|Year : 2011 | Volume
| Issue : 2 | Page : 139-145
1-methyl 4 -phenyl 1,2,3,6-tetrahydropyridine is a potent neurotoxin: Gamma-tocopherol recuperate behavior, dopamine, and oxidative stress on Parkinsonic mice
Kalaivani Karunanithi1, Anandhan Annadurai1, Mohankumar Krishnamoorthy1, Preetham Elumalai2, Tamilarasan Manivasagam1
1 Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu, India
2 Department of Biochemistry, Regensberg University, Germany
|Date of Submission||30-Dec-2010|
|Date of Acceptance||04-Feb-2011|
|Date of Web Publication||23-Aug-2011|
Biotechnology, Annamalai University, Annamalai Nagar- 608 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim : The present study was designed to investigate the neuroprotective effect of gamma-tocopherol on MPTP induced Parkinsonic mice. Materials and Methods: Oral administration of γ-tocopherol (48 mg/kg BW) in C57BL/6 mice for seven days. Parkinson's disease was induced by four intraperitoneal injections (from 4th to 7th day) of MPTP (30 mg/kg BW). On the end of experiment (8th day), behavioral studies were performed to understand motor skill abnormalities and then animals were sacrificed to procure midbrain and striatum. Subsequently, homogenized and centrifuged to get postmitochondrial supernatant which was used to assay a) Neurochemical -- Dopamine, DOPAC, HVA b) Biochemical -- TBARS, GSH, GPx, SOD, and Catalase. Results: Pretreatment of γ-tocopherol (48 mg/kg BW) signiﬁcantly attenuated the MPTP induced behavioral (rotarod performance, open field test, narrow beam walk test and hang test), neurochemical, biochemical alterations in mice suggesting their free-radical scavenging potential. Conclusions: Our results demonstrate that γ-tocopherol confers potent neuroprotection against MPTP-induced toxicity of dopaminergic neurons, and may become a potential therapeutic strategy for neurodegenerative disorder such as Parkinson's disease.
Keywords: Behavior, dopamine, 1-methyl 4 -phenyl 1,2,3,6-tetrahydropyridine, Parkinson′s disease, γ-tocopherol
|How to cite this article:|
Karunanithi K, Annadurai A, Krishnamoorthy M, Elumalai P, Manivasagam T. 1-methyl 4 -phenyl 1,2,3,6-tetrahydropyridine is a potent neurotoxin: Gamma-tocopherol recuperate behavior, dopamine, and oxidative stress on Parkinsonic mice. Int J Nutr Pharmacol Neurol Dis 2011;1:139-45
|How to cite this URL:|
Karunanithi K, Annadurai A, Krishnamoorthy M, Elumalai P, Manivasagam T. 1-methyl 4 -phenyl 1,2,3,6-tetrahydropyridine is a potent neurotoxin: Gamma-tocopherol recuperate behavior, dopamine, and oxidative stress on Parkinsonic mice. Int J Nutr Pharmacol Neurol Dis [serial online] 2011 [cited 2020 Feb 23];1:139-45. Available from: http://www.ijnpnd.com/text.asp?2011/1/2/139/84204
| Introduction|| |
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease (AD), affecting at least 2% of the population aged 65 and older. , Clinical manifestations of PD include akinesia, bradykinesia, a rhythmic involuntary tremor at rest (''pill rolling movement''), postural instability, and extra pyramidal rigidity in which major muscle groups become stiff, collectively referred to as Parkinsonism More Details. The appearance of Parkinsonism develops when loss of at least 50% of the dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) occurs, leading to a reduction of over 80% in dopamine levels in the striatum.  However, the precise pathogenic mechanism leading to neurodegeneration in PD is not known. To explore the disease mechanism and develop new therapies for PD different animal models treated with a number of neurotoxins namely cyanide, carbon monoxide, MPTP, 6-hydroxydopamine (6-OHDA), 3-nitropropionic acid (3-NP), malonic acid (MA), rotenone, paraquat, and azide  are developed. MPTP is a potent neurotoxin, capable of producing PD like symptoms in humans, nonhuman primates and some nonprimate animal such as mice. 
Recently, an increasing number of studies in the animal models of PD, including MPTP models, have suggested that the activation of microglia plays an important role in dopaminergic neurodegeneration.  The progressive neurodegeneration in PD is not halts but slowly gets down by the currently used drug therapies. Hence, current researchers are focusing on finding therapies, preferentially natural products including food supplements which could help in preventing or delaying the ongoing neurodegeneration in PD.  Further, supplementation of dietary antioxidants such as adenosine, selenium, α-tocopherol, β-carotene, ascorbic acid, N-acetyl cysteine, tea polyphenols, and flavonoids have been shown to protect against oxidative stress and exert neuroprotective action.,
The possible involvement of oxidative stress in PD implies the potential protective role of antioxidants.  There have been several reports on the effects of Vitamin-E against MPTP-induced damage to DA neurons in experimental animals. Structurally, natural vitamin-E includes two groups of closely related compounds, the tocopherol and tocotrienol, each with four analogues.  γ-Tocopherol is the most active and abundant form of vitamin-E in human diet, exhibiting in vivo antioxidant and anti-inflammatory activity.  Because of its different chemical structure, γ-tocopherol scavenges reactive nitrogen species, which, like reactive oxygen species, can damage proteins, lipids, and DNA. 5-Nitro-γ-tocopherol, which is formed from these scavenging reactions, may be useful in vivo marker for estimating the physiological relevance of such reactions.  Numerous methods have been previously described for the assessment of the behavioral impact of MPTP intoxication in mice,  including the rotarod test,  hang test, open field test and narrow beam walking  and changes in stride length.  However, whether these tests reflect actual DA loss or the peripheral toxicity associated with MPTP intoxication has been debated.  The majority of these methods were specifically designed to quantify behavioral deficits associated with striatal lesions. They are reported the sensitive methods in detecting functional impairments in MPTP administrated PD mouse models and quantify the potential efficacy of treatments designed to restore dopaminergic function. There is an increasing evidence indicating that oxidative stress may contribute to several CNS pathologies, including PD, aging and AD.  This study investigates the pretreatment effects of γ-tocopherol therapy on behavioral dysfunction, neurochemical, and biochemical alterations of our standardized MPTP mice model of PD.
| Materials and Methods|| |
Adult male C57BL/6 mice (25--30g) from the National Institute of Nutrition, Hyderabad, were used in the present study. The animals were kept under 12 h light/dark cycles, at 22 °C and 60% humidity with food and water ad libitum. The experimental protocols met with the National Guidelines on the Proper Care and Use of Animals in Laboratory Research (Indian National Science Academy, New Delhi, 2000) and were approved by the Animal Ethics Committee of the Institute (Approval No. 586/12-2008).
γ-Tocopherol, MPTP, thiobarbituric acid (TBA), reduced glutathione and 5,5-dithio-bis-nitrobenzoic acid (DTNB) were purchased from Sigma Chemical Company, Bangalore, India. All other chemicals were of analytical grade.
The mice were randomized and divided in to four groups of six animals each. Normal mice treated with saline were served as Group I. Group II mice were treated with intraperitoneal injection of MPTP (30 mg/kg BW).  Group III mice were given γ-tocopherol orally (48 mg/kg body weight) and then received MPTP for 4 consecutive days (from th fourth day to th seventh day of γ-tocopherol administration). MPTP was given after 1 h interval of γ-tocopherol administration to this group. Group IV mice were given γ-tocopherol alone orally for seven days as like group III mice.
Cage mates were transported to the testing room and immediately loaded into their respective open ﬁeld chamber. The mice were placed into one corner of an open field chamber (W 100 cm Χ D 100 cm Χ H 40 cm) made of wood and resin. The floor of this chamber was girded into 25 cm (5 Χ 5) squares, and the number of squares crossed (in 5 min) was counted manually in triplicate using a fore paw crossing of a grid line as the criterion (horizontal activity). Vertical activity was measured using the number of observations of grooming and rearing (5 min). The whole study was performed as blind study. 
The rotarod test, in which animals walk on a rotating drum, is widely used to assess motor status in laboratory rodents. Performance is measured by the duration that an animal stays upon the drum as a function of drum speed. Here we report that the task provides a rich source of information. Mice were allowed to adjust their posture in order to maintain their balance on a rotating rod at speeds of 5, 10, 15, and 20 r/min. The average retention time on the rod was calculated as described previously. 
In the narrow beam walking test (also known as the raised beam or raised bridge test), mice are trained to traverse a series of elevated, narrow beams to reach an enclosed escape platform. The protocol described here measures foot slips and latency to traverse the beam, although a number of other parameters of motor coordination and balance can also be measured. Animals were trained to walk on a narrow flat stationary wooden beam (L 100 cm Χ W 1 cm) placed at a height of 100 cm from the floor. The time taken to cross the beam from one end to the other was counted as described previously. 
Mice were placed on a horizontal grid and supported until they hold the grid. The grid was then inverted so that the mice will be allowed to hang upside down. Animals were allowed to stay on the grid for 30 s and 10 chances with 1 min interval and the fall values were recorded as described earlier. 
Dissection and homogenization
Animals were sacrificed by decapitation immediately after behavioral assessments on 8th day. Striatum of each animal was isolated by putting on ice and then weighed separately. A 10% (WV-1) tissue homogenates were prepared in 0.1 M phosphate buffer (pH 7.4). The homogenates were centrifuged at 10 000 Χ g at 4 °C for 15 min. Aliquots of supernatants were separated and used for biochemical estimations.
HPLC analysis of dopamine, dopamine and its metabolites 3,4-dihydroxy phenyl acetic acid (DOPAC) and homovanillic acid (HVA)
Dopamine and its metabolites DOPAC and HVA were analyzed using reversed phase ion-pair chromatography combined with electrochemical detection under isocratic conditions. The mobile phase (0.6 mM 1-octanesulfonic acid, 0.27 mM Na3 EDTA, 0.043 M triethylamine and 35 ml acetonitrile/l, adjusted to pH 2.95 with H3PO3) are delivered at a flow rate of 0.65 ml/min at 22 oC onto the reversed phase column filled with nucleosil 120-3 C18 (Knaur, Berlin, Germany). Data were calculated by an external standard calibration. 
Thiobarbituric acid reactive substances
Thiobarbituric acid reactive substances (TBARS) content was determined by the method of Utley et al0. Briefly, the tissue was homogenized in chilled 0.1 M Phosphate buffer. The assay mixture contained 0.67% TBA, 10% chilled TCA and homogenate (10%) in a total volume of 3 ml. The ratio of lipid peroxidation was expressed as nmol of TBARS for medh-1g-1 tissue using a molar extinction coefficient of 1.56 Χ 105 M-1 cm-1.
Reduced glutathione (GSH) levels were determined by the method of Jollow et al. PMS (1.0 ml) was precipitated with 1.0 ml of sulfosalicylic acid (4.0%). The samples were kept at 4 °C for 1 h and then subjected to centrifugation at 1200 Χ g for 15 min at 4 °C. The assay mixture contained 0.5 ml of ﬁltered aliquot, 2.3 ml of sodium phosphate buffer (0.1 M, pH 7.4), and 0.2 ml 5, 5-dithiobis-2-nitrobenzoic acid (DTNB) in a total volume of 3.0 ml. The optical density of yellow color thus developed was read immediately at 412 nm on a spectrophotometer.
Glutathione peroxidase activity
Glutathione peroxidase (GPx) activity was determined by the method of Mohandas et al.  The assay mixture consisted of 1.44 ml sodium phosphate buffer (0.1 M, pH 7.4), 0.1 ml EDTA (1 mM), 0.1 ml sodium azide (1 mM), 0.05 ml of glutathione reductase (1 IU/ml), 0.1 ml GSH (1 mM), 0.1 ml NADPH (0.02 mM), 0.01 ml of H2O2 (0.25 mM), and 0.1 ml PMS (10%) in a total volume of 2 ml. Oxidation of NADPH was recorded at 340 nm. The enzyme activity was calculated as nmol NADPH oxidized min-1 mg-1 protein, using a molar extinction coefficient of 6.22 Χ 103 M-1cm-1.
Catalase activity was measured by the method of Claiborne.  The reaction mixture was consisted of 1.95 ml phosphate buffer (0.1 M, pH 7.4), 1 ml H2O2 (0.09 M), and 0.05 ml 10% PMS in the final volume of 3 ml. Change in absorbance was recorded at 240 nm. Catalase activity was calculated in terms of nmol H2O2 consumed min-1 mg-1 protein.
Superoxide dismutase (SOD) activity was assayed using an indirect inhibition assay, in which xanthine and xanthine oxidase serve as a superoxide generator, and nitro blue tetrazolium (NBT) is used as a superoxide indicator. The assay mixture consisted of 960 μl of 50 mM sodium carbonate buffer (pH 10.2) containing 0.1 mM xanthine, 0.025 mM NBT, and 0.1 mM EDTA, 20 μl of xanthine oxidase, and 20 μl of the brain supernatant. Changes in absorbance were observed spectrophotometrically at 560 nm. The activity was expressed as units/min/mg protein. 
| Results|| |
No significant change in the body weight was observed between animals of lesioned and treated group when compared to normal. Degeneration of dopaminergic neurons following MPTP lesioning results in significant neurochemical alterations such as a decrease in DA content.
[Figure 1]a-c shows a significant decrease in DA and DOPAC levels was observed in striatal region of MPTP lesioned mice as compared to control, indicating a significant loss of DA neurons in the lesioned animals. DA and DOPAC level in MPTP + γ-tocopherol group were restored significantly by 38% and 36%, respectively. When compared to lesioned group no significant change was observed in the γ-tocopherol alone treatment group as compared to normal group. [Table 1] describes the levels of TBARS and GSH and the activities of SOD, catalase and GPx in the substantia nigra of the normal and experimental groups. The levels of TBARS and the activities of SOD and CAT in corpus striatum were significantly raised, and the levels of GSH and the activities of GPx were significantly diminished in MPTP treated animals (group II) as compared to control. Prior administration of γ-tocopherol to MPTP treated mice (group III) tends to reverse the oxidative stress.
|Table 1: Changes in the levels of TBARS, GSH and activities of SOD, catalase, and GPx in midbrain of|
control and experimental mice
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|Figure 1: (a) The levels of dopamine in control and experimental mice. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<</i>0.05 (DMRT). (b) The levels of DOPAC in control and experimental mice. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<</i>0.05 (DMRT). (c) The levels of HVA in control and experimental mice. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<</i>0.05 (DMRT).|
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[Figure 2]a and b shows the significant reduction (P < 0.05) in peripheral movements, rearing, and grooming in MPTP injected animals (group II) when compared to controls. Administration of γ-tocopherol (group III) to the MPTP-lesioned mice significantly increased the activity of the mice in the open field test (P < 0.05).
|Figure 2: (a) The behavior of control and experimental mice in peripheral movement. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ significantly at P<0.05 (DMRT). (b) The behavior of control and experimental mice in grooming and rearing. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<0.05 (DMRT).|
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[Figure 3]a and b shows that MPTP treatment increased beam-crossing duration and reduced hang time as compared with control mice (group I). Administration of γ-tocopherol (group III) to the lesioned animals significantly reduced crossing time and increased hang time (P < 0.05), which indicates an improvement in motor function.
|Figure 3: (a) The time taken to cross beam. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<0.05 (DMRT). (b) The time taken to hang. Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at P<0.05 (DMRT).|
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PD mice showed a significant reduction in retention time on the rotarod compared to controls. Administration of γ-tocopherol to the PD mice for 7 days improved the retention time in the PD mice compared to the γ-tocopherol untreated PD mice [Figure 4].
|Figure 4: Retention time of mice in rotarod at different rpm (5, 10, 15 and 20). Values are given as means ± SD for six mice in each group. Values not sharing a common superscript letter differ signifi cantly at|
Click here to view
| Discussion|| |
The neuroprotective effects of γ-tocopherol in conditions such as experimental autoimmune encephalomyelitis, stroke, Alzheimer's disease and Huntington's disease have been described previously, , but present study is an attempt to study neuroprotective effects of γ-tocopherol in an animal model of PD. Findings of the present study demonstrate the therapeutic prospective of γ-tocopherol in MPTP induced behavioral, biochemical and neurochemical alteration in rodents and suggesting the neuroprotective potential through the free radical scavenging action or anti-inflammatory potential of γ-tocopherol which is in accordance with the earlier reports. In the present study, MPTP treatment significantly caused alterations in motor function observed by behavioral tests, such as rotarod, narrow beam walking, open field, and hanging test have been designed to assess motor coordination in the animal model of PD. The decreases in rotarod performance caused by MPTP might be a consequence of disturbed motor coordination, but they could also be caused by bradykinesia, because this test requires fast and continuous adaptation to the moving rod, a third possibility is that hind limb rigidity makes it difficult for the animals to place all four limbs appropriately on the dowel to hold the balance. This example illustrates that test specificity is desirable, but a clear distinction is often impossible since even ''simple'' motor tasks can be highly complex.
The open field activity has a close relationship with dopaminergic activity.  According to the results of open field test, the mice treated with MPTP showed depletion of DA in the striatum and frontal cortex and reduced open field activity. The groups with γ-tocopherol treatment caused a recovery in DA levels, which was associated with more numbers of rearing, grooming, and longer distances.
In the present investigation, it is probable that the significant impairments of mouse motor initiation and coordination, observed on MPTP administration, are related to the challenging nature of this narrow beam walking task. The hang test evaluates neuromuscular strength and coordination and is sensitive to a loss of DA , reported that MPTP treated animals showed decreased step distance, increased forepaw faults, and tendency to lean on the wall and that these phenomena were related to DA content.
However, whether these tests reflect actual DA loss or the peripheral toxicity associated with MPTP intoxication has been debated.  Motor deficit tests were shown to not correlate well with the striatal DA levels.  Further γ-tocopherol treatment significantly reversed these behavioral alterations in MPTP-treated animals, which can be attributed to the antioxidant and anti-inflammatory potential of γ-tocopherol. So, these findings suggest their potential for management of PD like behavioral alterations.
The neuroprotective action of γ-tocopherol against MPTP has being consistently reported in various studies on mice. γ-Tocopherol administration significantly attenuates the degree of striatal dopamine depletion in MPTP-induced PD mice. Administration of MPTP destroys DA containing neurons in the SN, resulting in a severe depletion of DA in the nerve terminals region, nucleus caudate putamen (NCP) following systemic administration in mice.  The present study also shows that γ-tocopherol treatment could protect dopaminergic neurons from degeneration against MPTP. Pretreatment with γ-tocopherol could reverse the decrease of DA and DA metabolites, DOPAC and HVA.  DOPAC is believed to be derived largely from metabolism of released DA; the increases in DOPAC probably reflect release of DA. MPTP intoxicated mice and degenerated neurons in the SN, striatum and cortex, compensatory mechanisms might develop in the nigrostriatal and mesocortical pathway. MPTP challenge with γ-tocopherol pretreatment demonstrates reduced neurotoxicity.
The motor alterations can be explained on the basis of dopaminergic neuronal death due to excitotoxicity and oxidative burden. As both excitotoxicity and inflammation is closely linked to the production of reactive oxygen species (ROS) and high vulnerability of dopaminergic neurons for free-radical mediated death leads to the behavioral and motor abnormality in the MPTP treated animals.  The present study also demonstrated the increased lipid peroxidation and diminished levels of endogenous antioxidants such as SOD, catalase in MPTP treated animals, pointing toward involvement of oxidative stress in pathogenesis of PD. Similarly the γ-tocopherol treatments significantly attenuated the rise in DA levels, nitrite concentration and restored the endogenous antioxidant (SOD and Catalase) levels in MPTP treated animals. These findings provide another evidence regarding the antioxidant potential of γ-tocopherol, as inflammation is closely linked to the production of ROS, the molecular basis of the observed anti-inflammatory effects of γ-tocopherol may relate to their ability to block the production and/or activity of ROS.,
| Conclusions|| |
Based on the above study, described evidences indicating a neuroprotective potential of γ-tocopherol against MPTP induced PD like symptoms, oversee the effectiveness of γ-tocopherol may represent a novel and promising approach in the management of PD like symptoms.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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