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ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 154-162

Effect of Methanol Extract of Polygonum minus on Neuropathic Pain and Cognitive Dysfunction in Rats


1 Pharmacology Unit, Faculty of Pharmacy, AIMST University, Bedong, Kedah Darul Aman, Malaysia
2 Undergraduate, Faculty of Pharmacy, AIMST University, Bedong, Kedah Darul Aman, Malaysia

Date of Submission27-Nov-2020
Date of Decision17-Dec-2020
Date of Acceptance27-Dec-2020
Date of Web Publication22-Apr-2021

Correspondence Address:
Parayil Varghese Christapher
Pharmacology Unit, Faculty of Pharmacy, AIMST University, Bedong, Kedah Darul Aman
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_109_20

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   Abstract 


Introduction: Polygonum minus is one of the traditional medicinal plants. It contains various bioactive ingredients such as flavonoids and essential oil. It possesses the potential pharmacological actions, cytotoxicity, and antiproliferative actions. The role of Polygonum minus on neuropathic pain and cognitive functions remains to be explored. The present study was designed to evaluate the role of methanolic extract of Polygonum minus (PM) in paclitaxel (PT) and scopolamine (SCO) induced neuropathic pain and cognitive dysfunction in rats respectively. Methods: The PT (2 mg/kg; i.p. for 10 days) and SCO (1 mg/kg; i.p. for 4 days) were used for the induction of neuropathic pain and cognitive dysfunction in rats. The PM (200 and 400 mg/kg; for 10 days) was used for testing neuro-analgesic effect and the PM (150 mg/kg; for 4 days) was used for cognitive function study. The neuropathic pain was assessed by plantar, tail immersion, and pinprick tests. The cognitive function was assessed by the Morris water maze test. The reference drugs, that is, pregabalin (10 mg/kg) and donepezil (1 mg/kg) used for the assessment of neuropathic pain and cognitive function. Besides, the hippocampal tissue samples were used for the estimation of acetylcholinesterase activity, thiobarbituric acid reactive substances, reduced glutathione, and total protein levels. Results: The administration of PM ameliorated the PT- and SCO-induced neuropathic pain and cognitive dysfunctions in a dose-dependent manner. Conclusion: The PM possesses the potential neuroprotective actions due to its potential antioxidant, lipid peroxidation inhibition, and regulation of cholinergic neurotransmitter functions.

Keywords: Acetylcholinesterase activity, analgesic action, free radical scavenger, Morris water maze, neuroprotection, reduced glutathione


How to cite this article:
Christapher PV, Muthuraman A, Zhang LS, Jordon KY, Jonathan KH. Effect of Methanol Extract of Polygonum minus on Neuropathic Pain and Cognitive Dysfunction in Rats. Int J Nutr Pharmacol Neurol Dis 2021;11:154-62

How to cite this URL:
Christapher PV, Muthuraman A, Zhang LS, Jordon KY, Jonathan KH. Effect of Methanol Extract of Polygonum minus on Neuropathic Pain and Cognitive Dysfunction in Rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2021 Jun 12];11:154-62. Available from: https://www.ijnpnd.com/text.asp?2021/11/2/154/314380




   Introduction Top


Neurodegenerative disorders are the most common type of disease after the age of 50 years. Nowadays, the prevalence of these disorders is faster due to exposure to multiple neurotoxic events in brain tissue.[1],[2] It occurs via the death of neuronal cells in certain parts of the brain. So far, it is one of the toughest diseases to treat due to the involvement of a complicated cell signaling system.[3] Neuropathic pain and cognitive disorders are the major types of neurodegenerative disorders of the peripheral and central nervous systems, respectively. Some of the molecular mechanism is similar in both types of neurodegenerative disorders such as free radical formation, lipid peroxidation, mitochondrial dysfunction, DNA fragmentation, and alteration neurotransmitters and ion channel functions.[4],[5] The present study was focused to study the role of methanolic extract of Polygonum minus (PM) in paclitaxel (PT)- and scopolamine (SCO)-induced neuropathic pain and cognitive dysfunction in rats, respectively.

Paclitaxel (PT) is one of the major cancer chemotherapeutic agents for various cancers. However, 30% to 40% of cancer patients reported neuropathic pain symptoms after using PT.[6],[7] Furthermore, PT is known to leak out of blood cells to neuronal tissue via alteration of the nerve-blood barrier. Even in cellular systems, it causes free radical generation, lipid peroxidation, expression of apoptotic and inflammatory proteins, and neuronal death.[8],[9] SCO is an alkaloidal drug and is derived from nightshade plants (also called “Devil’s breath”), henbane and jimsonweed. Commercially, it is also known as hyoscine. It is used to treat motion sickness and postoperative nausea and vomiting.[10] The major mechanism of SCO in the prevention of nausea and vomiting is through inhibition of central cholinergic action via blocking of muscarinic receptors. It reduces the communication of vestibule nerves and brain vomiting center via inhibition of acetylcholine action. Because it is directly acting on the vomiting center, it is used as a potential agent for motion sickness, postoperative nausea, and reduction of saliva secretion before surgery.[11] It also causes sleepiness, blurred vision, pupil dilation, and mouth dryness.[12] Besides, it alters the cognitive function via the blocking of acetylcholine and its signals in the nervous system. Experimentally, PT and SCO were used as an experimental tool for the study of neuropathic pain and cognitive disorders respectively.[8],[13]

Clinically approved drugs for neuropathic pain disorders are limited, that is, carbamazepine, gabapentin, oxcarbazepine, topiramate, and pregabalin. However, the chronic usage of these drugs is also causing various undesirable side effects.[14],[15] Similarly, cognitive disorders are also managed with donepezil and memantine.[16],[17] Therefore, the present drug discovery expected potential and safer medicine from natural phytomedicines. The neuropathic pain disorders are managed with certain herbal extracts such as Ocimum sanctum,[18] Acorus calamus, [19] Butea monosperma,[20] and Vernonia cinerea.[21] Similarly, plant-derived medicines such as gallic acid,[8] ginsenoside Rg1,[22] and alkaloids such as oxymatrine, berberine, and lappaconitine[23] ameliorate neuropathic pain disorders.[24] Moreover, some plants such as Ginkgo biloba, Withania somnifera, Panax ginseng, Curcuma longa, Catharanthus roseus, Bacopa monnieri, Rosmarinus officinalis, and Camellia sinensis[25],[26] also ameliorate the cognitive dysfunction. Furthermore, plant compounds such as tolfenamic acid, morroniside, salidroside, curcumin, rosmarinic acid, and resveratrol are also produced the potential nootropic action.[27],[28]

PM is one of the traditional medicines and belongs to the Polygonaceae family. The leaves of PM have multiple bioactive phytochemicals such as alkaloids, glycosides, flavonoids, volatile oils, tannins, resins, and phenolic compounds.[29],[30] It is reported to produce effective pharmacological actions such as anti-platelet, anti-ulcer, anti-microbial, immunomodulatory, anticancer, anti-inflammatory, and neuroprotective actions.[29],[31] However, the role of PM in PT-associated neuropathic pain and SCO-associated cognitive dysfunction was not explored yet. Therefore, the present study focused to evaluate the role of PM in neuroprotective actions against the PT and SCO toxicity in rats.


   Materials and Methods Top


Animals used

The disease-free healthy male Sprague-Dawley (SD) rats (weight 180 ± 20 g) were employed in the present study. The animals were kept in Centralized Animal House, AIMST University, Malaysia with standard laboratory conditions. The rats were maintained with ambient room temperature with 12 hours of light and dark cycles. Food and water were supplied ad libitum. The current research protocol was duly approved by AIMST University Human & Animal Ethics Committee (AUAEC/FOP/2019/01 and AUAEC/FOP/2019/02). The care of animal was conducted according to the Institutional Animal Research Review Panel guidelines.

Preparation of methanolic extract of P. minus leaves

PM plant was collected from a herb farm at Sungai Petani, Kedah, Malaysia. The identification and authentication of the PM plant were made by a botanist. The leaves were collected and dried for the preparation of PM extract. The powdered form of leaves was weighed and extracted with pure methanol solution by using the direct maceration method. The crude PM extract was concentrated by the solvent evaporation method under pressure via a rotary distillation apparatus.[30] This PM extract was used for the testing of its role in neuropathic pain and cognitive disorders in the rat. Current animal research work consists of two independent studies, that is, Study 1: effect of methanolic extract of PM in PT-induced neuropathic pain in rats and Study 2: effect of methanolic extract of PM in SCO-induced cognitive dysfunction in rats.

Study 1: Effect of P. minus extract on paclitaxel-induced neuropathic pain in rats

This study consists of five groups of animals. Each group consists of six SD rats. Group 1 was served as a naive control group. Group 2 was served as a negative control, that is, PT (2 mg/kg; i.p.) for 10 consecutive days treated group. Groups 3 and 4 were served as groups treated with PM (200 and 400 mg/kg) orally (p.o.) for 10 consecutive days, respectively. Group 5 served as a positive control, that is, reference drug (PreG; 10 mg/kg; p.o.) for 10 consecutive days treatment group. The pain assessment of group 2 (PT alone treated) was started before 1 hour of the PT administration, whereas, the pain assessment of groups 3 to 5 was started after 1 hour of the PM or pregabalin administration. Pain assessments were carried out on days 0, 7, 14, and 21.

Assessment of paclitaxel-induced neuropathic pain in rats

Neuropathic pain assessments were made with pinprick test, tail immersion test, and plantar tests. The assessment of the pinprick test indicates the intensity of mechanical hyperalgesia; the tail immersion test indicates the cold hyperalgesia; and the plantar test indicates the tail heat hyperalgesia. The order of pain assessment tests was selected based on the intensity of pain stimuli. The details of neuropathic pain assessment as follows.

Pinprick test

The procedure for this test was adopted from the method described by Erichsen and Blackburn-Munro.[32] The rat was exposed to the wire grid surface. The right hind paw was engaged for blunt point needle application with adequate intensity to produce the gentle withdrawal response. The precaution of tissue injury was taken by adjusting the pressure of needle application. The paw lifting duration was noted in seconds using a stopwatch. A cut-off time of 20 seconds was maintained.

Tail immersion test

The procedure for this test was adopted from the method described by Necker and Hellon.[33] Rats were restrained gently with a soft cloth and the terminal (1 cm from the tail end) part of the tail was immersed in cold water (0–4°C). The precaution was made for excessive stress by handling procedures and duration. The assessment marker was the tail withdrawal threshold (in seconds) corresponding to cold temperature and a cut-off time of 20 seconds was maintained

Plantar test

The procedure for this test was adopted from the method described by Necker and Hellon.[33] Rats were restrained gently with a soft cloth and the left paw was placed on a radiant heat source surface without touching the lamp source. The precaution was made for excessive stress by handling procedures and duration. The assessment marker was paw withdrawal threshold (in seconds) corresponding to radiant heat intensity and the cut-off time of the 20 seconds was maintained.

Study 2: Effect of P. minus extract in scopolamine-induced cognitive dysfunction in rats

This study consisted of five groups of animals. Each group consisted of six SD rats. Group 1 served as a naïve control group. Group 2 served as a negative control, that is, SCO (1 mg/kg, i.p.) was administered 30 minutes after the assessment of 9th day Morris water maze (MWM) test. Groups 3 and 4 served as PM treated (150 and 300 mg/kg; p.o.) and were administered for 10 consecutive days from day 1 to day 10. On the day of MWM assessment, PM was administered 1 hour before the MWM test performance. Group 5 served as a positive control, that is, reference drug donepezil (DPZ; 1 mg/kg; p.o.) was administered for 10 consecutive days from day 1 to day 10. On the day of MWM assessment, PM was administered 1 hour before the MWM test performance. The dried PM extract and DPZ were suspended in 0.5% (w/v) of sodium-carboxy methylcellulose (CMC) solution. The oral dose of PM and DPZ were adjusted according to animal weight.

Assessment of cognitive function (learning and memory) in the Morris water maze test

The MWM water tank was divided into four equal quadrants, that is, Q1, Q2, Q3, and Q4 by using two black color threads. It was filled with water (23–25°C). The square platform was placed in the fourth quadrant as the target quadrant. The total study duration was 10 days. The acquisition trial was carried out on days 6 to 9 and the retrieval trial was carried out on day 10. The rats were placed gently and had face toward the wall of the MWM tank. The cognitive functions, that is, learning process were assessed by measurement of escape latency time (ELT, known as acquisition trial) in the MWM test method of cognitive functional assessment. Besides, the memory retention function was assessed by measurement of time spent in the target quadrant (TSTQ, known as retrieval trial) in the MWM test method of cognitive functional assessment. The four days (days 6–9) acquisition trials were assessed without the opaque condition of MWM tank water, whereas the retrieval trial was made with opaque condition of MWM tank water and without the platform. In this retrieval, the trial was assessed by a single-center placement of each animal in the MWM apparatus. During the four days of acquisition trials (learning process), the rat was placed in each quadrant for 120 seconds to find the platform. If the animal found the platform earlier, allowed for 10 seconds and taken back to the recovery cage. The time interval between each quadrant trail of the same animal was maintained for a minimum of 10 minutes.[34],[35]

Assessment of brain biomarker levels

On the last day of the experimental protocol, that is, 10th day, after MWM behavioral observation, the animals were sacrificed by cervical dislocation method. The brain tissue was isolated immediately and separated from the hippocampus of the brain. Thereafter, tissue was weighed and homogenated with a phosphate buffer (pH 7.4) solution. The aliquot was obtained by centrifugation (at 3000 rpm for 15 min) of the brain homogenate. These aliquot samples were stored for the estimation of biomarkers levels, that is, acetylcholinesterase (AChE) activity, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and total protein levels.

Estimation of AChE activity level

The tissue AChE activity levels were estimated by a spectrophotometric method as described by Ellman et al.[36] The yellow color chromogen changes of the test sample were noted by a recording of absorbance changes by a spectrophotometer (DU 640B Spectrophotometer, Beckman Coulter Inc., CA, USA) at 420 nm wavelength. The results were expressed as µM of acetylthiocholine hydrolysis per milligram of protein per minute.

Estimation of glutathione level

The tissue GSH levels were estimated as a described method of Ellman.[37] The yellow color chromogen changes of the test sample were noted by a recording of absorbance changes by spectrophotometer instruments at 412 nm wavelength. The results were expressed as µmol of GSH/mg of protein.

Estimation of TBARS level

The tissue TBARS levels were estimated as described by Ohkawa et al.[38] The pink color chromogen of test samples was noted by a recording of absorbance changes by spectrophotometer instruments at 535 nm wavelength. The results were expressed as nmol per mg of protein.

Estimation of total protein level

The tissue total protein levels were estimated as described by Lowry et al.[39] The changes of purple color chromogen of test samples were noted by a recording of absorbance changes by a spectrophotometer at 750 nm wavelength. The results were expressed as mg of protein per mL of supernatant.

Statistical analysis

All the results were expressed as mean ± standard error of the mean (SEM). Data obtained from behavioral tests were statistically analyzed using a two-way analysis of variance (ANOVA) followed by Tukey’s test were applied by using Graph pad prism version 5.0 software. The data of biomarkers changes, that is, AChE activity, GSH, and TBARS levels were analyzed using one-way ANOVA followed by Tukey’s multiple range tests that were applied for post hoc analysis by using Graph pad prism version 5.0 software. A probability value of P < 0.05 was considered to be statistically significant.


   Results Top


Effect of P. minus on paclitaxel-induced changes in neuropathic pain behavior

Neuropathic pain assessments were made with pinprick test, tail immersion test, and plantar tests. PM showed a statistically significant reduction in neuropathic pain. The details of neuropathic pain assessment are as follows:

Effect of methanolic extracts of Polygonum minus on paclitaxel-induced changes in pinprick test

The administration of PT (5 mg/kg; i.p.) shown a significant (P < 0.05) mechanical hypersensation by indication of increasing the paw withdrawal duration of the right hind paw when compared to the naive control group. Administration of PM (200 and 400 mg/kg; p.o.) attenuated PT-induced mechanical hypersensation in a dose-dependent manner. The result of the PM effect was comparable and similar to pregabalin (PreG; 5 mg/kg; p.o.) treatment group. The details are illustrated in [Figure 1].
Figure 1 Role of PM in pinprick test. Digits in parenthesis indicate dose in mg/kg. Data were expressed as mean ± SEM, n = 5 rats per group. aP < 0.05 when compared to the naive control group. bP < 0.05 when compared to the PT group. PM, methanolic extract of Polygonum minus; PreG, pregabalin; PT, paclitaxel.

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Effect of P. minus on paclitaxel-induced changes in the tail-flick test

The administration of PT (5 mg/kg; i.p.) was shown a significant (P < 0.05) thermal hyper-sensation by indication of increasing the tail withdrawal threshold when compared to the naive control group. Administration of PM (200 and 400 mg/kg; p.o.) attenuated PT-induced thermal hyper-sensation in a dose-dependent manner. The result of the PM effect was comparable and similar to PreG (5 mg/kg; p.o.) treatment group. The details are illustrated in [Figure 2].
Figure 2 Role of PM in tail immersion test. Digits in parenthesis indicate dose in mg/kg. Data were expressed as mean ± SEM, n = 5 rats per group. aP < 0.05 when compared to the naive control group. bP < 0.05 when compared to the PT group. PM, methanolic extract of Polygonum minus; PreG, pregabalin; PT, paclitaxel.

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Effect of P. minus on PT-induced changes in plantar test

The administration of PT (5 mg/kg; i.p.) shown a significant (P < 0.05) thermal hyper-sensation by indication of increasing the paw withdrawal threshold of the left hind paw when compared to the naive control group. Administration of PM (200 and 400 mg/kg; p.o.) attenuated PT-induced thermal hyper-sensation in a dose-dependent manner. The result of the PM effect was comparable and similar to PreG (5 mg/kg; p.o.) treatment group. The details are illustrated in [Figure 3].
Figure 3 Role of PM in the plantar test. Digits in parenthesis indicate dose in mg/kg. Data were expressed as mean ± SEM, n = 5 rats per group. aP < 0.05 when compared to the naive control group. bP < 0.05 when compared to the PT group. PM, methanolic extract of Polygonum minus; PT, paclitaxel; PreG, pregabalin.

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Effect of methanolic extracts of Polygonum minus on scopolamine-induced changes in cognitive functions

In the acquisition trial, day 9 ELT values of SCO-treated animals were shown to be significantly (p < 0.05) decreased, when compared to day 6 and day 9 ELT values of naive animal groups. However, the treatment of PM and DPZ showed significant ameliorative effects against SCO-induced changes of day 9 ELT values [Figure 4]. It indicates that PM has potential nootropic action against the SCO toxicities of cholinergic neurotransmission. In the retrieval test, naïve animals showed a significant (P < 0.05) rise in the TSTQ level when compared to the Q1-TSTQ values. The treatment of SCO showed a significant decrease in TSTQ levels when compared to the Q4-TSTQ levels of the naïve group. The treatment of PM and DPZ showed significant reversing of SCO-induced reduction of Q4-TSTQ levels [Figure 5]. It indicates that the PM possesses the potential memory retaining actions.
Figure 4 Effect of PM on learning function. Digits in parenthesis indicated dose in mg/kg. Data were expressed as mean ± SEM, n = 5. aP < 0.05 when compared to day 6 ELT value and day 9 naïve animal groups. aP < 0.05 when compared to day 9 ELT value SCO groups. DPZ, donepezil; ELT, escape latency time; PM, methanolic extract of Polygonum minus; SCO, scopolamine.

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Figure 5 Effect of PM on memory function. Digits in parenthesis indicated dose in mg/kg. Data were expressed as mean ± SD, n = 5 rats per group. aP < 0.05 when compared to Q1–TSTQ level of naïve group, bP < 0.05 when compared to Q4–TSTQ of normal group, and cP < 0.05 when compared to Q4–TSTQ of SCO group. DPZ, donepezil; PM, methanolic extract of Polygonum minus; SCO, scopolamine; TSTQ, time spend target quadrant.

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Effect of methanolic extracts of P. minus in scopolamine-induced biochemical changes in hippocampal tissue

The administration of SCO (1 mg/kg, i.p.) shown significant (P < 0.05) changes of hippocampal tissue biomarkers, i.e., rising of AchE activity and TBARS, and reduction of GSH. It indicates that SCO causing the cholinergic neurotransmitter modulation, lipid peroxidation, and raising oxidative stress when compared to the naïve control group. Administration of PM (200 and 400 mg/kg; p.o.) attenuated SCO-induced biochemical changes above hippocampal tissue biomarkers in a dose-dependent manner. The result of the PM effect was comparable and similar to DPZ (1 mg/kg; p.o.) treatment group. The data are tabulated in [Table 1].
Table 1 Effect of PM on SCO-induced hippocampal tissue biomarkers changes

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   Discussion Top


The methanolic extract of PM leaves was shown potential neuroprotective action against the PT- and SCO-induced neurotoxicity in rats. The neuropathic pain is accelerated by PT whereas administration PM (200 and 400 mg/kg; i.p.) attenuated the neuropathic pain progress. Similarly, the administration of PM (150 and 300 mg/kg; i.p.) attenuated the SCO-induced cognitive dysfunction in rats. Furthermore, PM extracts are also shown to the reduction of AChE and TBARS; and raise the GSH levels. These all effects are similar to that of reference drugs, i.e., PreG and DPZ.

PreG reduces the neuropathic pain by reduction of the synaptic release of neurotransmitters and blocking the α2–δ subunits type of voltage-gated calcium channels in the central as well as peripheral nervous system leads to a reduction in the neuronal excitability.[8] Furthermore, it reduces, directly or indirectly, free radical generation, lipid peroxidation, mitochondrial recycling, balancing of cellular homeostasis environment, and regeneration of neuronal tissue.[40] A similar effect was observed in the present study, PM potentially controls the progression of PT-induced thermal and mechanical hypersensitivity in rats. DPZ primarily inactivates the reversible cholinesterase activity that leads to reduce the hydrolysis of neuronal acetylcholine levels in brain tissue. Hence, the level of acetylcholine concentrations is regulated and maintained at the cholinergic synapse.[41],[42] Moreover, it is also reported to reduce oxidative stress and neuroinflammatory process. Therefore, it is used for the treatment of various cognitive disorders.[43] In the present research work, PM was also tested in this aspect in SCO-induced cognitive disorders. The results showed positive effects in the amelioration of cognitive dysfunction along with the reduction of AChE and TBARS. Reduced glutathione is one of the contributing factors to reduce the neurodegeneration and neuroinflammation via free radical scavenging g action.[44],[45] The treatment of PM evidenced that it raises the GSH level in hippocampal neuronal tissue. Hence, PM maybe a potential nootropic agent for neurotoxicity associated cognitive disorders.

Moreover, PM also proved that it has potential neuroprotective actions by regulation of humoral immune and immune-related gene expression,[46] anti-oxidative and anti-inflammatory actions,[47] controls the apoptotic pathways,[48] and enhances the neuroplasticity of brain via regulation of neurotransmitters level and strong MAO-A inhibition.[49] Further, PM also possesses the regulatory action of cellular mitochondrial and nucleic acid functions.[50] The findings of this study on memory improvement are in concordance with the report of a randomized clinical trial conducted on women with mood disturbance.[51] It is reported that one of the commercial supplementations of PM, exhibited improvement in both attention and short-term memory among women with mood disturbance.[52] Therefore, still need more depth analysis of PM’s role in neuroprotective action and ameliorative effect in various pathological conditions of neuropathic pain and cognitive disorders. Hence, it is concluded that PM possesses the potential ameliorative effect against the PT and SCO neurotoxicity associated with neuropathic pain and cognitive dysfunction due to its potential antioxidant, anti-inflammatory, lipid peroxidation inhibition, and regulation of cholinergic neurotransmission.

Acknowledgment

The authors are thankful to the Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100-Bedong, Kedah Darul Aman, Malaysia for supporting this study and providing financial and technical facilities for this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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