|Year : 2014 | Volume
| Issue : 1 | Page : 14-22
Pharmacological and anti-oxidant evaluation of Aspirin, nimodipine and its combination for anti-Parkinson's activity in MPTP induced rat model
Nilesh S Ambhore, Maruthi Prasanna, A Shanish Antony, MN Satish Kumar, K Elango
Department of Pharmacology, JSS College of Pharmacy, (A Constituent College of JSS University, Mysore) Rocklands, Ooty, The Nilgiris, Tamil Nadu, India
|Date of Web Publication||15-Apr-2014|
Nilesh S Ambhore
Department of Pharmacology, JSS College of Pharmacy, Rockland, Elkhill, Ooty 643 001, The Nilgiris, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Mitochondrial damage and oxidative stress plays important role in Parkinson's disease (PD). Mitochondria are very crucial part in the cell and have many cellular functions including the generation of ATP and intracellular calcium (Ca 2+ ) homeostasis. Mitochondria also contribute in the formation of reactive oxygen species (ROS) and activating the programmed cell death response, apoptosis. Usually ROS is eliminated by antioxidants present in body, but in case of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induction all the antioxidants become ineffective. Aim: The present study investigated the effects of the non selective cyclooxygenase (COX) inhibitor aspirin and L-type calcium channel inhibitor nimodipine in the prevention of motor impairments and observed anti-oxidant effects in rats after induction of early phase of Parkinson's disease by using neurotoxin MPTP. Materials and Methods: The PD was induced in animals by single injection of MPTP. After 48 hrs of induction animals were treated with aspirin and nimodipine for 60 days, then behavioral, biochemical and antioxidant parameters were evaluated to examine the effectiveness of treatment. Statistical analysis was carried out by using one-way ANOVA followed by Bonferroni multiple comparisons test. Results: The treatment with combination (Aspirin 50mg/kg, Nimodipine 30mg/kg) showed significant (P < 0.001) increase in brain dopamine level, improves the complex I activity and also ameliorate the amount of antioxidant enzymes like superoxide dismutase (SOD), glutathione reductase (GSH), catalase (CAT) and decrease in lipid peroxidation. Conclusions : These results strongly suggest that combination shows a good neuroprotective effect compared to single treatment on motor, biochemical and antioxidant parameters in early phase of Parkinson's disease.
Keywords: Catalase, Glutathione reductase, Parkinson′s disease, Superoxidedismutase, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
|How to cite this article:|
Ambhore NS, Prasanna M, Antony A S, Satish Kumar M N, Elango K. Pharmacological and anti-oxidant evaluation of Aspirin, nimodipine and its combination for anti-Parkinson's activity in MPTP induced rat model. Int J Health Allied Sci 2014;3:14-22
|How to cite this URL:|
Ambhore NS, Prasanna M, Antony A S, Satish Kumar M N, Elango K. Pharmacological and anti-oxidant evaluation of Aspirin, nimodipine and its combination for anti-Parkinson's activity in MPTP induced rat model. Int J Health Allied Sci [serial online] 2014 [cited 2019 Sep 16];3:14-22. Available from: http://www.ijhas.in/text.asp?2014/3/1/14/130603
| Inroduction|| |
Parkinson's disease (PD) is a progressive neurodegenerative disease due to loss of nigrostriatal dopaminergic neurons. The pathogenesis of PD remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. Some articles shown that deficiency or damage of complex I activity of the mitochondrial electron transport chain can lead to PD. Also there is evidence for increased numbers of activated microglia in both PD postmortem tissues as well as in animal models of PD. These activated microglia and mitochondrial dysfunctions may both contribute to oxidative damage in PD. There are number of therapeutic targets available which can target inflammation and mitochondrial dysfunction and can be efficacious in the MPTP model of PD. 
The neurotoxin MPTP has been shown to induce Parkinsonism More Details in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced Parkinsonism and Parkinson's disease. 
Several factors including inflammation are believed to be involved in the pathogenesis of this disease. The enzyme cyclooxygenase as well as inflammatory mediators such as nitric oxide have been reported to be increased in PD. , In the MPTP induced animal model of PD, mechanisms mediating inflammatory reactions are reported to contribute to the neuronal damage.  Supporting these findings, the nonselective COX-inhibitor, aspirin and the COX-2 preferential inhibitor meloxicam have been reported to confer neuroprotection in MPTP-induced dopamine (DA) depletion in mice.  However, other COX activity inhibitors like paracetamol, indomethacin, diclofenac or COX expression inhibitor dexamethasone were found to be ineffective in protecting neurons against MPTP neurotoxicity. 
Nimodipine, an L-type calcium channel antagonist, has been mainly used in treatment of cardiovascular related diseases, including angina pectoris, cardiac arrhythmia and hypertension.  Recently nimodipine has been found to be beneficial in many CNS disorders, including stroke, brain injury, cerebral ischemia, epilepsy, dementia and age-related degenerative disease.  The clinical studies showed a prosperous effect of nimodipine on the severity of neurological deficits which can be caused by cerebral vasospasm which come after subarachnoid hemorrhage (SAH).  Nimodipine has also been found to be protective in various in vivo models of cerebral ischemia.  In addition, nimodipine has been shown to afford neuroprotection against glutamate-induced neurotoxicity in vitro, and has been found to be effective in the treatment of old age dementias. However, the potential use of nimodipine in neurodegenerative diseases, such as PD has not been well studied. Less is known about the mechanisms underlying the neuroprotective effects of nimodipine.
| Materials and Methods|| |
Healthy, adult Wistar rats of both sexes (180-220 g) were obtained from the Central animal house facility from J.S.S College of Pharmacy, Ootacamund, Tamilnadu. The animals were kept in a well ventilated room and the animals had exposed to 12 hrs day and night cycle with a temperature between 20+/–3 0 C. The animals were housed in large spacious, hygienic polypropylene cages during the course of the experimental period. The animals were fed with water and rat feed ad libitum. All the experiments were performed after obtaining prior approval from CPCSEA and IAEC. The animals were housed in suitable environmental conditions.
Chemicals and reagents
The following chemicals and drug were used: 1-Methyl-4-phenyl-1, 2, 3, 6-tertahydropyridine (Merck India Ltd, Mumbai), Dopamine (Sd-Fine Chemicals Mumbai), Glutathione reductase, Ubiquinone, NADH, Reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Sigma Aldrich USA), Hexane sulfonic acid, Rotenone Thiobarbituric acid, Sodium dodecyl sulphate, Phenazine methosulphate, Nitro blue tetrazolium (Loba chemicals, Mumbai).
Grouping of animals
Animals were divided into six groups (I-VI), as per epidemiology of PD it occurs in both the genders so each group containing 5 male and 5 female rats, Group I: Acted as control and received 0.3% CMC solution orally, Group II: Was sham operated control, Group III: Received standard drug L-DOPA 6 mg/kg orally.  Group IV and V: Received Aspirin (50 mg/kg orally)  and Calcium channel blocker (Nimodipine 30 mg/kg Orally).  Group VI: Received combination of both NSAID + CCB (Aspirin 50 mg/kg + Nimodipine 30 mg/kg orally).
Induction of Parkinsonism by MPTP
On zero day animals form each group was administered an intraperitoneal (ip) injection of MPTP (20 mg/kg) in normal saline except control group. MPTP is a neurotoxin, which after absorption converted to MPP + radical due to central and peripheral monoamine oxidase-B (MAO-B) which specifically degenerate dopamine-producing neurons in the substantia nigra a part of a mid brain. Due to degeneration of dopaminergic neurons the amount of DA production will be reduces and leads to Parkinsonism. 
Aspirin, Nimodipine and aspirin plus Nimodipine combination treatment was given after 48 hrs of induction of MPTP till 60 days. L-DOPA was given as standard drug. Dose selection for aspirin, nimodipine and L-DOPA has done by referring earlier literatures. Treatment drugs were dissolved in 0.3% CMC solution. Control animals were treated with 0.3% CMC solution. The dose being administered twice a daily at 09:00 hr and 17:00 hr. After 60 days of treatment various parameters were evaluated to check the effect of treatment.
| Behavioural Evaluation|| |
Elevated plus maze
This apparatus is used for study the anti-anxiety effect in animals. The apparatus consist of four compartment two open and two enclosed compartments. After placing animals individually in the center of the maze, head facing towards the open arm, the experiment was started and the fallowing parameters were noted 5 min for each animal. 
- First preference of animal to open or enclosed arm
- No of entries in open and enclosed arm (An arm entry defined as the entry of four paws into arm)
- Average time each animal spend in each arm.
Then we compared the percentage preference of the animal to open/enclosed arm, average time spent in open arm and number of entries in open arm for each group.
Hanging wire test
This task was used as a measure of grasping ability and forelimb strength of the rats after MPTP induced brain injury. In this test MPTP rats (control and drug treated) were suspended by the forelimbs on a wire stretched between 2 posts 60 cm above a foam pillow. The time (in s) until the animal fell was recorded. 
| Biochemical Evaluation|| |
HPLC measurement of dopamine
The previously reported HPLC method was followed for Dopamine content analysis.  Dissected striata were immediately frozen on dry ice and stored at -80°C. Striatal tissues were sonicated in 0.1 M of perchloric acid (about 100 μl/mg tissue). The supernatant fluids were taken for measurements of levels of dopamine by HPLC. Briefly, 20 μl supernatant fluid was isocratically eluted through an 4.6-mm C18 column containing paracetamol (100 mg/ml) as the internal standard with a mobile phase containing 50 mM ammonium phosphate pH 4.6, 25 mM hexane sulfonic acid pH 4.04, 5% acetonitrile and detected by a UV spectrophotometer detector. The flow rate was 1 ml/min. Concentration of DA was expressed as nanograms per milligram of protein. The protein concentrations of tissue homogenates were measured by Lowry's method.
Estimation of total protein by Lowry's method
Protein levels were estimated with the Lowry's method, from similar rat brain slices which were used for dopamine assay and anti-oxidant enzymes estimations. 
Lipid peroxidation assay
Lipid peroxidation in rat brain homogenate was carried out essentially as described earlier.  Rat forebrain (stored at -80ºC for less than 2 weeks) was homogenize in 20 mM Tris-HCl, pH 7.4 (10 ml) at 4ºC using a Polytron homogenizer. The homogenate was centrifuged at 1000 g for 10 min at 4°C, and the supernatant collected. Then acetic acid 1.5 ml (20%; pH 3.5), 1.5 ml of thiobarbituric acid (0.8%) and 0.2 ml of sodium dodecyl sulphate (8.1%) were added to 0.1 ml of supernatant and heated at 100 ºC for 60 min. Mixture was cooled and 5 ml of n-butanol-pyridine (15:1) mixture, 1 ml of distilled water was added and vortexed vigorously. After centrifugation at 1200× g for 10 min, the organic layer was separated and absorbance was measured at 532 nm using an Elisa plate reader. Malonyldialdehyde (MDA) is an end product of lipid peroxidation, which reacts with thiobarbituric acid to form pink chromogen-thiobarbituric acid reactive substance.
Estimation of catalase (CAT)
Catalase measurement was carried out by the ability of CAT to oxidize hydrogen peroxide (H 2 O 2 ).  2.25 ml of potassium phosphate buffer (65 mM, pH 7.8) and 100 μl of the brain homogenate were incubated at 25 ºC for 30 min. A 650 μl H 2 O 2 (7.5mM) was added to the brain homogenate to initiate the reaction. The change in absorption was measured at 240 nm for 2-3 min and the results were expressed as CAT μmol/min mg of protein.
Estimation of Superoxide dismutase assay (SOD)
SOD activity was analyzed by the method described earlier.  Assay mixture contained 0.1 ml of supernatant, 1.2 ml of sodium pyrophosphate buffer (pH 8.3; 0.052 M), 0.1 ml of phenazine methosulphate (186 μm), 0.3 ml of nitro blue tetrazolium, 300 μM, 0.2 ml of NADH (750 μM). Reaction was started by addition of NADH. After incubation at 30 ºC for 90 s, the reaction was stopped by the addition of 0.1 ml of glacial acetic acid. Then added 4.0 ml of n-butanol and reaction mixture was stirred vigorously. Colour intensity of the chromogen in the butanol was measured spectrophotometrically at 560 nm and concentration of SOD was expressed as U/mg of protein.
Analysis of GSH/Glutathion
GSH was measured enzymatically by the method described by Owen.  The striata were homogenized in ice-cold perchloric acid (0.2 M) containing 0.01% EDTA. The homogenate was centrifuged at 10,000 rpm at 4°C for 10 min. The enzymatic reaction was started by adding 200 μl of clear supernatant in a spectrophotometric cuvette containing 500 μl of 0.3 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), 100 μl of 6 mM 5,5-dithiobis-2-nitrobenzoic acid (DTNB) and 10 μl of 25 units/ml glutathione reductase (all the above three reagents were freshly prepared in phosphate buffer at pH 7.5). The absorbance was measured over a period of 3 min at 412 nm at 30°C. The GSH level was determined by comparing the change of absorbance (ΔA) of test solution with the (ΔA) of standard GSH.
The collected data were subjected to appropriate statistical tests like one-way ANOVA (Analysis of Variance) followed by Bonferroni multiple comparisions test. P values of less than 0.001 were considered significant. The analysis was carried using Graphpad Instat software of version 3 published by GraphPad Software, Inc., a privately owned California corporation.
| Result|| |
Estimation of anxiety using elevated plus maze in rats
Evaluation of anxiety or fear is one of the very important psychological parameter in parkinson's disease, because anxiety is directly proportional to dopamine level in basal ganglia. The anxiety levels were estimated by using elevated plus maze. The rats treated with aspirin (50 mg/kg), nimodipine (30 mg/kg), and combination of both showed significant increase [Figure 1] in anxiety levels by increase in percentage preference to open arm when compared with sham operated control which reported in [Table 1].
|Table 1: Effect of aspirin, nimodipine and aspirin plus nimodipine on anxiety using elevated plus maze in rats |
Click here to view
|Figure 1: Study of anti-anxiety activity of treatment drugs in normal and Parkinson's disease induced rats|
Click here to view
Estimation of muscle grip strength using hanging wire test in rats
The treated animals showed increase in hanging time which indicates increase in muscle strength. When compared with control group, sham operated control showed more significant (P < 0.001) variation and reduction of hanging time. When compared with sham operated control, aspirin, nimodipine, aspirin plus nimodipine showed significant (P < 0.001) increase in hanging time [Figure 2] and [Table 2].
|Table 2: Effect of aspirin, nimodipine and aspirin plus nimodipine on hanging wire test in rats |
Click here to view
|Figure 2: Study of hang time test in the normal and Parkinson's disease induced rats|
Click here to view
Estimation of dopamines from brain homogenate
Dopamine concentration in striatal region was measured by HPLC using UV spectrophotometer detector and reported in [Table 3]. When compared with control animals, sham operated group showed more significant reduction in dopamine concentration (P < 0.001), but levodopa showed higher degree of dopamine levels. When compare with sham operated control, aspirin and nimodipine were not significant (P > 0.05) but combination group showed a significant increase in dopamine concentration (P < 0.5). But when compared combination group with control group it showed a significant reduction in the concentration of dopamine (P < 0.001) [Figure 3].
|Table 3: Effect of aspirin, nimodipine and aspirin plus nimodipine on dopamine estimation using HPLC in rats |
Click here to view
|Figure 3: Levels of dopamine in striatum of normal and Parkinson's disease induced rats|
Click here to view
Estimation of protein from brain homogenate
The protein estimation was performed by Lowry's method. The concentration of tissue protein in control group was 32.458 ± 0.2714. When compared with control group, all other groups showed a significant reduction in the concentration of tissue protein. While compared with sham operated control the level of protein was retained with more significance for all the groups (P < 0.001) [Figure 4] and [Table 4].
|Table 4: Effect of aspirin, nimodipine and aspirin plus nimodipine on protein concentrations in rats |
Click here to view
|Figure 4: Striatal protein concentration of normal and Parkinson's disease induced rats|
Click here to view
In vivo antioxidant parameters
The lipid peroxidation produced in brain tissues was analyzed and reported in [Table 5]. When compared with control animals the lipid peroxidation was significantly increased for sham operated, aspirin, and aspirin plus nimodipine (P < 0.001), but in nimodipine alone treated animals the level of lipid peroxidation was less compare with other treated groups (P > 0.05). When compared with sham operated control the level of lipid peroxidation was significantly reduced for test drug treated animals [Figure 5].
|Table 5: Effect of aspirin, nimodipine and aspirin plus nimodipine on antioxidant enzymes in rats |
Click here to view
|Figure 5: Striatal levels of lipid peroxidation and superoxide dismutase in normal and Parkinson's disease induced rats|
Click here to view
The superoxide dismutase was measured and statistically compared. When compared with control animals, it showed a significant reduction for sham operated, aspirin, nimodipine, and aspirin plus nimodipine. But when compared with sham operated control, aspirin plus nimodipine treatment significantly retained the level of SOD (P < 0.001). But aspirin and nimodipine treatment groups the retention of SOD was less significant with the value of (P < 0.05) [Figure 5] and [Table 5].
When compared with control animals the amount of glutathione reductase was significantly reduced for the sham operated, aspirin, nimodipine, and aspirin plus nimodipine (P < 0.001). But when compared with sham operated control, aspirin, nimodipine, and aspirin plus nimodipine showed significant retention of glutathione reductase. The treatment with aspirin, and aspirin plus nimodipine showed retention of glutathione reductase more over same level in all animals but less significance with nimodipine treatment [Figure 6] and [Table 5].
|Figure 6: Striatal levels of glutathion reductase and catalase in normal and Parkinson's disease induced rats|
Click here to view
When compared with control animals the sham operated, aspirin, nimodipine, and aspirin plus nimodipine showed a reduction in the level of catalase activity. While compared with sham operated groups the catalase activity was significantly increased for aspirin, nimodipine, and aspirin plus nimodipine (P < 0.001). This shows retention of catalase activity in treatment groups [Figure 6] and [Table 5].
| Discussion|| |
Parkinson's disease is one of the best understood of the Neurodegenerative disorders which effect human. Its core pathology and biochemistry have been established and there is effective treatment for controlling only the symptoms of the disease at least in its early stages. However the cause of cellular destruction in Parkinson's disease remains the mystery.
Acetylsalicylic acid (aspirin), the most commonly used drug to reduce inflammation, and pain, is known to inhibit COX by acetylating the active site of the enzyme, getting it deacetylated to form salicylic acid. Salicylic acid is an effective inhibitor of prostanoids formed at the site of inflammation in-vivo. This may suggest that the neuroprotective activity observed for salicylic acid is independent of prostaglandin mediation. Recent evidences suggest that salicylate exerts its anti-inflammatory actions through nuclear factor NF-kB activation, but COX-2 inhibitory action of SA was demonstrated to be independent of NF-kB activation. 
Aspirin reduced oxidative damage by suppressing the oxidative stress in treated groups. Literature on antioxidant activity on aspirin is unequivocal but it could protect neurons against glutamate induced hydroxyl radical mediated degeneration. Aspirin, the prodrug of salicylate reversed neurotoxicity of tetrahydrocannabinol in hippocampus neurons by scavenging free radicals. 
Continuous nimodipine administration for 60 days was chosen for two reasons. First, nimodipine is water-insoluble and application gastric intubation is possible with comfort of the animals. Secondly, MPP +, the presumed neurotoxic metabolite of MPTP, which is preferably retained by nerve terminals and fibres but not by somata, which stays for days in the primate brain, exceeding the half life of nimodipine, which lies in the range of hours. MPTP-treatment did not significantly affect clearance or metabolism of nimodipine 7 days after cessation of MPTP-treatment in rats. 
The anxiety level were accessed by elevated plus maze apparatus. The study was summarised by converting the numerical values into percentage preference to open arm. It is clear that percentage preference to open arm for the rats in the control group and aspirin, nimodipine and combination group values were close as levodopa treatment. It means the level of anxiety was less for these groups. Many literatures shown that, anxiety is directly proportional to the dopamine concentration in brain. Since excess dopaminergic activity is associated with anxiety and vice versa. From the above study it is clear that the dopaminergic activity for treatment groups were more than that of sham operated control group. Aspirin, nimodipine and aspirin plus nimodipine treatment was effective in increasing anxiety; this may be due to reduction in oxidative stress and retention of dopamine levels.
The muscle co-ordination activity was measured by hanging wire test. From the assessment of muscle co-ordination activity it is clear that sham operated control group lost its normal muscle co-ordination when compared with normal animals. Administration of aspirin, nimodipine and combination of both in the PD rats for 60 days improved motor function seen in the PD rats as determined by hanging wire test compared to the sham operated control group. As muscle co-ordination is depends on dopaminergic system of basal ganglia, hippocampus and motor cortex so it clearly indicated that treatments may improve the dopamine turnover in basal ganglia region by acting on dopaminergic system.
The estimation of total protein concentration was carried out to assess two factors one was to know the extent of protein degradation or catabolism that has taken place in the brain and the other is for estimation of DA present in the brain homogenates. The level of protein concentration in sham operated control decreased drastically as compare to treatment group. But alone levodopa, aspirin and nimodipine retain the protein level up to the control group which does not shown in combination group. This results suggest that treatment with alone drug can decrease catabolism of protein or hastens its denaturation.
Dopamine neurotransmitter plays important role in body movement and motor control. The reduced levels of catecholamines and oxidative stress leads neurodegeneration in PD and this causes to the loss of motor function in the patients with PD. , So it is very important to measure the striatal dopamine level. The DA concentration in the midbrain region showed a less level for sham operated control group, obviously it was higher in levodopa treated group. Aspirin and nimodipine treated group does not shows any significant increase in striatal dopamine level when compared with sham operated control, because may be aspirin and nimodipine does not alter the dopaminergic system directly so that they does not improve the turnover of striatal dopamine. But in combination they improves the dopamine concentration, and this may be due to compounding effect of ROS scavenging activity of salicylate and decrease the glutamate-induced neurotoxicity due L-type calcium channel blocker nimodipine which contribute to increase the life span of dopaminergic neurons.
MPP+ disturbed the calcium homeostasis which could induce calcium-dependent enzymes, which finally contribute to MPTP-induced neurotoxicity at the nigral cell level and attenuated by nimodipine. In this context it is interesting to note that it has been reported that nimodipine depresses the electrophysiological activity of dopaminergic midbrain neurons in vitro.  This supports a potential influence of nimodipine related events on dopaminergic substantia nigra neurons. Furthermore increased Ca 2+ levels activate proteases, lipases and endonucleases, with subsequent degradation of phospholipids and production of prostaglandins known to involve production of ROS.  This is one of the key players in depletion of all antioxidant parameters. In case of MPTP induction increase in lipid peroxidation, and decrease in GSH, CAT and SOD enzymes were observed. A reduction in GSH might impair H 2 O 2 clearance and promote hydroxyl radical formation and hence oxidative stress. In that all antioxidant defenses are interrelated, the disturbance in one might damage the balance in all.  Treatment with aspirin and nimodipine may act by decreasing the oxidative stress in PD to retain dopamine levels. The antioxidant enzymes were increased by treatment groups this may be due to decrease in ROS and H 2 O 2 production. The combination showed effective increase in antioxidant enzyme levels; this shows the combination was more effective than individual drugs alone.
| Conclusion|| |
Different types of studies were conducted for evaluating antiparkinson activities of aspirin, nimodipine, and aspirin plus nimodipine. We observed a consistent and pharmacological beneficial result for controlling Parkinsonism in animal models by using aspirin, nimodipine and aspirin plus nimodipine. Since these drugs are easily available, clinically proven, with less toxicity, it is worthful these drugs may be used routinely for effective treatment of Parkinsonism. To prove it, further in-vitro studies and molecular level investigations will be useful for utilizing these drugs and combination for the treatment of clinical Parkinsonism.
| References|| |
|1.||Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann N Y Acad Sci 2003;991:120-31. |
|2.||Kupsch A, Sautter J, Schwarz J, Riederer P, Gerlach M, Oertel WH. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level. Brain Res 1996;741:185-96. |
|3.||Iravani MM, Kashefi K, Mander P, Rose S, Jenner P. Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 2002;110:49-58. |
|4.||Knott C, Stern G, Wilkin GP. Inflammatory regulators in Parkinson's disease: INOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 2000;16:724-39. |
|5.||Kusuhara H, Komatsu H, Sumichika H, Sugahara K. Reactive oxygen species are involved in the apoptosis induced by nonsteroidal anti-inflammatory drugs in cultured gastric cells. Eur J Pharmacol 1999;383:331-7. |
|6.||Teismann P, Ferger B. Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease. Synapse 2001;39:167-74. |
|7.||Aubin N, Curet O, Deffois A, Carter C. Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice. J Neurochem 1998;71:1635-42. |
|8.||Langley MS, Sorkin EM. Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs 1989;37:669-99. |
|9.||Meyer FB, Tally PW, Anderson RE, Sundt TM Jr, Yaksh TL, Sharbrough FW. Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker. Brain Res 1986;384:180-3. |
|10.||Murray GD, Teasdale GM, Schmitz H. Nimodipine in traumatic subarachnoid haemorrhage: A re-analysis of the HIT I and HIT II trials. Acta Neurochir (Wien) 1996;138:1163-7. |
|11.||Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia: A systematic review. Stroke 2001;32:2433-8. |
|12.||Weiss JH, Pike CJ, Cotman CW. Ca 2+ channel blockers attenuate beta-amyloid peptide toxicity to cortical neurons in culture. J Neurochem 1994;62:372-5. |
|13.||Zhang H, Ma L, Wang F, Chen J, Zhen X. Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. Neuropharmacology 2007;53:125-33. |
|14.||Brzozowski T, Konturek P, Konturek SJ, Kwiecieñ S, Sliwowski Z, Pajdo R, et al. Implications of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin. Int J Colorectal Dis 2003;18:320-9. |
|15.||Batuecas A, Pereira R, Centeno C, Pulido JA, Hernández M, Bollati A, et al. Effects of chronic nimodipine on working memory of old rats in relation to defects in synaptosomal calcium homeostasis. Eur J Pharmacol 1998;350:141-50. |
|16.||Fujikawa T, Miguchi S, Kanada N, Nakai N, Ogata M, Suzuki I, et al. Acanthopanax senticosus Harms as a prophylactic for MPTP-induced Parkinson's disease in rats. J Ethnopharmacol 2005;97:375-81. |
|17.||Kulkarni SK. Handbook of Experimental Pharmacology. 3 rd revised ed. New Delhi: Vallabh Prakashan; 2007. p. 135-7. |
|18.||Mukherjee PK, Ahamed KF, Kumar V, Mukherjee K, Houghton PJ. Protective effect of biflavones from Araucaria bidwillii Hook in rat cerebral ischemia/reperfusion induced oxidative stress. Behav Brain Res 2007;178:221-8. |
|19.||Cleren C, Calingasan NY, Chen J, Beal MF. Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. J Neurochem 2005;94:995-1004. |
|20.||Sadasivam S, Manickam A. Biochemical Methods. 2 nd ed. New Delhi: New Age International Pvt. Limited Publication; 2004. p. 57-8. |
|21.||Raja S, Ahamed KF, Kumar V, Mukherjee K, Bandyopadhyay A, Mukherjee PK. Antioxidant effect of Cytisus scoparius against carbon tetrachloride treated liver injury in rats. J Ethnopharmacol 2007;109:41-7. |
|22.||Tariq M, Khan HA, Al Moutaery K, Al Deeb S. Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents. Brain Res Bull 2001;54:77-82. |
|23.||Sairam K, Saravanan KS, Banerjee R, Mohanakumar KP. Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. Brain Res 2003;966:245-52. |
|24.||Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): A review. Altern Med Rev 2000;5:334-46. |
|25.||Olanow CW. The pathogenesis of cell death in Parkinson's disease - 2007. Mov Disord 2007;22 Suppl 17:S335-42. |
|26.||Götz ME, Künig G, Riederer P, Youdim MB. Oxidative stress: Free radical production in neural degeneration. Pharmacol Ther 1994;63:37-122. |
|27.||Ahmad M, Yousuf S, Khan MB, Hoda MN, Ahmad AS, Ansari MA, et al. Attenuation by Nardostachys jatamansi of 6-hydroxydopamine-induced parkinsonism in rats: Behavioral, neurochemical, and immunohistochemical studies. Pharmacol Biochem Behav 2006;83:150-60. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Micro-XRD and nanoindentation investigation of bioceramics for dental pulp therapy
| ||Satish Alapati,Masahiro Iijima,William A. Brantley,Shuichi Ito,Takeshi Muguruma,Takashi Saito,Itaru Mizoguchi |
| ||MEDICAL DEVICES & SENSORS. 2019; : e10027 |
|[Pubmed] | [DOI]|
||Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of a-Synuclein via the Nrf2/HO-1 Pathway
| ||Min Gi Jo,Muhammad Ikram,Myeung Hoon Jo,Lang Yoo,Kwang Chul Chung,Seung-Yeol Nah,Hongik Hwang,Hyewhon Rhim,Myeong Ok Kim |
| ||Molecular Neurobiology. 2018; |
|[Pubmed] | [DOI]|
||Sealing Ability of Biodentine Versus Mineral Trioxide Aggregate as Root-End Filling Materials
| ||Mohamed Nabeel,Hossam M. Tawfik,Ashraf M.A. Abu-Seida,Abeer A. Elgendy |
| ||The Saudi Dental Journal. 2018; |
|[Pubmed] | [DOI]|
||Crystalline phases involved in the hydration of calcium silicate-based cements: Semi-quantitative Rietveld X-ray diffraction analysis
| ||Renata Grazziotin-Soares,Mohammad H. Nekoofar,Thomas Davies,Roberto Hübler,Naghmeh Meraji,Paul M.H. Dummer |
| ||Australian Endodontic Journal. 2017; |
|[Pubmed] | [DOI]|
||Calcium silicate-based cements and functional impacts of various constituents
| ||Mohammad Ali SAGHIRI,Jafar ORANGI,Armen ASATOURIAN,James L. GUTMANN,Franklin Garcia-Godoy,Mehrdad LOTFI,Nader SHEIBANI |
| ||Dental Materials Journal. 2016; |
|[Pubmed] | [DOI]|
||Evaluation of cytotoxicity and gelatinases activity in 3T3 fibroblast cell by root repair materials
| ||Varol Basak,Tuna Elif Bahar,Karsli Emine,Kasimoglu Yelda,Koruyucu Mine,Seymen Figen,Nurten Rustem |
| ||Biotechnology & Biotechnological Equipment. 2016; : 1 |
|[Pubmed] | [DOI]|
||Characterization and antibacterial activity of chlorhexidine loaded silver-kaolinite
| ||Seow Khai Jou,Nik Ahmad Nizam Nik Malek |
| ||Applied Clay Science. 2016; 127-128: 1 |
|[Pubmed] | [DOI]|
||Marginal Adaptation Evaluation of Biodentine and MTA Plus in “Open Sandwich” Class II Restorations
| ||Vivek Aggarwal,Mamta Singla,Suman Yadav,Harish Yadav,Harish Ragini |
| ||Journal of Esthetic and Restorative Dentistry. 2015; : n/a |
|[Pubmed] | [DOI]|
||A review of the physical, chemical properties of MTA
| ||Yong-Bum Cho |
| ||Korean Journal of Dental Materials. 2015; 42(1): 51 |
|[Pubmed] | [DOI]|