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[An Official Publication of ISF College of Pharmacy, Moga]



Original Article
Year : 2018   |  Volume : 10   |  Issue : 3   |  Page : 121-131  

Neuroprotective potential of Mangosteen in 3-nitropropionic acid-induced Huntington’s disease like behavioral and biochemical alterations in rats

Himanshi Khera, Sidharth Mehan, Rajesh Dudi

Correspondence Address:Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India. Pharmacology Division, CSIR-Indian Institute of Integrative medicine, Jammu, India

Source of Support: Nil, Conflict of Interest: None declared


DOI: 10.4103/2231-4040.197331

Abstract  

Huntington’s disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder, characterized by progressively worsening chorea, psychiatric disturbances, cognitive impairment, and weight loss. Gamma-aminobutyric acid-ergic neurons, medium spiny striatal neurons, and cortical neurons are involved in the progression of the neurodegeneration. Impaired energy metabolism, excitotoxicity, microglial activation, and production of pro-inflammatory cytokines leading to neuronal death, by both necrosis and apoptosis, are the major hallmarks of HD. Mangosteen (MGST) contains xanthones which are reported to have antioxidant properties. 3-nitropropionic acid (3-NP) is used to induce HD in animals. MGST (50, 100, and 150 mg/kg orally) was used for 14 days as a treatment for neurotoxicity. Further, MGST treatment significantly improved mitochondrial complex enzyme activity, attenuated inflammatory, and oxidative damage to the brain. In the current study, for the first time, we have tried to further explore the role of MGST as a pharmacological tool in 3-NP-induced neurotoxicity.

Keywords: Huntington’s disease, 3-nitropropionic acid, neurotoxicity, Mangosteen, excitotoxicity

How to cite this article:
Khera H, Mehan S, Dudi R. Neuroprotective potential of Mangosteen in 3-nitropropionic acid induced Huntington’s disease like behavioral and biochemical alterations in rats. Pharmaspire 2018;10(3):121-131.

INTRODUCTION

Huntington’s disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder, characterized by progressively worsening chorea, psychiatric disturbances, cognitive impairment, and weight loss.[1,2] The degenerative process primarily involves medium spiny striatal neurons (MSN) and to a lesser extent cortical neurons. Importantly, γ-aminobutyric acid (gamma-aminobutyric acid)ergic projection neurons of the striatum, which make up roughly 90% of the striatal neurons, are the most vulnerable in HD and their early dysfunction is responsible for the development of chorea.[3-6] To date, there is no cure or clinically proven treatment that slows the progression of this fatal disease. To investigate the mechanism of neurodegeneration in HD, animal models of HD have been generated using genetic manipulations, excitotoxins, and neurotoxins. Injections of N-methyl d-aspartate receptor agonists, such as quinolinic acid, into the striatum, induce HD-like pathology, with a loss of projecting MSN and sparing of cholinergic and nicotinamide adenine dinucleotide phosphate diaphorase neurons.[6] Peripheral injections into rodents or primates of several mitochondrial toxins, including 3-nitroproprionic acid (3-NP), also reproduce the aspects of behavioral, biochemical, and striatal pathology found in HD.[7,8] 3-NP, a mycotoxin, is a suicide inhibitor of succinate dehydrogenase (SDH), enzyme located in mitochondrial inner membrane, a member of both Kreb’s cycle (oxidizing succinate to fumarate), and an entry point for electrons into the respiratory chain at the level of ubiquinol.[9] Inhibition of SDH interferes with the electron cascade and interrupts oxidative phosphorylation. This phenomenon leads to reduced adenosine triphosphate synthesis and oxidative stress.[10,11] Growing body of evidence suggests the involvement of impaired energy metabolism, excitotoxicity, microglial activation, and production of pro-inflammatory cytokines leading to neuronal death, by both necrosis and poptosis. These events of neurodegeneration are relevant to the striatal cell loss seen in HD and are gaining prominence for 3-NP lesions.[12-14]
Despite substantial research into neuroprotection, treatment options for HD are still limited to supportive care and the management of complications. Currently available drugs provide symptomatic relief but do not stop the progression of disease.[15] Thus, the development of new therapeutic strategies remains an unmet medical need. Failure of current drug therapy may be due to their action at only one of many neurotransmitters involved[16] or their inability to upregulate signaling messengers reported to have important role in neuronal functioning,[17] neurotransmitter biosynthesis and release[18] neuronal growth and differentiation,[19] and synaptic plasticity and cognitive functioning.[20] Therefore, one of the alternative to inhibit the progression of HDs is restoration of anti-oxidant defense mechanism as well as to inhibit the release of inflammatory cytokines.Garcinia mangostana mangosteen (MGST) is believed to be a specific antioxidant and anti-inflammatory.[21-24] Based on the important and versatile role of MGST in the prevention of neuronal functions, the present study has been designed to investigate the role of MGST in 3-NP-induced cognitive dysfunction and oxidative stress.

MATERIALS AND METHODS

Experimental animals

The experimental protocol employed in this study received approval from the “Institutional Animal Ethics Committee” under the guidelines given by the “Committee for the Purpose of Control and Supervision of Experiments on Animals.” Wistar albino rats of either sex weighing about 200–300 g were used in the present study. The animals were acclimatized in the “institutional animal house” and maintained on rat chow and tap water. Rats were allowed ad libitum access to food and water. They were exposed to normal day and night cycles. The experiments are carried out in 5–6-months-old male Wistar rats (220–250 g). They are kept in polyacrylic cages and maintained under standard housing conditions with 12 h light/dark reverse cycle. The food in the form of dry pallets and water are made available ad libitum. All behavioral experiments are carried out between 10 am and 4 pm.

Drugs and chemicals

3-nitropropionic acid (3-NP) and 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB) are purchased from Sigma-Aldrich, USA. MGST is provided as ex gratia sample. All other chemicals used in the study are of analytical grade. Solutions of the drugs and chemicals are freshly prepared before use.

Drug administration

3-NP is dissolved in 5% DMSO saline (pH 7.4) and administered intraperitoneally at a dose of 10 mg/kg for 14 days. MGST dissolved in 2% gum acacia (vehicle) and administered by oral route.

GROUPING OF ANIMALS

Animals are randomly divided into eight groups of six animals in each.
Group 1 - Normal control (2% gum acacia orally)
Group 2 - 3-NP control (10 mg/kg, i.p. for 14 days)
Group 3 - MGST per se (150 mg/kg, orally)
Group 4 - 3-NP (10 mg/kg)+MGST (50 mg/kg, orally)
Group 5 - 3-NP (10 mg/kg)+MGST (100 mg/kg, orally)
Group 6 - 3-NP (10 mg/kg)+MGST (150 mg/kg, orally).

Parameters

Measurement of body weight

Body weight is noted on the 1st and last days of the experiment. Percentage change in the body weight is calculated in comparison with the initial body weight on the 1st day of the experimentation.

(Body weight (1st day - 15th day))/ (1st day body) * 100

Behavioral parameters

Morris water maze (MWM) test

Spatial learning and memory of animals are tested in a MWM.[25] It consisted of a circular water tank (180 cm diameter and 60 cm height) filled with water (25 ± 1°C) to a depth of 40 cm. A non-toxic water-dispersible emulsion is used to render the water opaque. Four equally spaced locations around the edge of the pool (North, South, East, and West) are used as start points, which divided the pool into four quadrants. An escape platform (10 cm in diameter) is placed in the pool 2 cm below the surface of water. The escape platform is placed in the middle of one of the randomly selected quadrants of the pool and kept in the same position throughout the entire experiment (northeast for this study). Before the training started, the rats are allowed to swim freely into the pool for 60 s without platform. Animals received a training session consisting of 3 trials per session (once from each starting point) for 3 days (day 11, 12, and 13), each trial having a ceiling time of 60 s and a trial interval of approximately 30 s. After climbing onto the hidden platform, the animals remained there for 30 s before the commencement of the next trial. If the rat failed to locate the hidden platform within the maximum time of 60 s, it is gently placed on the platform and allowed to remain there for the same interval of time. The time taken to locate the hidden platform (latency in seconds) is measured. 24 h after the acquisition phase, a probe test (day 13) is conducted by removing the platform. Rats are allowed to swim freely in the pool for 60 s and the time spent in target quadrant, which had previously contained the hidden platform, is recorded. The time spent in the target quadrant indicated the degree of memory consolidation which had taken place after learning.[26]

Spontaneous locomotor activity

Each animal is tested for spontaneous locomotor activity on days 1, 8, and 15. Each animal is observed over 5 min in a square closed arena equipped with infrared light-sensitive photocells using a digital photoactometer (INCO, India). Each interruption of a beam on the X- or Y-axis generated an electric impulse, which is presented on a digital counter. The apparatus is placed in a darkened, light, and sound attenuated and ventilated testing room. Each animal is observed over a period of 5 min, and values were expressed as counts per 5 min.[15,27]

Limb withdrawal test (LWT)

In this behavioral test, the animal is placed on a 20 cm high 30 cm × 30 cm Perspex platform containing four holes, two holes of 5 cm diameter for the hind limbs, and two holes with a diameter of 4 cm for the forelimbs. The rat is placed on the platform by positioning first the hind limbs and then the forelimbs into the holes. The time taken by the animals to retract their first hind limb and the contralateral hind limb is recorded. The difference between the retraction times (s) of both the hind limbs is determined. This is considered to be an important parameter to measure functional abnormalities of the hind limbs, which are indicative for the extent of striatal degeneration.[28] The test is performed 3 times with a 45 min interval, and the average values are reported.

String test for grip strength

The rat is allowed to hold with the forepaws a steel wire (2 mm in diameter and 35 cm in length), placed at a height of 50 cm over a cushion support. The length of time that the rat is able to hold the wire is recorded. This latency to the grip loss is considered as an indirect measure of grip strength.[29]

Estimation of biochemical parameters

All the biochemical parameters are measured in the brain homogenate on day 15 following 3-NP i.p. injections.

Brain homogenate preparation

Animals are sacrificed by decapitation and the brains are removed and rinsed with ice-cold isotonic saline. Brain tissue samples are then homogenized with ice-cold 0.1 M phosphate buffer (pH 7.4) in a volume 10 times the weight of the tissue. The homogenate is centrifuged at 10,000× g for 15 min, and the aliquots of supernatant were separated and used for biochemical estimation.

Protein estimation

Protein is measured in all brain samples by the method of Lowry et al. (1951) using bovine serum albumin (1 mg/ml) as a standard.[30]

Estimation of SDH activity

SDH is a marker of impaired mitochondrial metabolism in the brain. The quantitative measurement of SDH levels in the brain is performed according to the method as described in previous reports.[31] A 0.3 ml of sodium succinate solution is mixed with the 50 μl of gradient fraction of homogenate. The mixture is incubated at 37°C for 10–20 min, and then, 0.1 ml of solution of p-iodonitrotetrazolium violet (INT) is added and again incubated for further 10 min. The reaction is stopped by adding 1 ml of a mixture of ethyl acetate:ethanol:trichloroacetic acid 5:5:1 (v/v/w) and centrifuged at 15,000 rpm for 1 min, and the absorbance at 490 nm is determined with spectrophotometer (Shimadzu, UV-1700). Results are calculated using molar extinction coefficient of chromophore (1.36 × 104/M/cm) and expressed as INT reduced µmol/mg protein.

Estimation of malondialdehyde (MDA)

 

The quantitative measurement of MDA - end product of lipid peroxidation - in brain homogenate is performed according to the method of Wills (1966). The amount of MDA is measured after its reaction with thiobarbituric acid at 532 nm using spectrophotometer (Shimadzu, UV-1700). The concentration of MDA is determined from a standard curve and expressed as nmol per mg protein.

Estimation of reduced glutathione (GSH)

Reduced GSH in the brain is estimated according to the method described by Ellman et al. (1959)[32] 1 ml supernatant is precipitated with 1 ml of 4% sulfosalicylic acid and cold digested at 4°C for 1 h. The samples are centrifuged at 1200× g for 15 min. To 1 ml of the supernatant, 2.7 ml of phosphate buffer (0.1 M, pH 8) and 0.2 ml of DTNB are added. The yellow color that developed is measured immediately at 412 nm using a spectrophotometer. The concentration of GSH in the supernatant is determined from a standard curve and expressed as µmol per mg protein.

Estimation of nitrite

The accumulation of nitrite in the supernatant, an indicator of the production of nitric oxide (NO), is determined by a colorimetric assay using Griess reagent (0.1% N-(1-naphthyl) ethylenediamine dihydrochloride, 1% sulfanilamide, and 2.5% phosphoric acid) as described by Green et al.[33] Equal volumes of supernatant and Griess reagent are mixed, the mixture is incubated for 10 min at room temperature in the dark, and the absorbance was determined at 540 nm spectrophotometrically. The concentration of nitrite in the supernatant is determined from sodium nitrite standard curve and expressed as µmol per mg protein.

Lactate dehydrogenase (LDH) assay

A diagnostic kit (coral clinical system, Goa, India) is used to measure LDH activity in rat brain homogenate and expressed as IU/mg protein.[34,35]

Statistical analysis

The results are expressed as means ± standard deviation. The behavioral and biochemical values are analyzed by two-way and oneway analysis of variance followed by Bonferroni and Tukey’s post-hoc test. P < 0.05 is considered statistically significant. Data analysis is performed using the statistical software prism (GraphPad Prism for Windows Version 5.02; GraphPad Software, Inc. USA).

RESULTS AND DISCUSSION

Effect of MGST on body weight in 3-NP-treated rats

Chronic, 3-NP treatment caused a significant decrease in body weight as compared to vehicle-treated group [Figure 1 and Table 1]. Pretreatment with MGST (50, 100, and 150 mg/kg, p.o.) in 3-NPtreated rats significantly attenuated the 3-NP-induced loss in body weight and MGST 150 mg/kg, p.o., treatment was found to be most effective in curbing 3-NP-induced weight loss, as compared to MGST 50 and 100 mg/kg groups.

Evaluation of behavioral parameters

Effect of MGST on memory performance in MWM task in 3-NP-treated rats

Except 3-NP control, the latencies to reach the submerged platform decreased gradually in experimental animals of all other groups during 3 days of training in MWM task [Figure 2]. On day 10, there was no significant difference between the mean latencies of all groups. However, the mean latencies were found to be significantly prolonged on day 11 in the 3NP control as compared to vehicle control, indicating their inability to learn the task. However, the 3-NP-induced acquisition deficit was significantly improved by chronic treatment (for 14 days) with MGST (50, 100, and 150 mg/kg, p.o.). Between the treatment groups, namely MGST 50, 100, and 150 mg/kg used in the present study, the MGST 100 mg/kg treatment was found to be most effective in ameliorating 3-NP-induced spatial memory deficit. During the probe trial, with the platform removed, 3NP control rats failed to remember the precise location of the platform, spending significantly less time in the target quadrant compared to normal control. The mean time spent in the target quadrant by 3-NPadministered groups treated with MGST (50, 100, and 150 mg/kg, p.o.) was significantly increased as compared to 3NP control group in a dose-dependent manner, indicating improved consolidation of memory [Figure 3 and Table 2].

Effect of MGST on spontaneous locomotor activity in 3-NP-treated rats

The spontaneous locomotor activity on day 1 did not differ significantly among all the groups [Figure 4]. However, 3-NP treatment caused a significant decrease in locomotor activity as compared to normal group as observed on days 7 and 14. Further, chronic treatment with MGST (50, 100, and 150 mg/kg, p.o.) significantly improved locomotor activity in 3-NP-treated rats. However, MGST 100 mg/ kg on day 15 was found to be more effective compared to MGST 50 mg/kg.

Effect of MGST on LWT in 3-NP-treated rats

In LWT (day 15), 3-NP-treated group showed a significant increase in the retraction time of the hind limbs as compared to the normal control [Figure 5 and Table 3]. Chronic treatment with MGST (50, 100, and 150 mg/kg, p.o.) significantly decreased the retraction time compared to 3-NP-treated rats. However, no significant difference was observed between the dose effects of MGST 100 and 150 mg/kg, p.o.

Effect of MGST on string test for grip strength in 3-NP-treated rats

In 3-NP-administered group, a significant loss in grip strength was recorded and measured by the reduction in time to hold the metal wire as compared to normal control [Figure 6], However, chronic treatment with MGST (50, 100, and 150 mg/kg, p.o.) significantly improved 3-NP-induced loss in grip strength as compared to 3-NP control group in a dose-dependent fashion.

EVALUATION OF BIOCHEMICAL PARAMETERS

Effect of MGST on brain SDH activity in3-NP-treated rats

The activity of SDH was found to be decreased significantly in brain homogenate of 3-NP-treated rats as compared with those of normal control [Figure 7 and Table 6]. Pretreatment with MGST (50, 100, and 150 mg/kg, p.o.) significantly and dose-dependently restored the 3-NP-induced decrease in SDH activity as compared to 3-NP control group.

Effect of MGST on brain MDA levels in 3-NP-treated rats

The level of MDA rose significantly in 3-NP control as compared to those of normal-treated rats (P < 0.05). However, the treatment of these animals with MGST (50, 100, and 150 mg/kg, p.o.) significantly decreased MDA levels in a dose-dependent manner as compared with those of 3-NP control [Figure 8 and Table 7].

Effect of MGST on brain GSH levels in 3-NP-treated rats

The levels of GSH were found to be significantly depleted after 14 days of 3-NP treatment as compared to normal group animals. Chronic treatment with MGST (50, 100, and 150 mg/kg, p.o.) was able to restore GSH levels in 3-NP-treated rats [Figure 9 and Table 4].

Effect of MGST on brain nitrite levels in 3-NP-treated rats

The level of nitrite rose significantly following 14 days of 3-NP administration as compared to those of normal group. However, these animals when treated chronically (for 14 days) with MGST (50, 100, and 150 mg/kg, p.o.) showed dose-dependent significant decrease in the nitrite levels, as compared with those of 3-NP control group [Figure 10 and Table 5].

Effect of MGST on brain LDH levels in 3-NP-treated rats

The level of LDH in brain homogenate was found to be raised significantly in 3-NP control as compared to normal group [Figure 11 and Table 8], indicating extensive neuronal cell damage in 3-NP control rats. Chronic treatment of these animals with MGST (50, 100, and 150 mg/kg, p.o.) significantly reduced the LDH levels compared with those of the 3-NP control group.

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DISCUSSION

MGST (G. mangostana Linn.) or ‘‘MangKhut” in Thai is a tropical fruit and is known as the ‘‘Queen of fruits” in Asia. When MGST is riped, its rind becomes dark purple to red purple, while the flesh is white, soft, juicy, and sweet. Besides the edible flesh, MGST rind has been used to prepare traditional medicines for the treatment of diarrhea and skin infection, among other diseases, for years.[36,37] MGST rind is known as one of the best natural sources of xanthones, which are secondary plant metabolites.[21,38] Xanthones belong to a class of polyphenolic compounds commonly found in higher plant families.[37,39] Xanthones and their derivatives have been reported to have high antioxidant activity,[38,40,41] anti-inflammatory activity,[42,43] antibacterial activity,[44] anti-atherosclerotic activity,[45] and antimalarial activities.[46] In the current study, for the first time, we have tried to further explore the role of MGST as a pharmacological tool in 3-NP-induced neurotoxicity.
3-NP is a mycotoxin reported to inhibit SDH resulting in mitochondrial dysfunction and cellular energy deficit.[46] 3-NP is known to produce memory and cognitive deficit which could be related to its selective striatal damage and certain hippocampal neuronal damage associated with damaging of pyramidal neurons in the CA1 region as well as various neurons in the CA3 region and dentate hilar area.[47] In the present experiments, memory performance was tested through MWM tasks. Chronic treatment of 3-NP resulted in significant impairment of spatial memory in which retention latency on the 13th day was significantly higher as compared to normal animals. Furthermore, 3-NP has also been observed to cause a significant reduction in body weight and caused motor and behavioral abnormalities including bradykinesia, muscle weakness, and rigidity in animals. The present findings are in tune with earlier reports who also observed a variety of neurobehavioral abnormalities, cognitive impairment, and motor deficit in rats following 3-NP administration.[48]
HD patients often show degeneration of hypothalamic neurons and loss of body weight. Reduced body weight can be considered as an indicator of 3-NP neurotoxicity. MGST has shown to significantly improve body weight and attenuate 3-NP-induced hypoactivity in animals. The hypoactivity is a major late-stage symptom in HD patients. Loss in body weight and hypoactivity could be simply because of depressed energy metabolism after 3-NP treatment. Further, 3-NP treatment caused loss of grip strength on Rotarod performance suggesting motor impairment, whereas MGST treatment has been shown to significantly improved grip strength indicating an improvement in motor performance. LWT was used to measure the functional abnormalities of hind limbs, which are indicative for the extent of striatal degeneration. MGST has also shown to significantly reduce 3-NP-induced increase in retraction time which may indicate attenuation of striatal degeneration.[49-53]
3-NP induces energy deficit that leads to depolarization of membrane potential, followed by a release of substrate for radical species production and consequently oxidative stress. The lesions occur by a mechanism involving secondary excitotoxicity. It has been shown that excitotoxicity may be linked to free radical generation. Previous evidence for the involvement of oxidative stress in 3-NP-induced neurotoxicity includes the production of hydroxyl free radicals (¨OH), changes in endogenous antioxidants, and increased 3-nitrotyrosine, a marker for peroxynitrite-mediated damage. Recently, it was reported that systemic administration of 3-NP leads to oxidized proteins in the striatum and cortex, as well as massive loss of striatal neurons. Moreover, mitochondrial dysfunction and oxidative stress have also been implicated in the pathophysiology of HD. MDA is an end product of lipid peroxidation, and it was suggested that plasma MDA may be used as a potential biomarker to test treatment efficacy of drugs used in HD. On the other hand, GSH (gamma-glutamyl-cysteinyl-glycine) is the most abundant intracellular antioxidant thiol which is central to redox defense during oxidative stress. Therefore, decreased level leads to the imbalance of the redox status in the cell leading to oxidative stress. Furthermore, the role of GSH in cognitive function and synaptic plasticity processes as well as its involvement in neurotrophic and neurodegenerative events has been documented. The maintenance of normal GSH level is important for the acquisition of spatial memory, whereas GSH unavailability has been reported to induce failure in hippocampal synaptic plasticity mechanisms, which could be possibly related to a spatial memory deficit.
Supporting to the earlier reports, in the present study, 3-NP significantly increased lipid peroxidation, protein carbonyl formation, and nitrite levels and decreased GSH levels in rat brain, whereas MGST treatment in these animals has shown to significantly attenuate an increase in the levels MDA (indicator of the lipid peroxidation due to free radicals), nitrite, and protein carbonyl formation and restored GSH levels following 3-NP administration, suggesting the antioxidant action of MGST. In addition, MGST has also been demonstrated to have antioxidant potential and reported to scavenge hydroxyl radicals.
In conclusion, using a rodent HD model system that shows an impairment in motor and cognitive functions and an increase in oxidative–nutritive stress, we obtained results suggesting that MGST has neuroprotective effects against 3-NP-induced neurotoxicity. It has been widely reported that systemic administration of 3-NP can produce selective striatal lesions that closely replicate the histologic, neurochemical, and clinical features of HD.[48] Moreover, the symptoms developed by chronic administration of 3-NP are akin to juvenile onset and late hypokinetic stages of HD.

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