Protective effect of Pluchea lanceolata against aluminum chloride-induced neurotoxicity in Swiss albino mice
Ravi Mundugaru1, Senthilkumar Sivanesan2, Padmaja Udaykumar3, Niranjan Rao4, Naveen Chandra5
1 Department of Pharmacology, S.D.M. Centre for Research in Ayurveda and Allied Sciences, Kuthpady, Udupi, Karnataka, India
2 Department of Research and Development, Saveetha University, Chennai, Tamil Nadu, India
3 Department of Pharmacology, Father Muller Medical College, Mangalore, Karnataka, India
4 Department of PG Studies in Panchakarma, S.D.M. College of Ayurveda, Kuthpady, Udupi, Karnataka, India
5 Department of Biochemistry, S.D.M. Centre for Research in Ayurveda and Allied Sciences, Kuthpady, Udupi, Karnataka, India
|Date of Submission||07-Apr-2017|
|Date of Acceptance||17-May-2017|
|Date of Web Publication||11-Oct-2017|
Department of Research and Development, Saveetha University, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Aluminum chloride (AlCl3) is a known potent environmental neurotoxin causing progressive neurodegenerative changes in the brain. The herb Pluchea lanceolata is commonly known as “Rasana” and used as a nerve tonic in neuroinflammatory conditions in Indian system of medicine. Objective: To evaluate the neuroprotective activity of hydroalcoholic extract of P. lanceolata in chronic AlCl3-induced neurotoxicity in Swiss albino mice. Materials and Methods: Albino mice were categorized into four different groups; Group 1served as vehicle control, Group 2 mice were administered with AlCl3, 40 mg/kg body weight by intraperitoneal route for 45 consecutive days. Groups 3 and 4 mice were administered with AlCl3, 40 mg/kg body weight intraperitoneal for 45 consecutive days along with hydroalcoholic extract of P. lanceolata at 200 and 400 mg/kg body weight. Results: Chronic administration of AlCl3resulted in behavioral deficits, triggered lipid peroxidation, increased acetylcholinesterase (AChE) activity, and histological alterations. Co-administration of hydroalcoholic extract of P. lanceolata attenuated many of the AlCl3-induced alterations such as behavioral, lipid peroxidation, AChE, and histological changes of brain tissue. Conclusion: The results of the present study have demonstrated the protective role of hydroalcoholic extract of P. lanceolata against AlCl3-induced neurotoxicity in Swiss albino mice. The neuroprotective efficacy of P. lanceolata can help reduce the symptoms caused by toxic protein aggregates in several degenerative diseases.
Abbreviations used: HAPL: Hydro alcoholic extract of Pluchea lanceolata; CAT: Catalase; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; TBARS: Thio-barbituric acid reactive substances; MDA: Malondialdehyde; AChE: Acetylcholine esterase; AOT: Acute oral toxicity; CNS: Central nervous system; H2O2: Hydrogen peroxide; ML: molecular layer; GL: granular layer; MC: microcytic changes; BV: blood vessels; DG: dentate gyrus; PC: pyramidal cells; LD: Lethal dose; ANOVA: Analysis of variance; SEM: Standard error of mean; PCL: Pyramidal cell layer; OCL: Outer granular layer; BV: blood vessels; PM: Pia mater.
Keywords: Acetylcholinesterase, aluminum chloride, lipid peroxidation, neurotoxicity, Pluchea lanceolata
|How to cite this article:|
Mundugaru R, Sivanesan S, Udaykumar P, Rao N, Chandra N. Protective effect of Pluchea lanceolata against aluminum chloride-induced neurotoxicity in Swiss albino mice. Phcog Mag 2017;13, Suppl S3:567-72
|How to cite this URL:|
Mundugaru R, Sivanesan S, Udaykumar P, Rao N, Chandra N. Protective effect of Pluchea lanceolata against aluminum chloride-induced neurotoxicity in Swiss albino mice. Phcog Mag [serial online] 2017 [cited 2021 Oct 26];13, Suppl S3:567-72. Available from: http://www.phcog.com/text.asp?2017/13/51/567/216340
- The hydro alcoholic extract of Pluchea lanceolata showed neuroprotective activity in albino mice against AlCl3 toxicity
- The benefits of Pluchea lanceolata against AlCl3 toxicity includes reduced lipid peroxidation and acetylcholine esterase activity with improved behavioral functions
- The hydro alcoholic extract of Pluchea lanceolata rendered protection against AlCl3 in forebrain, midbrain, cerebellum and hippocampus
- Therefore Pluchea lanceolata holds pharmacological potentials for treating diseases associated with neuronal toxicity.
| Introduction|| |
Aluminum is a potent environmental neurotoxin that particularly interferes with several enzymes and proteins related to neurotoxicity leading to many cognitive diseases, especially Alzheimer's disease and Parkinson's disease. Chronic aluminum accumulation can induce oxidative stress and pathological changes in vital areas of the brain. There are varieties of aluminum sources from where the human beings can expose routinely, such as diet, water purification process, antacids, vaccines, and cosmetic agents. The average dietary intake of aluminum in adults ranges from 3 to 12 mg/day. The population routinely exposed to different sources of aluminum may have higher chances of neurotoxicity.,
The possible mechanism of aluminum chloride (AlCl3)-induced neurotoxicity involves severe oxidative stress followed by inflammatory changes leading to neurodegeneration. AlCl3 is a nonredox active metal and capable of increasing the cellular oxidation by potentiating the prooxidant properties. Chronic aluminum exposure generates reactive oxygen species which in turn causes lipid peroxidation and decreased intracellular antioxidants. AlCl3 on accumulation leads to affect the slow and fast axonal transport, induces inflammatory responses, and causes synaptic structural abnormalities, which results in progressive neurodegeneration. It is also reported that AlCl3 can cause degeneration of cholinergic nerve terminals in cortical and hippocampus areas, leading to cellular depletion and severe learning disability.
Plants are considered as rich sources of natural antioxidants, which alleviate the oxidative stress and improve cellular antioxidant status. Pluchea lanceolata (family-Asteraceae) popularly known as “Rasana” in Ayurveda is a rapidly spreading perennial rhizomatous weed and distributed throughout the northwestern part of India and neighboring Asian countries. In Ayurveda, it is widely used in the treatment of rheumatoid arthritis, fever, pain, and inflammation. It is also used as a nerve tonic in conditions such as neuritis, sciatica, and chronic inflammation of nervous system.,, It has been reported to possess anti-inflammatory, analgesic, immunosuppressant, and antimalarial activities.,,, The phytochemicals such as quercetin and isorhamnetin have been identified in P. lanceolata. It has been reported that the flavanols derived from P. lanceolata possess significant antioxidant properties and well attenuated the cadmium chloride-induced oxidative stress and genotoxicity.
Thus, development of potential neuroprotective drugs will be the effective strategy in the management of patients with neurodegenerative cognitive impairment disorders, and hence, there is a great demand for drugs which possess potent anti-inflammatory and antioxidant properties. In the present study, we have evaluated for the first time the neuroprotective activity of hydroalcoholic extract of P. lanceolata in AlCl3-induced neurotoxicity in Swiss albino mice.
| Materials and Methods|| |
Sodium dodecyl sulfate, thiobarbituric acid, glutathione standard, n-butanol, and pyridine were purchased from Himedia-Mumbai, India. Aluminum chloride hexahydrate (AlCl3.6H2O) was obtained from Thomas Baker Pvt. Chemicals, Mumbai, India. Acetylcholinesterase (AChE) kit was purchased from Piramal Healthcare Ltd. Thane, Mumbai, India. All other chemicals and reagents used in the present work were of analytical grade.
Plant material and extract preparation
The rhizome of P. lanceolata were procured from Jamnagar, India, during May 2015 and authenticated in Pharmacognosy Laboratory at SDM Centre for Research in Ayurveda and Allied Sciences, Udupi, Karnataka. The voucher specimen no. 15031401-02 has been deposited for future reference. The rhizome was shade dried and powdered at SDM Pharmacy, Udupi, with the help of pulverizer. The hydroalcoholic extract was prepared by soaking 500 g of powdered rhizome of P. lanceolata in 2 L of 50% ethanol and 50% cold distilled water for 24 h, filtered, and concentrated by evaporating on water bath till free from water.
Male Swiss albino mice weighing 30–40 g body weight were obtained from animal house attached to Pharmacology and Toxicology Laboratory at SDM Centre for research in Ayurveda and Allied Sciences Udupi, India. The animals were maintained at standard laboratory conditions such as temperature at 25°C–27°C, humidity of 50%–55%, and natural light and dark cycles. Animals were fed with commercial pellet diet (Pranav Agro Industry, Pune) and water ad libitum.
Acute oral toxicity test
It was carried out as per OECD guidelines 425, using AOT software. The hydroalcoholic extract of rhizome of Pluchea lanceolata [HAPL] was made into a suspension in 0.5% carboxymethyl cellulose (CMC) and dosed in the following order: 175, 550, and 2000 mg/kg body weight. The animals were observed for 14 days for mortality. The LD50 was determined by AOT 425 software.
The mice were randomized into four different groups, each comprising six animals. Group 1 mice (vehicle control) were given 0.5% CMC orally for 45 consecutive days. Group 2 (AlCl3 control) were treated with 40 mg/kg AlCl3 (pH 7) intraperitoneally for 45 consecutive days. Group 3 and 4 mice were treated with HAPL, 200 and 400 mg/kg body weight, respectively, for 45 consecutive days. The test drug was made as suspension in 0.5% CMC and administered at 1 ml/100 g body weight orally using gavage attached with syringe. The AlCl3 (40 mg/kg body weight, pH 7) was administered intraperitoneally for Groups 3 and 4 for 45 consecutive days an hour after the HAPL treatment. At the end of the experimental period, animal behavior was evaluated. Animals were anesthetized, sacrificed, and serum separated from collected blood. The brain tissues were collected from each group. Three brain samples were stored in 10% formalin and used for histopathological studies, whereas remaining three brain samples were homogenized and used for biochemical investigations.
Behavioral assessment tests
Forced swim test
Animals were subjected to forced swim test on the last day of experimentation. An hour after giving the last dose of group-specific treatment, individual mouse was put into water filled (30 cm) glass cylinder measuring about 40 cm in height and 18 cm diameter, and observations were made for 6 min. First 2 min were not considered for recording the drug effect and were taken as stabilizing time. The limb movements and the effort of the mice to get out of the cylinder in the next 4 min were noted and subtracted later from total time (6 min) to find the time of immobility. This was considered as the index of depression.
Tail suspension test
The total duration of immobility induced by tail suspension was measured according to a standard method. Mice isolated both acoustically and visually were suspended 50 cm above the floor by adhesive tape placed approximately 1 cm from the tip of the tail. Immobility time was recorded during a 6-min test and the immobility time considered as an index of CNS depression.
Estimation of serum acetylcholinesterase
The AChE was estimated by the method described by recommendation of the German society of clinical chemistry. The AChE hydrolyses butyrylthiocholine under release of butyric acid and thiocholine. Thiocholine reduces yellow potassium hexacyanoferrate (III) to colorless potassium hexacyanoferrate (II). The decrease in the absorbance was measured at 405 nm.
Preparation of brain homogenate
Brain was excised and cleaned with ice cold saline and stored at −20°C in freezer. Tissues were thawed and homogenized in phosphate buffered saline pH 7.4, centrifuged at 4000 rpm, and supernatant was stored at −20°C. The homogenate was subjected to determination of catalase, glutathione peroxidase activity, and lipid peroxidation.
Determination of catalase activity
The brain tissue homogenate (1 ml) was mixed with 5 ml of phosphate buffer and 4 ml of 0.2 M H2O2 in phosphate buffer and time was noted. Exactly after 180 s after adding H2O2, a set of 1 ml of reaction mixture from the above was taken in 2 ml dichromate acetic acid. It was kept in boiling water bath for 10 min, cooled all the tubes under running tap water, and finally noted the reading at 570 nm against reagent blank. Catalase activity in the tissue was expressed as micromoles H2O2 consumed/mg protein/min.
Determination of lipid peroxidation
Lipid peroxidation activity was determined by measuring the content of the thiobarbituric acid reactive substances. The level of lipid peroxidation was expressed as millimoles of malondialdehyde formed/g wet tissue.
Determination of glutathione peroxidase
Glutathione peroxidase was estimated using a standard protocol, and the glutathione peroxidase activity was expressed as micromolar glutathione utilized per mg protein per minute at 37°C.
Three brain samples from each group were used, and ten slices per sample were examined for histopathological study. Immediately after the excision from mice, the brain tissue was transferred into 10% formalin. Sections of 5 μm thickness of brain tissue were prepared using microtome and stained with hematoxylin and eosin for microscopic observations. All slides were then evaluated under light microscope (ZEISS Axio Lab A1 India).
The obtained data were expressed as mean ± standard error of mean and analyzed by one-way ANOVA, followed by Dunnett's multiple comparison t-test using GraphPad Prism 3. P < 0.05 was considered as statistically significant.
| Results|| |
The acute toxicity study revealed no mortality with HAPL in any dose up to 2000 mg/kg body weight. The LD50 of HAPL is more than 2000 mg/kg. The dose taken for neuroprotective study was 1/10th and 1/5th of the higher dose of the study and found to be safe.
Effect of hydroalcoholic extract of Pluchea lanceolata on aluminum chloride-induced behavioral changes in behavioral despair test
In behavioral despair test, the duration of freezing time was significantly increased in AlCl3 alone group as compared to vehicle control (P < 0.01). Co-administration of HAPL has significantly attenuated the freezing time at both dose levels as compared to AlCl3 alone group (P < 0.01) [Table 1].
|Table 1: Effect of hydroalcoholic extract of Pluchea lanceolata in behavioral despair test|
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Effect of hydroalcoholic extract of Pluchea lanceolata on aluminum chloride-induced behavioral changes in tail suspension test
The duration of immobility time was significantly increased in AlCl3-treated mice as compared to vehicle control. Whereas co-administration of HAPL considerably attenuated the freezing time, however, the observed changes were not statistically significant as compared to AlCl3 alone group [Table 2].
|Table 2: Effect of hydroalcoholic extract of Pluchea lanceolata in tail suspension test|
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Effect of hydroalcoholic extract of Pluchea lanceolata on acetylcholinesterase
A significant increase in the level of AChE activity was observed in the animals treated with AlCl3 as compared to vehicle control (P < 0.01). The HAPL co-administration with AlCl3 considerably attenuated the AlCl3-induced elevation in the AChE; however, the observed changes were not statistically significant as compared to AlCl3 alone group [Table 3].
|Table 3: Effect of hydroalcoholic extract of Pluchea lanceolata on serum acetylcholinesterase activity|
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Effect of hydroalcoholic extract of Pluchea lanceolata on antioxidant parameters
In the present study, repeated administration of AlCl3 significantly increased lipid peroxidation as compared to vehicle control (P < 0.01). The elevated lipid peroxidation was significantly attenuated at both the dose levels of HAPL as compared to AlCl3 alone group. Whereas repeated administration of AlCl3 caused marked oxidative stress, which led to decrease in the antioxidant enzymes activities such as catalase and glutathione peroxidase in comparison to control group mice; while HAPL co-administered with AlCl3 has increased the activity of catalase and caused no significant changes in glutathione peroxidase levels as compared to AlCl3 alone group [Table 4].
|Table 4: Effect of hydroalcoholic extract of Plantago lanceolata on antioxidant parameters in aluminum chloride-induced neurotoxicity|
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Chronic administration of AlCl3 produced moderate intensity of neurodegeneration in different parts of the brain such as hippocampus, midbrain, forebrain, and cerebellum. In hippocampus, there is a decrease in the pyramidal cells population, with apparent cellular disorganization and distorted cells as compared to control group. The forebrain and midbrain sections of AlCl3 alone group have shown edematous changes, cellular disorganization, and cell distortion. There are microcytic changes observed in the cellular layer of cerebellum, and these changes were attenuated to moderate extent by administration of HAPL at the higher dose level [Figure 1],[Figure 2],[Figure 3],[Figure 4].
|Figure 1: Photomicrograph of representative brain sections focused on hippocampus region of vehicle control (a), aluminum chloride group (b) and hydroalcoholic extract of rhizome of Pluchea lanceolata administered at 200 and 400 mg/kg + aluminum chloride (c and d). Aluminum chloride-administered group showed decrease in the pyramidal cells population, cellular disorganization, and distorted cells. These changes were considerably reversed by the administration of hydroalcoholic extract of rhizome of Pluchea lanceolata at higher dose level. DC: Dentate gyrus; PC: Pyramidal cells|
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|Figure 2: Photomicrograph of representative brain sections focused on midbrain region of vehicle control (a), aluminum chloride group (b) and hydroalcoholic extract of rhizome of Pluchea lanceolata administered at 200 and 400 mg/kg body weight + aluminum chloride (c and d). The midbrain sections from aluminum chloride group show edematous changes, cellular disorganization, sparsely cellular light staining areas, and cell distortion. The sections from hydroalcoholic extract of rhizome of Pluchea lanceolata-treated groups showed mild-to-moderate edematous changes and less cell infiltration|
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|Figure 3: Photomicrograph of representative brain sections focused on forebrain region of vehicle control (a), aluminum chloride group (b), hydroalcoholic extract of rhizome of Pluchea lanceolata administered at 200 and 400 mg/kg body weight + aluminum chloride (c and d). The forebrain sections from aluminum chloride group showed edematous changes, cellular disorganization, and cell distortion. The sections from low-dose hydroalcoholic extract of rhizome of Pluchea lanceolata (200 mg/kg)-treated group exhibited edematous changes with cellular disorganization and distortion whereas high-dose hydroalcoholic extract of rhizome of Pluchea lanceolata (400 mg/kg)-treated group showed almost normal cytoarchitecture|
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|Figure 4: Photomicrograph of representative brain sections focused on cerebellum region of vehicle control (a), aluminum chloride group (b), and hydroalcoholic extract of rhizome of Pluchea lanceolata administered at 200 and 400 mg/kg body weight + aluminum chloride (c and d). The cerebellum sections from aluminum chloride group exhibited caused microcytic changes in the cellular layer of cerebellum. The sections from hydroalcoholic extract of rhizome of Pluchea lanceolata (200 and 400 mg/kg)treated groups exhibited normal cytoarchitecture. ML: Molecular layer; GL: Granular layer; MC: Microcytic changes; BV: Blood vessels|
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| Discussion|| |
Aluminum being an important environmental neurotoxin also acts as a prooxidant. On chronic exposure, it can cause severe oxidative stress in brain tissues. The oxidative stress can lead to neuroinflammation followed by neurodegenerative changes. It has been reported that the phytoconstituents such as curcumin, quercetin, naringin, and catechin have potential antioxidant properties and has shown potent neuroprotective activity in AlCl3-induced neurotoxicity.,
P. lanceolata contains flavonoids such as quercetin and isorhamnetin and also chemicals such as sesquiterpenes, monoterpenes, and triterpenoids. These chemicals possess significant antioxidant and anti-inflammatory activities.,, It has been reported that the decoction prepared from the P. lanceolata was used in pain and inflamed conditions such as arthritis. The taraxasterol derived from P. lanceolata has significant role in reducing neuroinflammation in C6 rat glial cells. By extraction method, the fractions isolated from P. lanceolata were reported to have immunosuppressive properties by inhibiting the cytokines. So far, there are no reports to substantiate the neuroprotective effect of P. lanceolata in AlCl3 toxicity.
In the present study, two neurobehavioral tests were carried out to explore the degree of cognitive impairment and depressant component of the central nervous system. The chronic exposure to AlCl3 significantly increased the freezing time in behavioral despair test and increased immobility time in tail suspension test. This indicates on repeated dose of AlCl3 decreased motor activity, and CNS depression is evident. On the other hand, the co-administration of HAPL significantly attenuated AlCl3-induced CNS depression.
Normal brain cells maintain intact antioxidant milieu of enzymatic and nonenzymatic mediators. The enzymatic components such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and the nonenzymatic components such as glutathione, thioredoxin, and thiol-containing molecules play a major role in maintaining cellular integrity. SOD converts superoxide anions into H2O2 and oxygen, and it is neutralized by CAT and GSH-Px. Thus, the enzymes and indigenous antioxidant molecules protect the cells from damaging aggressive hydroxyl radicals. In the present study, chronic exposure to AlCl3 significantly increased the lipid peroxidation levels (P < 0.01) and significantly decreased the activity of CAT and moderately the GSH-Px, whereas these adverse effects were significantly (P < 0.01)attenuated by co-administration of HAPL, except for GSH-Px.
Acetylcholine is an important neurotransmitter in the cholinergic system, and AChE is an important enzyme involved in the metabolism of acetylcholine neurotransmitter. The increase in the AChE level in turn increases the metabolism of acetylcholine and leads to oxidative stress causing neurobehavioral changes, especially memory and cognitive failure. However, recently, it has been shown that circulating AChE activity reflects inflammatory response since acetylcholine suppresses inflammation. Based on this contention, donepezil, an AChE inhibitor, is being investigated for neuroprotective activity. In the present study, significant elevation in serum AChE activity was observed in AlCl3-administered group in comparison to the control. This elevation was found to be moderately attenuated by HAPL drug treatment. This observation can be considered as an additional evidence for the neuroprotective activity indicating the role of P. lanceolata in the regulation of cholinergic function.
The histological investigation also supports the pathological changes induced by chronic exposure of AlCl3. The high-dose HAPL drug has shown considerable protective effect. AlCl3-induced microcytic changes in the cellular layer of cerebellum and in forebrain sections with evidence of edematous changes, cellular disorganization, and cell distortion in few mice could be visualized. In the hippocampus, there was a decrease in the pyramidal cells population, cellular disorganization, and distorted cells. Thus, chronic administration of AlCl3 produced moderate intensity of neurodegeneration in different parts of the brain such as forebrain, hippocampus, and cerebellum. The test drug administered at higher dose level attenuated the AlCl3-induced histopathological changes from mild to moderate extent. These results support the protective role of HAPL in AlCl3-induced neurotoxicity and improved functional outcome.
| Conclusions|| |
Based on the findings of the present work, it can be concluded that the hydroalcoholic extract of P. lanceolata exhibited neuroprotection in mice against AlCl3 neurotoxicity. Our preliminary experiments using histological, behavioral, and biochemical analysis support this proof of concept and warrants deeper investigations in future using HAPL for gaining better pharmacological information and intervention.
The authors are highly grateful to Research Director and Dean, Saveetha University, Chennai, for their constant motivation to carry out this research work. The authors thank revered President Dr. D. Veerendra Heggade for his constant support, and Dr. B. Yashoverma, Secretary, SDM Educational Society and Dr. B. Ravishankar, Director, SDM Research Centre, Udupi, for their guidance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]