusions containing alpha-synuclein with consequent locomotor dysfunction.[4],[10] Concerning oxidative stress, it still remains unclear whether the degenerating neurons themselves or misfolded proteins directly result in the toxicity. The degenerating neurons may also produce endogenous toxins and reactive oxygen species that may also damage the normal neurons.[17] Oxidative stress has been widely accepted to be an important pathogenetic mechanism of neuronal apoptosis in PD.[18] An increase in LPO, protein oxidation, and Deoxyribonucleic acid (DNA) damage in the substantia nigra has been well documented in the patients with PD.[19] The importance of polyphenolic flavonoids in enhancing cell resistance to oxidative stress goes beyond the simple scavenging activity and is of most interest in diseases in which oxidative stress plays an important role.[20] The cytotoxic aldehydes produced during the process of LPO could also lead to the oxidation of proteins and enhance the progression of the disease.[21] GSH is an important thiol-containing antioxidant in the brain.[22] It plays a pivotal role in preventing oxidative damage. The depletion in the levels of GSH has been reported in patients with PD.[23] The exposure of flies with PD to myricetin results in the restoration of GSH level. An increase in the GST activity has also been reported in patients with PD as well as in various experimental models of PD.[24],[25] The detection of substantially high levels of oxidized lipids,[26] protein,[21] and nucleic acid in postmortem PD brains suggests that the cell death in PD could be a consequence of the increased generation of free radicals or decreased cellular antioxidant defenses.[27] The exposure of flies with PD to myricetin also results in the reduction of MAO activity. The inhibitors of MAO could also act as possible therapeutic agents, because an increase in the activity of MAO has been reported in patients with PD.[28] MAO activity has also been implicated in enhancing oxidative stress in various neurodegenerative disorders. The pathological hallmarks of idiopathic PD are very consistent with the increase in the oxidative stress markers, that is, increased levels of lipid peroxides, protein oxidation, GST activity, and decreased GSH content. Hence, any agent curtailing oxidative stress could act as a possible neuroprotective agent. The mutations in a number of genes encoding for various proteins such as alpha-synuclein, parkin, ubiquitin C-terminal hydrolase-1, DJ-1, phosphate and tensin homolog-induced kinase 1, leucine-rich repeat kinase 2, Omi/Htr A2, ATP 13A2, and glucocerebrosidase have also been reported as one of the factors for the propensity of the disease.[2] Due to ethical limitations, the studies cannot be performed directly on humans; hence, model organisms such as mice, Drosophila, Caenorhabditis elegans, and a number of cell lines are widely used for studying the different aspects of the disease.[29],[30],[31] Among the model organisms, Drosophila has emerged as a valuable model for studying neurodegenerative disorders[32] because it has orthologs for about 75% of the human disease genes. The yeast-based UAS-GAL4 system is an efficient bipartite approach in the activation of gene expression in Drosophila.[33] Using this approach, a number of transgenic fly models have been developed to study the various processes of neurodegenerative diseases.[10] Alpha-synuclein is a membrane-bound protein, whose exact function is still unknown; however, it has been reported to have a synaptic role in the neurons.[34] The overexpression of this protein results in aggregation and leads to the formation of Lewy bodies. Lewy bodies contain other proteins, neurofilaments, and other cytoskeletal elements, suggesting that coprecipitants might be important in aggregation.[35] The formation of Lewy bodies not only results in the death of the dopaminergic neurons, but also generates free radicals leading to oxidative stress.[34] A number of studies on the Drosophila model of PD have shown the existence of oxidative stress during the progression of the disease.[4] This strain used in our study has been successfully used to validate the efficacy of natural plant extracts/products against the PD symptoms exhibited by the flies with PD.[3],[4],[11],[36],[37],[38] The reduction in oxidative stress is attributed to the free radical scavenging ability of myricetin.


   Conclusion Top


The exposure of flies with PD to myricetin showed a dose-dependent decrease in oxidative stress. Oxidative stress has been linked to both the initiation and the progression of PD; the results obtained showed a reduction in oxidative stress. Hence, it can be concluded that myricetin is potent in reducing oxidative stress induced due to the expression of human alpha-synuclein and the formation of Lewy bodies in the brain of model flies with PD.

Acknowledgements

We are thankful to the Chairman, Department of Zoology, Aligarh Muslim University, Aligarh for providing laboratory facilities.

Financial support and sponsorship

The financial assistance received from the University Grants Commission (UGC), New Delhi as UGC Women Post Doctoral Fellowship (F.15-1/2014-15/PDFWM-2014-15-GE-UTT-22847 (SA-II)) to Dr. Gulshan Ara is gratefully acknowledged.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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