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ORIGINAL ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 3  |  Page : 158-169

Scopolamine induced behavioral and biochemical modifications and protective effect of Celastrus paniculatous and Angelica glauca in rats


1 Department of Pharmacology, Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela, Odisha, India
2 Department of Pharmacology and Toxicology, College of Pharmacy, KLE University, Belgaum, Karnataka, India
3 Department of Pharmaceutical Sciences, Kumaon University, Nainital, Uttarakhand, India
4 Department of Criminology and Forensic Science, School of Applied Sciences, Dr. Harisingh Gour Central University, Sagar, Madhya Pradesh, India
5 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Centre for Advances Research in Pharmaceutical Sciences, New Delhi, India

Date of Submission11-Feb-2014
Date of Acceptance13-Mar-2014
Date of Web Publication16-May-2014

Correspondence Address:
Prakash Chandra Bhatt
Faculty of Pharmacy, Centre for Advances Research in Pharmaceutical Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.132675

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   Abstract 

Introduction: Nootropic agents, including cholinesterase inhibitors are being used to improve memory, mood and behavior, but the side-effects associated with these agents have made their use limited. The present study has therefore been undertaken to assess the synergistic effects of Celastrus paniculatous and Angelica glauca on scopolamine induced dementia in rats. Materials and Methods: Rats were treated with scopolamine (1 mg/kg body weight, i.p.) alone and with donepezil (2 mg/kg body weight p.o.), C. paniculatous (150 mg/kg body weight, p.o) and A. glauca (150 mg/kg body weight, p.o.). The changes in behavioral and biochemical parameters were assessed in rats. Results: Scopolamine treated rats showed impaired learning and memory, increased activity of acetylcholinesterase (AChE) (18%), lipid peroxidation (60%), protein carbonyls (47%) and decreased levels of reduced glutathione (GSH) (35%), activity of superoxide dismutase (34%) and catalase (42%) in hippocampus as compared with control. Simultaneous treatment of C. paniculatous and A. glauca with scopolamine also caused an improvement in the learning and memory activity associated with AChE activity in hippocampus of rats as compared to those treated with scopolamine alone. Combined treatment of C. paniculatous, A. glauca and scopolamine significantly improved the learning and memory function and AChE activity (30%) associated with decreased lipid peroxidation (33%), protein carbonyls (27%) and increased levels of antioxidant enzymes like reduced GSH (46%), activity of superoxide dismutase (50%) and catalase (62%) in hippocampus of rats as compared with those treated with scopolamine alone. Conclusion: The results of the present study exhibit protective efficacy of combined treatment of C. paniculatous and A. glauca in scopolamine induced dementiaand promising as a memory enhancing agents that is associated with its strong antioxidant potential.

Keywords: Angelica glauca , Celastrus paniculatous, dementia, donepezil, oxidative stress, scopolamine


How to cite this article:
Puri A, Srivastava P, Pandey P, Yadav RS, Bhatt PC. Scopolamine induced behavioral and biochemical modifications and protective effect of Celastrus paniculatous and Angelica glauca in rats. Int J Nutr Pharmacol Neurol Dis 2014;4:158-69

How to cite this URL:
Puri A, Srivastava P, Pandey P, Yadav RS, Bhatt PC. Scopolamine induced behavioral and biochemical modifications and protective effect of Celastrus paniculatous and Angelica glauca in rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2019 May 26];4:158-69. Available from: http://www.ijnpnd.com/text.asp?2014/4/3/158/132675


   Introduction Top


Cognitive dysfunctions are the common neurological disorder in clinical practices that may found to be associated with the Alzheimer's disease, epilepsy, depression, schizophrenia, and stroke. [1],[2],[3],[4] Cognitive deficits may be congenital or caused by environmental factors such as brain injuries, neurological disorders or mental illness. [5],[6],[7] It has promoted a growing awareness that, like schizophrenia and neurological disorders, mood disorders may be associated with a distinct pattern of cognitive impairment. Dementia is characterized by loss of intellectual ability leading to disruption of multiple higher cortical functions including memory, reasoning, orientation, learning capacity, and emotional stability. [8],[9] Progressive dementia is associated with Alzheimer's disease, which is a progressive neurodegenerative disorder associated with loss of neurons and is characterized by the presence of excessive amounts of neuritic plaques containing amyloid β protein and abnormal tau protein filaments in the form of neurofibrillary tangles. [10],[11],[12] Degeneration of cholinergic neurons, particularly in the basal forebrain, has been found to be associated with loss of the neurotransmitter acetylcholine. [13],[14] Depletion of acetylcholine level in Alzheimer's disease patients appears to be a critical element in producing dementia. [15] At present, the most appropriate approaches focused on modulation of acetylcholinesterase (AChE) activity. AChE inhibitors such as tacrine, donepezil, physostigmine, galantamine and heptylphysostigmine have been tested for the symptomatic treatment of Alzheimer's disease. Studies reported that these agents increase the availability of acetylcholine at cholinergic synapses, slow the progression of dementia symptoms and enhance cognitive process in humans and animals. [16],[17],[18] However, these drugs suffer from drawbacks in form of their therapeutic efficacy and adverse side-effects to limit their application. [19],[20]

Generation of free radicals associated with enhanced oxidative stress has been found to be attributed in the pathogenesis of Alzheimer's disease resulting in aging and cell apoptosis. [21] A number of studies, including us have been suggested the involvement of reactive oxygen species (ROS) in the neurological and neurodegenerative disorders, [22],[23] thus directing the role of free radicals in progression of Alzheimer's disease. Scopolamine induced models for memory deficits have been widely implicated for screening of anti-dementia drugs. [24],[25] Enhance oxidative stress in different brain regions and decreased activity of AChE in the hippocampus has also been reported following treatment with scopolamine. [26]

The use of herbal and natural extract in the treatment of neurological, psychiatric and neurotoxicological disorders has been increased tremendously due to their no or less side-effects. [23],[27],[28],[29] Angelica glauca, is a high value medicinal and aromatic plant species of the Himalayan region, traditionally used for treatment of migraine, nervous tension and stress. [30],[31] Besides it has also been used traditionally as anti-inflammatory, diuretic, expectorant and diaphoretic and remedy for influenza, hepatitis, chronic bronchitis, rheumatism, and diseases of the urinary system. [31] This herb has long been used to get relief from stomach troubles, bilious complaints, menorrhagia, infantile atrophy and also as a stimulant. [32] Celastrus paniculatous, a treasured medicinal herb has been used for centuries in Ayurveda for sharpening the memory, increasing intellect, and improving concentration. [28],[33],[34] Medicinal oil obtained from the seed of plant C. paniculatous decreased the turnover of all the three central monoamines and implicates in the aminergic systems which regulate learning and memory process. [33],[35] Aqueous extract of C. paniculatous seed has been shown to have cognitive-enhancing effects that could be due to its antioxidant effect. [28],[34],[36],[37]

In view of the fact that etiology of Alzheimer's disease has been found to be modulated through multiple mechanisms and pathways, combined usage of two or more drugs aiming at varied targets could bring about the expected outcome in more diversified manner. [38] Recently, neuroprotective effects of meloxicam (cyclooxygenase-2 inhibitor) and selegiline (an irreversible inhibitor of monoamine oxidase-B against scopolamine-induced cognitive impairment have been demonstrated. [39] In an another study protective effects of donepezil and prucalopride (a 5-hydroxytryptamine four receptor antagonist) [40] and rivastigmine (an AChE inhibitor) and methylthioninium chloride have been reported in scopolamine induced cognitive deficits. Deiana et al., [41] have demonstrated that combination therapy met with better achievement as compared to single drug administration. Keeping this view in mind, the present study has been carried out to evaluate the combined effect of C. paniculatous and A. glauca against scopolamine induced memory deficit through behavioral paradigms by means of Morris water maze, and passive avoidance test. In addition, the activities of AChE and antioxidant enzyme including reduced glutathione (GSH), superoxide dismutase and catalase and the levels of thiobarbituric acid reactive substance (TBARS) and protein carbonyl within the hippocampus of the rats were evaluated to illuminate the biochemical mechanism of the anti-amnesia effect.


   Materials and methods Top


Animals

The protocol for the study was approved by the Institutional Animal Ethics Committee and all experiments have been carried out in accordance with the guidelines laid down by the committee for the purpose of control and supervision of experiments on animals, Ministry of Environment and Forests (Government of India), New Delhi, India (Reg. No. 273). Male albino rats weighing 200 ± 20 g obtained from the animal breeding colony of Uttarakhand Technical University, Dehradun were used for the study. Rats were housed in an air conditioned room at 25°C ± 2°C with a 12 h light/dark cycle under standard hygiene conditions and fed pellet diet and water ad libitum.

Authentication of plant material and preparation of extract

The roots of A. glauca and seeds of C. paniculatous were purchased from Himachal Drugs Pvt. Ltd, Dehradun. Both the samples were authenticated by Dr. H.C. Pandey, Taxonomist, Botanical Survey of India, Dehradun. Voucher specimen (A-31) was deposited in the Department of Pharmacognosy, SBS (PG) Institute of Biomedical Sciences and Research, Balawala, Dehradun, India. Both the plant material (each of 650 g) were dried under shade condition, powdered mechanically and then extracted separately with petroleum ether for 48 h solvent. The solvent was evaporated under reduced pressure to obtain a semisolid mass and then vacuum dried to yield solid residues.

Experimental protocol and treatment schedule

Animals were divided into six groups containing 10 animals each. In Group I, rats were treated with scopolamine dissolved in normal saline (1 mg/kg body weight, i.p.). In Group II, rats were simultaneously treated with donepezil dissolved in normal saline (2 mg/kg body weight p.o.) and scopolamine dissolved in normal saline (1 mg/kg body weight, i.p.). In Group III, rats were simultaneously treated with A. glauca (150 mg/kg body weight p.o) and scopolamine dissolved in normal saline (1 mg/kg body weight, i.p.). In Group IV rats were simultaneously treated with C. paniculatous extract dissolved in distill water (150 mg/kg body weight p.o.) and scopolamine dissolved in normal saline (1 mg/kg body weight, i.p.). In Group V rats were simultaneously treated with A. glauca extract in distill water (150 mg/kg body weight p.o.), C. paniculatous extract in distill water (150 mg/kg body weight, p.o.) and scopolamine in normal saline (1 mg/kg body weight, i.p.). In Group VI, rats were treated with normal saline (1 ml/kg body weight, p.o) for the duration of the treatment to serve as control. C. paniculatous, A. glauca and donepezil were given for total duration of 10 days while scopolamine was administered 30 min prior to behavioral paradigm in all the representative groups. Behavioral studies were carried out after the 24 h of last dose of treatment. For neurochemical assay animals were sacrificed by cervical decapitation and the brains were removed and washed with ice-cold isotonic saline, dissected into brain regions and used for the study.

Behavioral parameters

Morris water maze test

Morris water maze is one of the most widely used tasks for testing spatial learning and memory in rodents and the procedure used in the present experiment was a modification. [42] In this test, water maze consists of a circular pool (1.6 m diameter and 50 cm height) colored with black nontoxic dye filled to a depth of 44 cm with water. The temperature in pool was maintained at 25°C ± 1°C. Four equally spaced points around the edge of the pool were designed as North (N), East (E), South (S) and West (W). A black colored round platform of 9 cm diameter was placed 1 cm below the surface of water. The rats were trained to navigate the submerged platform. The rats were given a maximum time of 120 s (cut-off time) to find the hidden platform and were allowed to stay on it for 30 s. The platform remained in the same position during the training days. Rat that failed to locate the platform within 120 s was put on platform only in the first session. The animals were given a daily session of five trials. Escape latency time to reach the platform was recorded in each trial.

Probe trial

One day after last training trial sessions, rats were subjected to a probe trial (without platform) in which the platform was removed from the pool, allowing the rats to swim for 120 s. to search for the platform placed during previous training sessions. A record was kept of the swimming time in the pool quadrant where the platform had previously been placed.

Passive avoidance paradigm

The passive avoidance test was performed according to the method as described by Yadav et al., [27] with slight modification. The rats were subjected to the passive avoidance test by placing in a light compartment of shuttle box. The light compartment was isolated from the dark compartment by a guillotine door. After an acclimatization period of 30 s, the guillotine door was opened and closed after entry of the rat into the dark compartment. The subject received a low-intensity foot shock (0.5 mA; 10 s) in the dark compartment. The transfer of the animal from one compartment to another was recorded as transfer latency time (TLT) in seconds. The duration of a trial was 270 s. The first trial was for acquisition and retention was tested in a second trial given 24 h after the first trial. The shock was not delivered in the retention trials to avoid reacquisition. The criterion for learning was taken as an increase in the TLT on retention trials when compared with acquisition trial.

Neurochemical parameters

Assay of acetylcholinesterase activity

The activity of AChE has been estimated in hippocampus using acetylthiocholine iodide as substrate following the colorimetric method. [43] Briefly, the reaction mixture in a final volume of 1.0 ml contained phosphate buffer (0.1 M, pH 7.4), postmitochondrial fraction of hippocampus containing around 15-20 μg protein, acetylthiocholine iodide and 5'dithionitrobenzoic acid (DTNB) (5 mM). The degradation of acetylthiocholine iodide was measured at 412 nm and the results are expressed as μmoles/mg protein.

Assay of lipid peroxidation

As a measure of lipid peroxidation, TBARS was measured in hippocampus following the method of Ohkawa et al. [44] Briefly, homogenate of hippocampus in phosphate buffer (0.1 M, pH 7.4) was incubated with sodium dodecyl sulfate (10%, w/v) for 10 min followed by the addition of 20% acetic acid. The reaction mixture was incubated with thiobarbituric acid (0.8%) for 1 h in boiling water bath. The intensity of pink chromogen formed was read at 532 nm and the amount of TBARS was calculated using a molar extinction coefficient of 1.56 × 10 5 M/cm.

Assay of protein carbonyl levels

Protein carbonyl levels in hippocampus was measured following the method of Levine et al., [45] using 2,4-dinitrophenylhydrazine (DNPH) as a substrate. Hippocampus was homogenized in phosphate buffer (50 mM, pH 7.4, 10% w/v) and centrifuged at 11,000×g for 15 min. The resulting supernatant was used for reaction with DNPH. The difference in absorbance between the DNPH treated and the HCl treated samples was determined on spectrophotometer at 375 nm and the amount of carbonyl content (C) was calculated using a molar extinction coefficient (ε) of 22.0 m/M/cm for aliphatic hydrazones.

Assay of reduced glutathione levels

Levels of reduced glutathioneGSH in hippocampus was measured following the standard method. [46] Briefly, 10% homogenate was deproteinized with an equal volume of trichloroacetic acid (10%) and allowed to stand at 4°C for 1 h. The contents were centrifuged at 3000×g for 15 min. The supernatant (0.5 ml) was added to 2 ml of Tris-HCl buffer (0.4 M, pH 8.9) containing ethylenediaminetetraacetic acid (0.02 M, pH 8.9) followed by the addition of 5, DTNB, 0.01 M. The volume was made up to 3 ml by addition of 0.5 ml of distilled water and absorbance of yellow color read on a spectrophotometer at 412 nm and the results are expressed as μg GSH/g tissue.

Assay of glutathione peroxidase activity

The activity of GSHglutathione peroxidase in hippocampus was measured by the standard procedure. [47] Briefly 5% homogenate of brain regions prepared in phosphate buffer (0.1 M, pH 7.4), was centrifuged at 1,500×g for 10 min at 4°C. The supernatant was transferred in to another tube and centrifuged at 10,000×g for 30 min at 4°C. The supernatant obtained after this step was used for the assay of glutathione peroxidase activity. The absorbance of reaction mixture was recorded at 420 nm and values are expressed as nmol GSH oxidized/min/mg protein.

Assay of superoxide dismutase activity

Activity of superoxide dismutase in hippocampus was measured following the method of Kakkar et al., [48] with slight modifications. The reaction mixture was mixed vigorously with 4.0 ml of n-butanol and the mixture was allowed to stand for 10 min followed by centrifugation for 10 min at 3,000×g to separate the butanol layer. The color intensity of the chromogen (purple) in butanol layer was measured at 560 nm against butanol on spectrophotometer. A mixture without enzyme preparations was run in parallel to serve as reagent blank. The activity of superoxide dismutase is expressed in units/min/mg protein. One unit of the enzyme is the amount required to inhibit the rate of chromogen formation by 50%.

Assay of catalase activity

The activity of catalase in hippocampus was assayed following the method of Aebi, [49] using H 2 O 2 as substrate. Briefly, reaction mixture in a final volume of 1.0 ml contained phosphate buffer (0.1 mM, pH 7.4), postmitochondrial fraction of sample (100 μl) and H 2 O 2 (30 mM). The decrease in optical density was measured for 150 s at 240 nm using the spectrophotometer. The activity of the enzyme was calculated using the molar extinction coefficient 43.6 M/cm.

Protein estimation

Protein content in samples was measured following the method of Lowry et al., [50] using bovine serum albumin as a reference standard.

Statistical analysis

Statistical analysis of data was performed by wPad Prism software, version 5. Data have been analyzed using one-way analysis of variance (ANOVA) followed by post-hoc Newman-Keuls test for multiple pair wise comparisons among various groups. All values have been expressed as mean ± standard error of the mean (SEM) value up to P < 0.05 has been considered as significant.


   Results Top


Effect on escape latency using Morris water maze

Morris water maze task training for 10 days leads to progressive improvement in the ability of rats to explore the hidden platform in the target quadrant. The scopolamine-treated animals exhibited longer escape latencies (time taken to find platform) throughout training days than vehicle treated controls (P < 0.05) indicating impairment of memory. The saline treated control group rapidly learned the location of the platform. A. glauca root (w.e) and C. paniculatous seed (w.e) and combination treated groups significantly attenuated the effects of scopolamine on escape latency (P < 0.05), as did donepezil treated groups [Table 1].
Table 1: Effect on escape latency in rats following exposure to scopolamine, AG, CP and their simultaneous treatment along with standard donepezil


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Effect on time spent in platform quadrant during probe trial

Probe trial data of rats exposed to scopolamine shows significant decrease in inclination toward the target quadrant as evident by reduced time spent by animals as compared to vehicle treated group. Moreover, the shorter swimming times within the platform quadrant induced by scopolamine were significantly reversed by A. glauca root (w.e) and C. paniculatous seed (w.e) and combination treated group simultaneously like donepezil treated groups [Table 2].
Table 2: Effect on probe trial method in rats following exposure to scopolamine, AG, CP and their simultaneous treatment along with standard donepezil


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Effect on passive avoidance paradigm in response to assess learning and memory in rats

Exposure of rats to scopolamine caused a significant decrease in TLT of the retention trials as compared to the acquisition trial indicating decrease in the learning and memory activity of rats in comparison to controls [Figure 1]. The TLT in rats in the control and in simultaneous treatment with donepezil and scopolamine group were significantly increased in the retention trial as compared to acquisition trial. Furthermore, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant increase in the in the retention trial as compared to acquisition trial. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats caused a significant increase in the retention trial as compared to acquisition trial indicating improved learning and memory in rats [Figure 1].
Figure 1: Effect on passive avoidance response in mice following exposure to scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ± SEM of five animals in each group significant difference (*P < 0.001, two-tailed) from the acquisition trial of respective group (Student's t-test paired)

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Effect on the activity of acetylcholinesterase in hippocampus of rats

Exposure of rats to scopolamine caused a significant increase in the activity of AChE, an enzyme involve in the metabolism of acetylcholine in hippocampus (18%, P < 0.001) as compared to controls [Figure 2]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant decrease in the activity of AChE in hippocampus (39%, P, 37 %, < 0.001) as compared to those treated with scopolamine alone. Furthermore, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant increase in the activity of AChE in hippocampus (43%, P < 0.01, 47%, P < 0.05) as compared to those treated with scopolamine alone. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant decrease in the activity of acetylcholinestearse in hippocampus (30%, P < 0.01) as compared to those treated with scopolamine alone [Figure 2].
Figure 2: Effect on the activity of acetylcholinesterase in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ± SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05 - 0.001)

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Effect on the level of lipid peroxidation in hippocampus of rats

Exposure of rats to scopolamine caused a significant increase in the level of lipid peroxidation in hippocampus (60%, P < 0.001) as compared to controls [Figure 3]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant decrease in the level of lipid peroxidation in hippocampus (35%, P < 0.001) as compared to those treated with scopolamine alone. Furthermore, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant decrease in the level of lipid peroxidation in hippocampus (20%, P < 0.05, 27%, P < 0.05) as compared to those treated with scopolamine alone. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant decrease in the level of lipid peroxidation in hippocampus (33%, P < 0.01) as compared to those treated with scopolamine alone [Figure 3].
Figure 3: Effect on lipid peroxidation in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ± SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05)

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Effect on the level of protein carbonyl in hippocampus of rats

Exposure of rats to scopolamine caused a significant increase in the level of protein carbonyl in hippocampus (47%, P < 0.05) as compared to controls [Figure 4]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant decrease in the level of protein carbonyl in hippocampus (29%, P < 0.05) as compared to those treated with scopolamine alone. Furthermore, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant decrease in the level of protein carbonyl in hippocampus (22%, P < 0.05, 22%, P < 0.05) as compared to those treated with scopolamine alone. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant decrease in the level of protein carbonyl in hippocampus (27%, P < 0.05) as compared to those treated with scopolamine alone [Figure 4].
Figure 4: Effect on protein carbonyl contents in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard Donepezil Values are mean ± SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05)

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Effect on the level of reduced glutathione in hippocampus of rats

Exposure of rats to scopolamine caused a significant decrease in the level of reduced GSH in hippocampus (35%, P < 0.05) as compared to controls [Figure 5]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant increase in the level of reduced GSH in hippocampus (43%, P < 0.01) as compared to those treated with scopolamine alone. Also, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant increase in the level of reduced GSH in hippocampus (32%, P < 0.05, 29%, P < 0.05) as compared to those treated with scopolamine alone. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant increase in the level of reduced GSH in hippocampus (46%, P < 0.01) as compared to those treated with scopolamine alone [Figure 5].
Figure 5: Effect on reduced glutathione in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ± SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05 - 0.01)

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Effect on the activity of superoxide dismutase in hippocampus of rats

Exposure of rats to scopolamine caused a significant decrease in the activity of superoxide dismutase, an enzyme involve in the dismutation of superoxide radical in hippocampus (34%, P < 0.05) as compared to controls [Figure 6]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant increase in the activity of superoxide dismutase in hippocampus (50%, P < 0.05) as compared to those treated with scopolamine alone. Also, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused a significant increase in the activity of superoxide dismutase in hippocampus (44%, P < 0.05, 43%, P < 0.01) as compared to those treated with scopolamine alone. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant increase in the activity of superoxide dismutase in hippocampus (50%, P < 0.05) as compared to those treated with scopolamine alone [Figure 6].

Effect on the activity of catalase in hippocampus of rats
Figure 6: Effect on the activity of superoxide dismutase in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ±SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05 - 0.01)

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Exposure of rats to scopolamine caused a significant decrease in the activity of catalase in hippocampus (42%, P < 0.05) as compared to controls [Figure 7]. Simultaneous treatment of donepezil and scopolamine in rats caused a significant increase in the activity of catalase in hippocampus (68%, P < 0.05) as compared to those treated with scopolamine alone. Also, simultaneous treatment of A. glauca and C. paniculatous with scopolamine separately in rats caused an increase in the activity of catalase in hippocampus (49%, P > 0.05, 45%, P > 0.05) as compared to those treated with scopolamine alone while the activity of catalase remained decreased as compared to rats in the control group. Combined treatment of A. glauca, C. paniculatous and scopolamine in rats produced a significant increase in the activity of catalase in hippocampus (62%, P < 0.05) as compared to those treated with scopolamine alone [Figure 7].
Figure 7: Effect on the activity of catalase in hippocampus of mice following exposure to Scopolamine, Angelica glauca, Celastrus paniculatous and their simultaneous treatment along with standard donepezil values are mean ± SEM of five animals in each group acompared to control group, bcompared to scopolamine treated group *Significantly differs (P < 0.05)

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   Discussion Top


Functional behavior including learning and memory has been found to be associated with cholinergic system and acetylcholine levels in the brain of humans and animals. [51],[52] Role of acetylcholine, a neurotransmitter involve in the synaptic transmission process, in learning and memory function is well-established. [53],[54] Alterations in the levels of acetylcholine or AChE activity may affect the cholinergic transmission process and leads to learning and memory deficits. [55],[56] The increased levels of acetylcholine in brain regions as a function of AChE inhibition may leads to strengthen the learning and memory and implication of neurological disorders has been demonstrated by a number of investigators. [24],[57],[58] Scopolamine, a nonselective muscarinic antagonist block cholinergic signaling and produce memory and cognitive dysfunctions and subsequently causes learning and memory deficits including long-term and short term memory impairment. [25],[26] It also exerts amnesic effect in rats and rat model of cognition. [59],[60] Scopolamine has been found to increase oxidative stress and impaired the anti-oxidative defense system. [61],[62] Many clinical studies have reported strong evidence that oxidative stress in involved in the pathogenesis of Alzheimer's disease. The oxygen free radicals are implicated in the process of age related decline in the cognitive performance may be responsible for the development of Alzheimer's disease. [63],[64] A significant increase in the AChE activity associated with impaired learning and memory in rats following treatment with scopolamine has been observed in the present study. These effects was further found to be associated with the increased levels of lipid peroxidation, protein carbonyls and decrease in the levels of GSH, activity of superoxide dismutase and catalase in hippocampus of rats following treatment with scopolamine.

Involvement of oxidative stress associated with enhanced generation of ROS in the neurological and psychiatric disorders has been widely accepted. [65],[66] A. glauca, a high value medicinal and aromatic plant species has been reported to be useful to cure stomach troubles, bilious complaints, menorrhagia, and infantile atrophy and as a stimulant. [30],[31],[32] A. glauca mainly consists of mono and sesquiterpenes and the key constituents of its oil are alpha-phellandrene, trans-carveol, beta-pinene, thujene, beta-caryophyllene oxide, beta-caryophyllene, gamma-terpinene, nerolidol, beta-bisabolene and germacrene D. [67] In the present study, simultaneous treatment of root extract of A. glauca and scopolamine caused a significant protection against scopolamine induced learning and memory impairment associated with decreased AChE activity and increased oxidative stress in hippocampus of rats as compared to rats treated with scopolamine alone. Although the protective changes were not at the control level, but still a trend of protection was observed that could be due to its strong antioxidant potential.

C. paniculatous is a treasured medicinal herb that is revered for its effects on the brain and has been used for centuries in Ayurveda for sharpening the memory, increasing intellect, and improving concentration. Studies have shown that C. paniculatous to contain sesquiterpene alkaloids which are involved in the improvement of learning and memory. Alkaloidal ingredients of C. paniculatous include celapanin, celapanigin, celapagin, celastrin, and paniculatin. Besides its seeds consist of palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid. [68] C. paniculatous seed oil causes an overall decrease in the turnover of all the three central monoamines and implicated the involvement of these aminergic systems in the learning and memory process. [33] C. paniculatous seed oil has also been found to be effective in acute and chronic immobilization stress in mice. These protective effects were found to link with its antioxidant potential. [35] Godkar et al., [36] demonstrated the protective efficacy of water soluble seed extract of C. paniculatous against hydrogen peroxide induced oxidative injury in neuronal cells that are associated with its free radical scavenging properties. In another study Godkar et al., [28] further reported that water soluble seed extract of C. paniculatous has capability to modulate glutamate receptor function and protect neuronal cells against glutamate induced toxicity. Further, the cognitive enhancing properties of aqueous extract of C. paniculatous seed associated with its antioxidant potential have also been reported. [34] Bhanumathy et al., [37] studied the effect of aqueous extract of C. paniculatous seeds on learning and memory using elevated plus maze and passive avoidance test in hypoxia model of rats and found significant improvement in learning and memory that has been found to be associated with the modulation of acetylcholine level in rat brain. In the present study, simultaneous treatment of seed extract of C. paniculatous and scopolamine caused a significant protection against scopolamine induced learning and memory impairment associated with decreased AChE activity and increased oxidative stress in hippocampus of rats as compared to rats treated with scopolamine alone suggesting antioxidant potential of C. paniculatous.

In the present study, water extract of both plant potentially exhibit potency as a memory enhancer in scopolamine induced amnesia. Treatment of both plant extract preferred a salutary effect on rodent model of memory deficit commonly used to screen as an anti-dementia drug such as cholinesterase inhibitor like donepezil and nootropics agent like piracetam. [69] In the present study, A. glauca root and C. paniculatous seed was administered improved learning and memory in both exteroceptive and interoceptive behavior models. The combined treatment of A. glauca, C. paniculatous and scopolamine showed a significant increase in the cognitive performance assessed by water Morris maze and passive avoidance test and decreased activity of AChE in hippocampus of rats suggesting modulation of AChE activity as compared to rats treated with scopolamine alone. These rats also exhibits decreased lipid peroxidation and protein carbonyl contents and increased levels of GSH and activity of superoxide dismutase and catalase in the hippocampus of rats as compared to those treated with scopolamine alone indicating anti-oxidative potentials of both drugs. It is expected that decrease AChE activity may enhance cholinergic activity by raising acetylcholine level, thereby maintaining/improving cognitive functions. In accordance, higher AChE inhibition does not necessary mean better cognitive performance and the finding denotes that there is an optimal balance between cholinergic transmission and cognitive performance. No mortality was observed following oral administration of A. glauca root and C. paniculatous seed even with higher dose (1500 mg/kg, p.o.). All the doses of A. glauca root (w.e) and C. paniculatous seed (w.e) had no toxic effect on the normal behavior of the mouse.


   Conclusion Top


The present study demonstrated that extracts from roots of A. glauca and seeds of C. peniculatous has shown promising memory enhancing effects individually but combination of these extracts have shown the more potential effect as a standard drug (donepezil) against a scopolamine induced cognitive dysfunction in rats. Further studies are required to explore the molecular mechanism of neuroprotection of these herbal extracts.


   Acknowledgment Top


The authors would like to thank Department of Pharmaceutical Sciences, Kanak Manjari Institute of Pharmaceutical Sciences Rourkela, Orissa, India and Uttarakhand Technical University, Dehradun for their support provided for the research work.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2]


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