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ORIGINAL ARTICLE
Year : 2018  |  Volume : 8  |  Issue : 2  |  Page : 59-65

Neuroprotective Effect of Agaricus Blazei Extract Against Rotenone-Induced Motor and Nonmotor Symptoms in Experimental Model of Parkinson’s Disease


1 Department of Anatomy, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India
2 Department of Anatomy, Velammal Medical College, Madurai, Tamil Nadu, India
3 Department of Anatomy, Sree Balaji Medical College, Chennai, Tamil Nadu, India

Date of Web Publication26-Apr-2018

Correspondence Address:
Srinavasagam Rajasankar
Department of Anatomy, Velammal Medical College, Madurai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_20_18

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   Abstract 

Introduction: In our earlier studies, we reported that rotenone-induced mitochondrial dysfunction, oxidative stress, and apoptosis in the brain of mice have been protected through treatment with Agaricus blazei (A. blazei) extract. The present study is focused on the efficacy of A. blazei in the mitigation of motor and nonmotor symptoms induced by rotenone. Materials and Methods: Mice were randomly divided into four groups and treated with rotenone and simultaneously with A. blazei. Results: Rotenone treatment altered both the motor and nonmotor behavioral deficits as compared to controls. Concurrent treatment with rotenone and A. blazei significantly restored these behavioral deficits. Conclusion: The results of the present study strengthen the fact that the nutritional supplement of A. blazei extract in rotenone-affected areas might offer the neuroprotection.

Keywords: Motor and nonmotor symptoms, Parkinson’s disease, rotenone A. blazei


How to cite this article:
Venkateshgobi V, Rajasankar S, Johnson WM, Prabu K, Ramkumar M. Neuroprotective Effect of Agaricus Blazei Extract Against Rotenone-Induced Motor and Nonmotor Symptoms in Experimental Model of Parkinson’s Disease. Int J Nutr Pharmacol Neurol Dis 2018;8:59-65

How to cite this URL:
Venkateshgobi V, Rajasankar S, Johnson WM, Prabu K, Ramkumar M. Neuroprotective Effect of Agaricus Blazei Extract Against Rotenone-Induced Motor and Nonmotor Symptoms in Experimental Model of Parkinson’s Disease. Int J Nutr Pharmacol Neurol Dis [serial online] 2018 [cited 2019 Jul 16];8:59-65. Available from: http://www.ijnpnd.com/text.asp?2018/8/2/59/231268


   Introduction Top


Parkinson’s disease (PD) is one of the neurodegenerative diseases that mainly affects the aged population. It is characterized clinically by resting tremor, rigidity, bradykinesia, and postural instability that primarily arised due to the degeneration of dopaminergic neurons in the substantia nigra (SN), which synthesize dopamine (DA), a chemical messenger responsible for transmitting signals to produce smooth and focused muscle activity. Classically, PD is considered to be a motor system disease, but nonmotor symptoms (NMS) occur throughout the course of the disease. NMS such as depression, fatigue, and olfactory disorders appeared at the earliest stage of the disease in patients with untreated PD.[1] Few nonmotor features of PD presumably occurred due to the contribution of the nondopaminergic systems including serotoninergic, noradrenergic, and cholinergic transmission.[2]

By using the animal models, the reliability, replicability, and internal validity resembling human PD can be achieved. Toxin models represent the classic experimental PD models, which are able to replicate most of the phenotypic and/or pathological features of PD. The neurotoxic agents have been used to induce the models of PD in a board range of organisms from small single cell yeast to the large nonhuman primates including 6-Hydroxy Dopamine (6-OHDA), Methyl,4-Phenyl 1, 2, 3, 6-Tetrahydropyridine (MPTP), paraquat, and rotenone. Rotenone belongs to cytotoxic retinoid family extracted from some plants of Leguminosae family such as Derris malaccensis, Derris elliptica, Lonchocarpus utilis, and Lonchocarpus urucu.[3] Rotenone is reported to cause reactive oxygen species (ROS) generation, adenosine triphosphate (ATP) depletion, and cell death in neurons due to its inhibitory action on mitochondrial complex I. Rotenone toxicity mimics many pathological hallmarks of PD, including motor and NMS, loss of dopaminergic neurons in SN, and formation of Lewy bodies which is presumably due to oxidative damage, mitochondrial dysfunction, and disruption of axonal transport.[4],[5]

In the folk medicine, Agaricus blazei Murill (A. blazei), an edible mushroom, is used for the treatment of cancer, leukemia, and hypertension,[6] which are attributed due to its active compounds such as glycoproteins, β-d-glucans, saponins, steroids, tannins, polysaccharides, ergosterol, and fatty acids. Previous studies from our laboratory[7],[8] and others indicated reported that aqueous extracts of A. blazei offered the neuroprotective effect against the experimental model of PD and aging due to its antioxidant, anti-inflammatory, and antiapoptotic functions.[9] Motor function is normally measured by performing a number of behavioral analysis specifically, open field test, hang test, narrow beam walking,[10] rotarod performance,[11] stride length,[12] swim test, akinesia, and catalepsy.[13] Behavior analysis is reported as more sensitive technique to detect functional impairments in PD rodent models and to quantify the therapeutic efficacy that restores dopaminergic function. Baydar et al.[14] reported that the analysis of behavioral changes is more sensitive than neurochemical alterations and indicators of NMS during neurotoxin exposures. Various behavior tests were performed to measure depression,[15] anxiety,[16] and memory impairment.[17] As rotenone model mimics both the motor and NMS of PD,[18],[19] the neuroprotective effect of A. blazei against rotenone-induced motor and nonmotor impairments was assessed.


   Materials and Methods Top


Chemicals

Rotenone was purchased from Sigma Chemical Company, Bangalore, India.

Preparation of methanolic extract of A. blazei

Mushrooms were collected and then air-dried in an oven at 38°C. For methyl alcohol extraction, 20 g of dried mushroom samples was weighed, ground into a fine powder, and then mixed with 200 ml of methyl alcohol at room temperature at 17×g for 24 h. The residue was re-extracted under the same conditions until the extraction solvents became colorless. The extract obtained was filtered on a Whatman no. 1 paper and the filtrate was collected; then methyl alcohol was removed using a rotary evaporator at 38°C to obtain the dry extract. The extract was placed in a plastic bottle and then stored at −80°C.

Animals and drug treatment

Male albino mice (25–30 g) aged 10 weeks were procured from the Biogen Laboratory, Bangalore, India. They were kept under ambient conditions and fed with standard pellet and water ad libitum. All the experimental protocols conformed to the National Guidelines on the proper care and use of Animals in Laboratory Research (Indian National Science Academy, New Delhi, India, 2000) and were approved by the Animal Ethics Committee (SJC/IAEC/2015–2016/01; dated 05/10/2015).

Experimental group

Twenty-four animals were randomized and distributed into four groups (n = 6): Group I − control (0.1 ml of sunflower oil i.p. for 45 days), Group II − mice treated with rotenone (1 mg/kg/day i.p. in sunflower oil for 45 days),[7] Group III − mice treated with A. blazei extract (100 mg/kg b.w.p.o for 45 days)[7] and rotenone (as group II), and Group IV − mice treated with A. blazei extract alone (100 mg/kg). After the end of the experimental period, behavior tests such as open field, stride length, akinesia, catalepsy, forced swim, sucrose intake, and elevated plus maze test were performed. Then the animals were sacrificed. The striatum and SN were procured and utilized for the protein expression studies of apoptotic indices. Data were not shown in this manuscript.

Motor behavioral assessment

Open field test

The floor of the open field apparatus (100 cm × 100 cm × 40 cm) was covered with rexine cloth that have drawn lines, dividing them into 25 equal squares (20 cm × 20 cm). Animals were placed individually in the corner of the apparatus and its behavior for the following was noticed for 300 s: peripheral locomotor activity − the number of lines crossed in the inner nine squares; rearing activity − the number of the time rat standing alone with its fore legs, and grooming activity − the number of times the rat washing face or scratching or licking the fur. Between each session, the apparatus was thoroughly cleaned with alcohol and dried.[20]

Stride length measurement

The experimental mice were trained to walk along a straight line. Forepaws were dipped in black ink, and the length of forepaw steps during normal walking on a clean sheet of paper was measured. Stride length was assessed by measuring the distance between each step of the same side of the animal. Stride length was measured from the middle toe of the first step to the heel of the second step.[21]

Catalepsy

The term implies the inability of an animal to correct an externally imposed posture. The animal is taken up by lifting its tail and is placed on its forepaws on a horizontal wooden bar (diameter: 1.25 cm; height: 10 cm). The duration taken for the first movement of paws was measured as cataleptic time. The maximum descent latency for at least 30 s was said to be cataleptic and maximum time was fixed at 180 s.[22]

Akinesia

This tests replicate the difficulty in initiating movement in PD. Akinesia was assessed by measuring the latency in seconds of the animals to move all four limbs with the test finished within 180 s. Before performing akinesia test, each mouse was acclimatized for 5 min on a wooden elevated (100 cm) platform (100 cm × 150 cm). Using a stopwatch, the time taken by the animal to move all the four limbs was recorded.[23]

Nonmotor behavioral assessment

Modified forced swim test

In forced swim test, rodents developed immobile posture, if they are exposed to an inescapable situation, resembling depression in humans. It was performed in two sessions: training and test. In the training session, the mice were allowed to swim in water containing tank (40 cm length × 25 cm width × 16 cm height) for 15 min. Twenty-four hours after the training session, animals were allowed to swim for 5 min, for the subsequent quantification of immobility time (time needed to attain the lack of motion of the whole body with only the necessary movements to keep the animal’s head above the water). The water was changed after each animal to avoid the influence of smell.[24] This test has been performed on 28th day (training session) and 29th day (test session) after the last day of rotenone injection (experimental days 38 and 39, respectively).

Sucrose preference test

Sucrose intake test is used to determine anhedonia, a decreased ability to experience pleasure, a core symptom of human depression. Mice were transferred into single housing cages with free access to food. Each rat was provided with two bottles of preweighed water, on the extreme sides of the cage during the 24 h training phase to acclimatize the mice to drink water from two bottles. After training, one bottle was randomly switched to contain 1% sucrose solution for 1 h, as described previously,[15] and 24 h later, the bottles were reversed, and provided for 1 h. The sum of water consumption and sucrose solution consumption was defined as the total intake. The percentage of sucrose intake was calculated by using the following equation (% sucrose preference = sucrose intake × 100/total intake). The test was performed between 9:00 and 11:00 AM, beginning 1 week prior to the rotenone exposure (to provide baseline values) and finishing on 14th and 21st day after that. After the sucrose preference test, all the mice received free access to food and water.

Elevated plus maze test

Elevated plus maze test is primarily used to measure unconditioned anxiety in rodents and is modified to evaluate spatial learning and memory. This test was performed according to the procedure described by Hlinak and Krejci[25] but with minor modifications. The apparatus contains two open and two closed arms. From a central platform, arms are extended and the maze was elevated to a height of 50 cm from the floor. On the first day, each animal was placed separately at the end of an open arm. The time taken by the mice to move in one of the enclosed arm was recorded as transfer latency on the first day. By placing the mice in an open arm, retention of memory was measured by calculating the retention latency on day 4 of the initial retention transfer latency (ITL) and was termed as the final retention transfer latency.

Statistical analysis

Statistical analysis was executed by the one-way analysis of variance followed by Duncan’s multiple range test using Statistical Package for the Social Science software package version 15.0. All data are expressed as mean ± standard deviation (SD) for six mice from each group. Results were considered statistically significant at P < 0.05.


   Results Top


Effects of A. blazei extract on rotenone-induced locomotor activity

Exploratory behavior in the new environment is measured using open field test. Locomotion (peripheral and central) and nonlocomotion activities (rearing and grooming) of control and experimental animals were observed by open field test. Rotenone injection led to a significant reduction in the peripheral and central movements [[Figure 1]A and [Figure 1]B] along with diminished rearing and grooming activities [[Figure 1]C]. Coadministration of A. blazei extract 100 mg/kg b.w dose to rotenone (group III) treated mice showed a significant increase in the locomotion and nonlocomotion activities as compared to rotenone (group II) intoxicated mice. However, no significant changes were observed in A. blazei extract (100 mg/kg b.w) alone treated mice as compared to saline-treated control mice.
Figure 1: Effect of peripheral and central movements and grooming and rearing activities in open field test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SD of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effects of A. blazei extract on rotenone-induced stride length measurement

Shortened stride length is one of the chief characteristics of abnormal gait in PD. The result of this study demonstrated a significant decrease in forelimb and hind limb stride length in the rotenone-induced mice [Figure 2]. Meanwhile, the stride length measurement in the A. blazei extract (100 mg/kg b.w) and rotenone-treated mice was longer than those of rotenone animals; in addition, no significant differences in stride lengths were observed between A. blazei extract and saline-treated control mice.
Figure 2: Effect of forelimb and himdlimb measurement in stride length measurement of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± standard error of the mean (SEM) of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effects of A. blazei extract on rotenone-induced initial movement impairment

Impairment in the initiation of movement was measured by akinesia test. Chronic administration of rotenone caused impaired ability to initiate movement (akinesia) as compared to control mice (P < 0.05). Oral administration of A. blazei extract (100 mg/kg b.w) significantly attenuated rotenone-induced akinesia [Figure 3]. Moreover, no significant variations were observed between control and A. blazei extract alone treated mice.
Figure 3: Effect of akinetic time in akinesia test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SEM of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effects of A. blazei extract on rotenone-induced movement impairments

Impaired coordination in movement was observed by catalepsy test. Chronic administration of rotenone caused impairment in the correction of an externally imposed posture (catalepsy) as compared to control mice. Coadministration of A. blazei extract (100 mg/kg b.w) to rotenone-treated mice significantly attenuated rotenone-induced catalepsy [Figure 4]. Moreover, no significant changes were observed between control and A. blazei extract alone treated mice.
Figure 4: Effect of catalepsic time in catalepsy test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SEM of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effects of A. blazei extract on rotenone-induced forced swim test

Rotenone-administered mice showed more immobility time in forced swim test as compared to control mice [Figure 5]. Rotenone and A. blazei extract (100 mg/kg b.w) administered animals (group III) had significantly reduced immobility time on the water tank as compared with the rotenone alone treated animals. No significant differences were observed between A. blazei extract and control animals in forced swim test [Figure 5].
Figure 5: Effect of immobility time in forced swim test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SEM of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effect of A. blazei extract on rotenone-induced sucrose preference test

Depressive-like behavior was indicated by sugar intake test. Rotenone-induced animals showed significant decrease in pleasure to drink sweet water (sucrose intake test) as compared to control mice [Figure 6]. Coadministration of A. blazei extract (100 mg/kg b.w) significantly improved the sucrose intake. Moreover, no significant variations were observed between control and A. blazei extract alone treated mice.
Figure 6: Effect of sucrose intake in sucrose intake test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SEM of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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Effect of A. blazei extract on rotenone-induced elevated plus maze test

Anxiety-like behavior was expressed in elevated plus maze test. Mice treated with rotenone spend more time in the enclosed arms than the open arms as compared to control mice [Figure 7]. Coadministration of A. blazei extract (100 mg/kg b.w) significantly improved the anxiety-like behavior. Moreover, no significant variations were observed between control and A. blazei extract alone treated mice.
Figure 7: Effect of time spent in elevated plus maze test of mice exposed to rotenone and A. blazei and their cotreatment. Values are mean ± SEM of six animals in each group. (#) Significantly differs (P < 0.05) compared to control group; (*) significantly differs (P < 0.05) compared to rotenone alone treated group

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   Discussion Top


Performance of open field, stride length, akinesia, and catalepsy test are used to assess the locomotion and activity, gait disturbance, delay in commencing a movement, and rigidity respectively, whereas sucrose intake, elevated plus maze, and swim test are performed to measure the nonmotor impairments including depression, anhedonia, and anxiety in experimental rodents. Chronic administration of rotenone exhibited a significant impairment in motor and nonmotor functions as compared to control mice. DA levels are closely associated with the open field activity.[26] In the open field test, peripheral square crossing indicates the general motor performance and acclimatization attempt, whereas central square crossing indicates the exploratory behavior. Rearing and grooming activities are also the indicators of stress. Rearings are known to be highly sensitive to striatum (ST) or SN lesions.[26] Reduced performance of square crossing and activities in rotenone-induced animals could be associated with dopaminergic loss.[27] Stride length measurement is directly correlated with major motor symptoms of PD such as bradykinesia and rigidity. Moriss et al.[28] demonstrated that the patients with PD present a shortened stride length with a shuffling gait and reduced velocity (gait hypokinesia). The swim test and stride length measurement were established as a sensitive index of nigrostriatal pathway function.[12],[13] In the present study, the administration of rotenone exhibited impaired the ability to initiate movement (akinesia) and rigidity or inability to correct an externally forced posture (catalepsy). Behavioral assessment of akinesia in rodent models of PD resembles limb akinesia and gait problems of patients with PD.[29],[30] Rotenone destroyed the dopaminergic neurons selectively and resulting in impaired motor function.[31] In the present study, depletion of brain DA levels in rotenone-treated mice caused behavioral abnormalities as seen in patients with PD. Enhancement of striatal DA and its regulators including tyrosine hydroxylase by A. blazei clearly indicated the neuroprotective efficiency of this extract in protecting dopaminergic neurons and thereby normalizing the behavior.[32],[33]

Sucrose preference is frequently used as a measure of anhedonia, another form of depression in rodents. Damages to dopaminergic, serotonergic, and noradrenergic systems have been postulated to the prevalence of depression in PD.[34] Depletion of monoamine neurotransmitters by rotenone leads to depressive behavior,[35],[36],[37] whereas A. blazei offers neuroprotective effect that may be due to its antidepressive action. In the forced swim test, rodents were placed in an inescapable and stressful, state thus developing an immobile condition, after starting initial escape oriented movements. In the subsequent exposure, the immobility commences faster and marked. This is known as "behavior despair" and commences due to the animals response to the depression.[38] In the elevated plus maze test, due to its aversive behavior, mice enter into the enclosed arms from the open arms.[16] The time for which the animal moves from the open arm to the closed arm might be shortened if the animal has previously experienced entering the open arms. If so, the shortened transfer latency was related to memory. The cholinergic system plays a vital role in learning and memory related functions, as Kaur et al.[39] demonstrated that increase in AChE activity might be accountable for diminished memory in rotenone-treated mice.


   Conclusion Top


A. blazei extract ameliorated both the motor and NMS of PD in this study, which may be by modulating dopaminergic and nondopaminergic pathways. Further studies are needed to know the impact of specific phytochemicals of A. blazei against PD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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