|Year : 2016 | Volume
| Issue : 2 | Page : 90-96
Abrogation of locomotor impairment in a rotenone-induced Drosophila melanogaster and zebrafish model of Parkinson's disease by ellagic acid and curcumin
Dharmendra Kumar Khatri, Archana Ramesh Juvekar
Department of Pharmaceutical Sciences and Technology, Pharmacology Research Lab-I, Institute of Chemical Technology, Mumbai, Maharashtra, India
|Date of Web Publication||11-Apr-2016|
Archana Ramesh Juvekar
Department of Pharmaceutical Sciences and Technology, Pharmacology Research Lab-I, Institute of Chemical Technology, Mumbai - 400 019, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: In this study, we investigated the potential protective effects of ellagic acid and curcumin against the toxicity induced by rotenone (ROT) in zebrafish and Drosophila melanogaster. Materials and Methods: Adult zebrafish were concomitantly exposed to ROT 5 μl/L and ellagic acid (20, 40 mg/kg) and curcumin (20, 40 mg/kg) intramuscularly for 14 days whereas adult wild-type flies were concomitantly exposed to ROT (500 μM), respectively and ellagic acid (0.05% and 0.1%) and curcumin (0.05% and 0.1%) in the food during 7 days. Results: ROT produced marked decreased in the zebrafish swimming behavior and flies had a poorer performance (21-31%) in the negative geotaxis assay (i.e., climbing capability) when compared to control group. Ellagic acid and curcumin treatment offered protection (54-80%) against the ROT-induced locomotor impairment and performed better in zebrafish and in the negative geotaxis assay suggesting attenuation of ROT-induced locomotor deficits. Conclusion: The results of this study suggest that ellagic acid and curcumin was effective in reducing the toxicity induced by ROT in zebrafish and D. melanogaster as well as confirm the significance of this model to explore possible therapeutic approaches on movement disorders, including Parkinson disease.
Keywords: Curcumin, Drosophila melanogaster, ellagic acid, locomotor, Parkinson′s disease, rotenone, zebrafish
|How to cite this article:|
Khatri DK, Juvekar AR. Abrogation of locomotor impairment in a rotenone-induced Drosophila melanogaster and zebrafish model of Parkinson's disease by ellagic acid and curcumin. Int J Nutr Pharmacol Neurol Dis 2016;6:90-6
|How to cite this URL:|
Khatri DK, Juvekar AR. Abrogation of locomotor impairment in a rotenone-induced Drosophila melanogaster and zebrafish model of Parkinson's disease by ellagic acid and curcumin. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2019 Nov 21];6:90-6. Available from: http://www.ijnpnd.com/text.asp?2016/6/2/90/179969
| Introduction|| |
In the 21 st century, there will be a great medical challenge due to neurodegenerative diseases such as Parkinson's, Alzheimer's, and motor neuron diseases because of their extremely debilitating effects and profound lack of effective therapies that replace dead or dying neurons.  Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 1% of the population over the age of 65, and approximately 4-5% over the age of 85.  PD is characterized by selective loss of the pigmented dopaminergic neurons located in the substantia nigra pars compacta, a region of the brain that controls movement and degeneration of nondopaminergic systems such as noradrenergic, serotonergic, and cholinergic systems.  This results in depletion of the neurotransmitter dopamine (DA),  formation of filamentous intraneuronal α-synuclein inclusions (Lewy bodies), and extrapyramidal movement disorders. , While much is known about the pathophysiology of this life-threatening disease, the cause of PD still remains unknown.  The motor symptoms of bradykinesia, rigidity, and resting tremors can be relieved by DA replacement therapies such as levodopa, DA receptor agonists, and monoamine oxidase B inhibitors.  The three main drug development strategies for PD have focused on: (1) Improvements in dopaminergic therapies and prevention of the motor complications; (2) the identification of nondopaminergic drugs for symptomatic improvement; and (3) the discovery of disease-modifying or neuroprotective compounds. , To understand the mechanisms underlying the neurotoxicity of PD-inducing agents or to screen for new therapeutic compounds, a variety of animal models have been established.  Many of the neurotoxins involved in PD, such as 6-hydroxydopamine, 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP), paraquat and rotenone (ROT) induce neurodegeneration via the formation of reactive oxygen species (ROS) are employed.  These toxins all selectively destroy nigrostriatal DA neurons, producing a syndrome that resembles idiopathic PD in animals. 
In recent years, zebrafish and Drosophila melanogaster models have been developed for several neurodegenerative diseases, such as Huntington's disease, PD, and Alzheimer's disease to assess the therapeutic potential of phytochemicals. ,, ROT, a commonly used natural pesticide is a classic high-affinity specific inhibitor of mitochondrial complex I which is capable of causing mitochondrial perturbations, dose-dependent ATP depletion, oxidative damage, and early mortality that mimics PD.  This lipophilic compound freely crosses cell membranes and accesses cytoplasm and mitochondria. Chronic systemic exposure to ROT has been extensively used to model PD in animal models because it parallels the human response to L-dopa therapy.  Exposure of adult Drosophila to sublethal doses of ROT in the diet over 7 days causes a concentration-dependent locomotor deficits, specific dopaminergic neuronal loss, and reduction in the DA levels in adult flies. Since then ROT model has been widely and effectively employed by numerous workers to screen putative neuroprotective phytochemicals.  Growing studies have indicated that a range of pure compounds derived from herbal materials, herbal extracts/fractions, and herbal formulations are effective on in vitro and in vivo PD models via modulation of multiple targets involved in the pathogenesis of PD. 
Ellagic acid and curcumin are the naturally occurring polyphenols. Ellagic acid, 2, 3, 7, 8-tetrahydroxy-chromeno (5, 4, 3-cde) chromene-5, 10-dione, is a naturally occurring powerful bioactive compound found in a range of plant species, especially fruits. It has potential pharmacological and industrial applications.  Curcumin is the chief, active curcuminoid of the dietary spice found in the rhizomes of Curcuma longa (turmeric), a plant in the ginger family (Zingiberaceae). Turmeric has been consumed for medicinal purposes for thousands of years. The curcuminoids are a mixture of three principal compounds: Curcumin (curcumin I; 77%), demethoxycurcumin (curcumin II; 17%), and bisdemethoxycurcumin (curcumin III; 3%). The chemical name of curcumin is 1, 7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6- diene-3,5-dione; the chemical formula is C21H20O6; and pKa value is 8.54.  Extensive research on curcumin and ellagic acid over the past few decades has revealed the health benefits and wide range of pharmacological properties such as anti-mutagenic, anti-oxidant, and anti-inflammatory activity in bacterial and mammalian systems. ,
The aim of the present investigation was to evaluate the ability of ellagic acid and curcumin enriched diet to modulate the ROT-induced locomotor deficits employing a co-exposure model in zebrafish and D. melanogaster.
| Materials And Methods|| |
Curcumin (Cur; assay: 95%) was obtained as gift samples from Konark Herbals and Healthcare Pvt. Ltd., (Mumbai, India) with Certificate of Analysis and dimethyl sulfoxide (DMSO), ROT, were procured from Sigma Chemical Co., St. Louis, USA. All other chemicals used were of analytical grade.
Adult male and female zebrafish were obtained from commercial suppliers from Mumbai, India. Fish were fed 3 times daily (Aquafin Micro Plelle, KW ZONE, Malaysia), and kept on a 14:10 light-dark cycle. Water temperature was maintained between 24°C and 26.5°C.
Rotenone and drug treatment
The stock solution of ROT was prepared at the concentration of 5 mg/ml in DMSO. The concentration of ROT was selected based on our explorative experiment. We used 2, 3, 5, 10 mg/L ROT 21 days exposure. Finally, we found that the appropriate concentration was 5 mg/L. ROT at concentration of 2 mg/L have no effects on an explorative zebrafish motility and ROT 10 mg/L caused fish death after 48 h (data not shown). Hence, we used 5 mg/L concentration because it had significant effects and the zebrafish were still alive until 4 weeks. Six fish were placed in 7 tank (L × W × H: 25.0 cm × 16.5 cm × 12.5 cm) for each group, fed 3 times daily and the medium was changed every 48 h. Control fish were injected with similar volumes of 0.9% NaCl. The volume of injections was 3-5 mg/L, depending on the weight of the fish (0.3-0.5 g). After injections, fish were kept in an extensively aerated water tank until they recovered from the ice water (15-17°C) anesthesia.  All fish were reared under a photoperiod of 14:10 (dark: light). Ellagic acid and curcumin was administered intramuscularly using Hamilton syringes at different concentrations (20 and 40 mg/kg) in the same time with ROT for 21 days. All fish were then kept under equal conditions.
Dysfunction of locomotor activity is clinical syndrome for PD. One of them is bradykinesia (decreasing locomotor activity). The locomotor activity of adult zebrafish was assessed in a 2 L tank (L × W × H: 25.0 cm × 16.5 cm × 12.5 cm) filled with 1 L water system. The normal behavior of fish is to swim back and forth along the length of the tank. The simple observation was used to determine the locomotor activity of adult zebrafish. Three vertical lines were drawn on the tank at equal distances, dividing the tank into four zones (the length of each zone was 6.25 cm). Locomotor activity was measured for 5 min by counting the number of lines that adult zebrafish crossed. Therefore, the total distance that the adult zebrafish traveled was in direct proportion to the total number of lines that the fish crossed. The locomotor activity was calculated by the total number of lines that the zebrafish crossed, divided by time, and expressed in the number of crossed lines/5 min. 
Measurement of locomotor deficits: Negative geotaxis assay
D. melanogaster wild-type, Canton special strain was obtained from the Tata Institute of Fundamental Research, Mumbai, India. The flies were grown in 2.5 cm × 6.5 cm vials containing 5 mL of a standard medium (8.3%, w/v maize flour; 5%, w/v glucose; 2.5%, w/v sucrose; 1.5%, w/v agar; 2%, w/v yeast tablet powder; 0.04%, v/w propionic acid; 0.6%, v/w orthophosphoric acid; 0.7%, v/w methyl hydroxybenzoate) at constant temperature and humidity (23°C ± 1°C; 60% relative humidity, respectively) under 12 h dark/light cycle. All experiments were performed with the same strain.
The PD (ROT treated) flies were exposed to different doses of ellagic acid and curcumin mixed in the culture medium. Ellagic acid (0.05% and 0.1%) and curcumin (0.05% and 0.1%) was added in the medium at final concentrations of 5 mg/mL, 10 mg/mL. Vials of PD flies without test compound were used as control. Flies (male adult, 7-8 days old) were divided into six groups: (1) Control; (2) ROT (500 μM); (3) ROT plus ellagic acid (0.05%) (4) ROT plus ellagic acid (0.1%) (5) ROT plus curcumin (0.05%) (6) ROT plus curcumin (0.1%). The total food medium contained a volume of 1% of DMSO, ROT or ROT plus ellagic acid and curcumin. The flies were exposed to treatments during 7 days and the vials containing flies were maintained at 23°C ± 1°C before being used for assays.
The motor function was assessed using a negative geotaxis assay. , During their light cycle, 20 flies were transferred into a graduated flat bottom glass tube (length 25 cm; diameter 2 cm) and allowed to habituate for at least 5 min. The tube was gently tapped at the bottom and observed for 60 s for the climbing activity (20 flies/trial; 3 trials/replicate). Locomotor behavior was expressed as percent flies escaping beyond a minimum distance of 10 cm in 60 s.
Results are represented as the group means ± standard error of the mean, n = 20. #P < 0.05 compared with normal group and ***P < 0.05 compared with ROT (negative control) group using one-way ANOVA followed by Tukey's Multiple Comparison Test. All statistical analyses were performed using GraphPad Prism 5.0 Version for Windows, GraphPad Software (San Diego, CA, USA).
| Results|| |
Zebrafish motility observation
To know the effect of ROT toward locomotor activity we measured the zebrafish motility for 5 min. Intramuscular injections of the dopaminergic neurotoxins ROT produced marked alterations in the zebrafish swimming behavior [Figure 1]. The result showed that ROT decreased motility and total distance significantly ( #P < 0.001) starting from 1 st week and continuing decreased at the 2 nd week and 3 rd week. Both ellagic acid and curcumin administration gradually increased (***P < 0.001) the zebrafish motility and total distance in a dose-dependent manner.
|Figure 1: Effect of ellagic acid (E) and curcumin (C) on locomotor activity of zebrafish. Data expressed as mean ± standard deviation n = 6. #P < 0.001 compared with control group and *P < 0.05, **P < 0.01, ***P < 0.001 compared with rotenone group using one-way ANOVA followed by Dunnett's test|
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The results of this study reveal that response of the PD induced flies was significantly lower than that of control flies that were co-exposed with phytoconstituents showed marked improvement. ROT (500 μM) treated flies exhibited severe impairment of locomotor activity (measured on day 7) as evident by the increased number of flies remaining at the bottom of the glass column [Figure 2].
|Figure 2: Effect of ellagic acid (E) and curcumin (C) on locomotor activity of Drosophila melanogaster as evaluated by negative geotaxic assay. Data expressed as mean ± standard error of the mean. n = 20. #P < 0.05 compared with normal group and ***P < 0.05 compared with rotenone (negative control) group using one-way ANOVA followed by Tukey's Multiple Comparison Test|
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Interestingly, co-exposure with ellagic acid and curcumin resulted in marked improvement in locomotor deficits, and the effect was concentration-dependent suggesting robust protection. Both ellagic acid and curcumin showed significant improvement in locomotor activity, whereas curcumin was found to be more effective than ellagic acid at lower concentration (0.05%) and higher concentrations (0.1%). The addition of ellagic acid and curcumin to the culture medium significantly improved the climbing ability of the PD induced flies. A time-dependent loss of dopaminergic neurons and the intracellular aggregates of α-synuclein (Lewy bodies) were reported by Feany and Bender in the transgenic flies. These changes were followed by a functional loss in climbing ability.
| Discussion|| |
The zebrafish (Danio rerio) has emerged as extensively used the model system for the study of development and gene function. Zebrafish are vertebrates and, therefore, more closely related to humans than other genetic model organisms such as Drosophila or Caenorhabditis elegans.  Several factors recommend that the zebrafish is a great tool for the study of human diseases: Patterning, pathfinding and connectivity in the central nervous system have all been interpreted and interrelated with the human central nervous system  touch and behavioral responses such as movement patterns can be monitored. 
ROT has been used to model PD in the rat, in which it was shown to induce dopaminergic neurodegeneration, Parkinson-like behavior, reproduce the neurochemical and neuropathological feature. , One of the cardinal sign of Parkinson's is the rigidity or decreasing the ability of movement. Significant decreasing motility of zebrafish started from week 1 st , which may be caused by decreasing motor nerve conducting velocity.
Chronic exposure to ROT may serve not only as a relevant experimental model of motor neuropathy but also as a peripheral marker of dopaminergic neuronal damage to the central nervous system. Tyrosine hydroxylase is the rate-limiting enzyme responsible for the conversion of L-dopa to DA, decreases the immunoreactivity in ROT-induced rat.  The increase in dopaminergic neurotransmission leads to increased locomotor activity and a decrease in dopaminergic neurotransmission leads to decreased locomotor activity. It seems that the decreasing DA level is due to both syntheses of tyrosine hydroxylase and degradation of DA by free radicals. 
Currently, D. melanogaster has been used as an alternative animal model for screening of natural therapeutic agents for the treatment of neurodegenerative diseases, including PD.  In this study, ROT caused locomotor deficits among flies during a 7-day exposure period. Additional, ROT-induced neurotoxicity could be demonstrated by the high rate of locomotor deficits as measured in the negative geotaxis assay. Flies with locomotor deficits have tendency to stay at the bottom of glass column and do not appear to coordinate their legs in a normal fashion. This phenotypic expression has been explained earlier due to the high energy requirement of ambulatory and flight muscles which are rich in mitochondria. Although speculative, it is likely that uncoupled mitochondrial machinery may be responsible for the same under conditions of severe complex I inhibition. 
Another possible reason might be due to the differential and significant depletion of DA concentration. Both curcumin and ellagic acid were able to rescue the flies significantly from deteriorating locomotor dysfunctions indicating their potential to protect at the mitochondrial level with possible restoration of DA pool. This is consistent with earlier findings such as the significant correlation between locomotor dysfunction and DA deficiency.  The Drosophila model in the recent past has emerged as an effective primary screen for several phytochemicals. Since ROT is a well-known redox disruptor; we chose this chemical model in flies to obtain evidence in favor of our hypothesis. Thus, the neurotoxicant (MPTP, paraquat, and ROT) models of Drosophila have been extensively used to understand not only the mechanisms underlying the development of PD and other major neurodegenerative diseases but also serve as an ideal platform to screen various putative neuroprotective compounds. ,
In this study, ROT exposure to flies induced concentration related locomotor deficits which are in agreement with previous reports.  However, the precise mechanism of ROT action which leads to neurodegeneration is not well-understood. Evidence suggesting the involvement of oxidative stress mechanism/s stem from both in vitro and in vivo models relevant to PD.  Similarly in the insect model, ROT-induced neurotoxicity is attributed to the specific sensitivity of dopaminergic neurons to ROS and oxidative damage. Interestingly, similar signs of oxidative damage have been detected frequently in dopaminergic neurons from PD patients, suggesting an implication of oxidative stress in this disease. ,
PD is characterized by several abnormalities, including inflammation, mitochondrial dysfunction, iron accumulation, and oxidative stress.  Loss of motor coordination is a key symptom of PD that is normally caused by selective loss of the dopaminergic neurons of the substantia nigra. Parkinson's-like motor dysfunction has been mimicked in Drosophila by the expression of wild-type and mutant α-synuclein. 
Commonly known as turmeric, C. longa has been noted for its coloring, flavoring and digestive properties since ancient times. C. longa has a variety of biological activities mediated by curcumin (diferuloylmethane), derived from its rhizome, which have led to it being a candidate for the prevention and treatment of disabling age-related neurodegenerative disorders.  For example, curcumin binds amyloid and inhibits Aβ aggregation, fibril, and oligomer formation.  Curcumin has been shown to possess extensive pharmacological activities, including cardiovascular disorders, anti-tumor activities, cholesterol-lowering, antidiabetic, anti-inflammatory, myelodysplastic syndromes, and in neurodegeneration. However, molecular mechanisms of curcumin-mediated anti-PD are still unknown. , Ellagic acid has been explored for its neuroprotective activity by improving locomotor activity in rats (Nichols 2006) and attenuates oxidative stress on the brain and sciatic nerve and improves histopathology of the brain in streptozotocin-induced diabetic rats. 
In the modern era, the potential of natural compounds to reduce the endogenous redox level in vivo has been considered as an effective approach to achieve neuroprotection. , In view of that, we demonstrated the modulatory ability ellagic acid and curcumin on Drosophila employing a dietary approach. Ellagic acid and curcumin enrichment brought about a significant reduction in the locomotor activity.
| Conclusion|| |
In summary, this study demonstrates that both curcumin and ellagic acid improves locomotor performance and reduce the toxicity in ROT-induced zebrafish and D. melanogaster fly PD model. This study confirms the utility of this model to investigate therapeutic strategies that may be promising in the treatment of neurodegenerative diseases.
The author would like to acknowledge financial support from University Grant Commission, New Delhi, India to carry out the research work.
Financial support and sponsorship
University Grant Commission, New Delhi, India.
Conflicts of interest
There are no conflicts of interest.
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