Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2015), Vol. 6, Issue 9 (Research Article)

Received on 08 October, 2014; received in revised form, 28 July, 2015; accepted, 22 August, 2015; published 01 September, 2015

IN-VITRO ANTI-CHOLINESTERASE ACTIVITIES BY PIPERINE, AN ALKALOID FROM

THE SPICE FAMILY PIPERACEAE
E. J. Okello*, A. Coleman and C. J. Seal
Human Nutrition Research Centre, School of Agriculture, Food and Rural Development, Faculty of
Science and Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom.
Keywords: ABSTRACT: The alkaloid piperine from the spice family Piperaceae has been reported to
possess poly-pharmacological activities including anti-depressant and cognitive enhancing
Piperine, Acetylcholinesterase, effects. It has been suggested that its neurocognitive benefits may be via its activity on the
Butyrylcholinesterase, Kinetics of cholinergic system, particularly on the enzyme acetylcholinesterase (AChE), a
Inhibition pharmacological target for neurodegenerative disease such as Alzheimer’s disease (AD). The
paucity of information on the potential mechanism of inhibition of acetylcholinesterase and
Correspondence to Author:
butyrylcholinesterase (BuChE), also a primary target for drug development for the treatment
Dr. Edward J. Okello
of AD, prompted this in vitro investigation. Dose-dependent inhibition of AChE and BuChE
Human Nutrition Research Centre, by piperine was determined using a modified classic colorimetric method of Ellman. Kinetics
School of Agriculture, Food and Rural of inhibition was determined by Lineweaver-Burk methods. Piperine inhibited both AChE and
Development, Faculty of Science and BuChE in a concentration dependent manner with IC50 values of 0.12 mM and 0.067mM,
Engineering, Newcastle University, respectively. Piperine exhibited a higher selectivity towards BuChE with a BuChE/AChE ratio
Newcastle upon Tyne, NE1 7RU, United of 0.56mM. Kinetic values for AChE classify piperine as a competitive inhibitor whereas the
Kingdom . values for BuChE classify it as a mixed inhibitor. Compared to galanthamine (a mixed
competitive non-competitive AChEinhibitor, IC50 of 1.068 nmol/ml under similar assay
E-mail: Edward.Okello@ncl.ac.uk conditions) we conclude that although the AChE inhibition by piperine is not as potent as that
of galanthamine, in addition to its known antioxidant and anti-inflammatory activities,
piperine could provide a novel poly-pharmacological lead of potential benefit for the
symptomatic treatment of AD and therefore warrants further investigation.

INTRODUCTION: Alzheimer’s disease (AD) is However, acetylcholinesterase inhibitors (AChEIs)

generally recognised as the most prevalent form of have become the mainstay for the symptomatic
dementia. It is an irreversible and progressive treatment of AD. AChEI drugs approved in the US
disease which destroys memory and cognitive skills and UK are: donepezil (Aricept®), rivastigmine
and eventually leads to death. 1 AD is a multi- (Exelon®) and galantamine (Reminyl®). In
aetiology disorder. Risk factors for AD include Europe, availability differs from country to
non-modifiable factors such as age and genetics, as country. The general mechanism of AChEI is to
well as modifiable factors such as dietary and increase the brain availability of the
lifestyle choices. 2 The current pharmacological neurotransmitter acetylcholine (ACh) through the
options available for the treatment of AD include inhibition of the enzyme acetylcholinesterase
cholinesterase inhibition, glutamate receptor (AChE) that plays a role in its hydrolysis. 3
modulation, anti-oxidants and anti-inflammatory Inhibiting AChE prolongs the time ACh molecules
agents. 3 remain in the synaptic cleft, to combine with
muscarinic receptors thus enhancing cholinergic
QUICK RESPONSE CODE neurotransmission.3
DOI:
10.13040/IJPSR.0975-8232.6(9).3726-32
Two types of cholinesterases exist; AChE, which
Article can be accessed online on:
selectively hydrolyses ACh, and
www.ijpsr.com butyrylcholinesterase (BuChE), which hydrolyses
other choline esters in addition to Ach. 3 BuChE is
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.6(9).3726-32 present in all human and mouse tissues, and is more

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Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732. E-ISSN: 0975-8232; P-ISSN: 2320-5148

abundant than AChE in all body tissues except the O

brain. People who have no BChE activity due to a
genetic variation are healthy, which has led to the O
hypothesis that BChE has no physiological
N
function. 4 Over the course of AD however, AChE
activity decreases while BuChE activity stabilizes O
and even increases. Xie and co-workers 5 have FIG.1: CHEMICAL STRUCTURE OF PIPERINE
shown that cholinergic pathways lacking AChE are
sensitive to the toxic effect of BuChE selective MATERIALS AND METHODS:
inhibitors. These data suggest that BuChE may act Chemicals/reagents:
as a compensatory mechanism for Ach metabolism Acetylcholinesterase (EC 3.1.1.7) from
and support the potential of BuChE as a suitable Electrophorus electricus – homologous to human,
target for the treatment of AD. acetylthiocholine iodide (ATChI),
butyrylcholinesterase (EC 3.1.1.8) from equine
Black pepper (Piper nigrum) is the most widely serum, butyrylthiocholine (BTCh I), 5:5-dithiobis-
used among spices and belongs to the family 2-nitrobenzoic acid (DTNB) sodium bicarbonate
Piperaceae, cultivated for its fruit (berries) that are and Piperine (97% purity) (P49007) were
dried and used as a food seasoning. The spiciness purchased from Sigma Chemical Co., UK.
of the pepper compound is due to the nitrogenous
alkaloid substance piperine (1-piperoylpiperidine) Acetylcholinesterase activity:
(Fig.1), found both in the outer layer and seed Assessment of AChE inhibition was carried out
inside the fruit berries. Piperine is present in black using a calorimetric method of Ellman, et al.13 as
pepper (P.nigrum), long pepper (P. longum) and modified by Okello et al.14 A typical run consisted
other piper spices (Family: Piperaceae). 6 of 5 µL of AChE solution, at a final assay
concentration of 0.03 U/ml; 20 µL of 0.1M
Piperine, as seen in the historic remedies, is the phosphate buffer pH 8; 5 µl of DTNB, at a final
vital compound that exerts antipyretic and anti- concentration of 0.3 mM prepared in 0.1 M
inflammatory properties for medicinal uses. Other phosphate buffer pH 7 with 0.12 M of sodium
biological effects that piperine possess are; bicarbonate; and 5 µl of a piperine extract solution
analgesic 7, anticonvulsant 8, anti-ulcer 9, in 95% ethanol (EtOH). The reactants were mixed
antidepressant 10, cognitive enhancing 6, 11, in a 96-well, flat bottom polystyrene microtitre
cytoprotective and anti-oxidant. 12 The antioxidant plate. The mixture was shaken and pre-incubated at
properties in piperine have also been linked to 30oC for 10 minutes. The reaction was initiated by
improvements in cognitive function. In one study adding 5µl of ATChI at a final concentration of 0.5
11
, piperine was administered to Wistar male rats, at mM. Each sample was assayed in triplicate. The
doses ranging from 5, 10 and 20 mg/kg/day orally wells were again shaken before incubation at 30oC
for 4 weeks and the neuropharmacological activity for 10minutes. As a control 5 µl of the extract
was determined after single, 1, 2, 3 and 4 weeks of solution was replaced with 5 µl of 95% ethanol.
treatment.
The control was also assayed in a triplicate. To
The results showed that across the entire dosage monitor the non-enzymatic hydrolysis in the
range piperine possessed anti-depression-like reaction mixture, a blank consisting of 5 µl buffer
activity and a cognitive enhancing effect during the pH 8 replaced the AChE enzyme and 5 µlbuffer,
entire treatment duration. Although the precise pH 8 replaced the piperine solution. A kinetic run
mechanism is unknown, it was suggested that it absorbance at 405nm was measured on a Thermo
might be through the inhibition of lipid Labsystems Multiskan (Ascent software version
peroxidation and the acetylcholinesterase enzyme 2.6) 96-well plate reader for a period of 16 minutes
and that further studies were essential to understand at 30oC. The first 6 minutes were maintenance time
the precise mechanism of piperine’s activity 6, for problems reported by 15, 16, 17 that EtOH
hence the objective of this in vitro study. prevented inhibition of E. electricus AChE. Using a
low concentration of 1.2% EtOH in the assay and

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Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732. E-ISSN: 0975-8232; P-ISSN: 2320-5148

maintaining the mixed reagents in the plate for an equation obtained from the log inhibition curve was
extra 6 minutes prevented this inhibition. 0.067mM. There was a difference in efficiency
between the two enzymes with piperine inhibiting
Butyrylcholinesterase activity: BuChE 47% more effectively than AChE at the
Assessment of BuChE inhibition was performed as same concentration; despite AChE reaching 100%
described above, with the exception of 5µlBuChE maximum inhibition and BuChE reaching 67%
replacing AChE and 5µlBTChI replacing ATChI. maximum inhibition. The ratio between the IC50
values is 0.56mM, of which a higher ratio would
Determination of dose response curve and have supported a higher selectivity for the AChE
kinetic parameters: enzyme.
The concentration of piperine that inhibited the
hydrolysis of substrate by 50% (IC50) was
determined by monitoring the effect of various 120

concentrations (0.03125 to 0.5mM). The per cent

inhibition of AChE and BuChE was calculated 100

using the following formula:

80
((Control (abs/min) – Piperine concentration

Inhibition [%]
(abs/min))/ control (abs/min)) * 100 = % inhibition. 60

Each concentration was run equivalent to n=6. 40

Dose-response curves were fitted to the data points

using Microsoft Excel software and Sigma Plot 11. 20

The IC50 value was calculated from the standard

curve equations using Sigma Plot 11. For inhibition 0
0.0 0.1 0.2 0.3 0.4 0.5 0.6
kinetic studies, the serial dilutions of the piperine Concentration [mM]
were pre-incubated with different substrate FIG.2: DOSE-DEPENDENT INHIBITION OF AChE BY
concentrations ranging from (0.0625 mM to 0.5 PIPERINE
mM). Piperine concentration of 0.0625 mM and
0.125 mM were chosen for the kinetics studies as
70
they were concentrations similar to the specific
BuChE and AChEIC50 values respectively. The 65
data for substrate kinetics were analysed using the
Lineweaver-Burk models for the determination of 60

Km and Vmax constants.

Inhibition [%]

55

RESULTS: 50

Effect of piperine on AChE and BuChE activity:

45
Analysis of data showed that piperine inhibited
AChE activity in a concentration dependent manner 40

(Fig.2). The maximum inhibition (100%) was

35
observed at the final assay concentration of 0.5 0.0 0.1 0.2 0.3 0.4 0.5 0.6
mM. The IC50 value calculated from the equation Conentration [mM]
obtained from the log inhibition curve was FIG.3: DOSE-DEPENDENT INHIBITION OF BuChE BY
0.12mM. This contrast with an IC50 value of 1.068 PIPERINE
nmol/ml for galanthamine, as previously
determined under identical assay conditions. 18 Determination of the kinetic profile of AChE
Piperine also exhibited a concentration dependent and BuChE against piperine:
inhibition of BuChE activity (Fig. 3), maximum The mechanism by which piperine inhibited the
inhibition (67%) was observed at the final assay enzymes AChE and BuChE was investigated using
concentration of 0.5 mM. The IC50 value from the the Lineweaver-Burk plots (Figures 4 & 5) and

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Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732. E-ISSN: 0975-8232; P-ISSN: 2320-5148

Lineweaver-Burk constants (Table 1a and 1b). The as a mixed-inhibitor; where the Vmax values are
control (no piperine), 0.0625mM and 0.125 mM variable whereas the Km values increase. Compared
concentrations were used. The kinetic values for to galanthamine (a mixed competitive non-
AChE classified piperine as a competitive inhibitor; competitive inhibitor, piperine is not as potent as
where the Vmax values remained more or less this positive reference (IC50 of 1.068 nM/ml) as
constant while the Km values increased. However, previously tested under the same assay conditions.
18
the kinetic values for BuChE classified piperine’s

FIG.4: LINEWEAVER-BURK PLOT FOR AChE inhibition(● No piperine, Piperine 0.0625 mM)

FIG. 5: LINEWEAVER-BURK PLOT FOR BuChE inhibition (● No piperine, Piperine 0.125mM)

TABLE 1a: KINETIC CONSTANTS FOR AChE

Kinetic Constants
1 -1
/Vmax[mM/min] Vmax[mM/min] /Km [mM] Km [mM]
No piperine 70.652 0.014 6.19 0.16
Piperine 0.0625 mM 67.633 0.015 2.41 0.41

TABLE 1 b: KINETIC CONSTANTS FOR BuChE

Kinetic Constants
1 -1
/Vmax[mM/min] Vmax[mM/min] /Km [mM] Km [mM]
No piperine 50.678 0.020 11.01 0.09
Piperine 0.125 mM 8.45 0.118 0.13 7.47

DISCUSSION: Previous studies on piperine have further research was essential in order to
used animal models to assess the protective 6 and understand the precise inhibitory mechanism
11
cognitive enhancing effects against piperine exhibits against AChE and BuChE. This
neurodegeneration and cognitive deficit. However study therefore focussed on identifying the

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Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732. E-ISSN: 0975-8232; P-ISSN: 2320-5148

cholinesterase inhibitory property of piperine via glial and BuChE-dependent acting within
kinetic study. Our study demonstrated that piperine conditions of decreased AChE activity such as in
exhibited anti-cholinesterase activity in a dose the Alzheimer’s disease brain. Two pools show
dependent manner. Furthermore, analyses of the different kinetic properties with regard to
Lineweaver-Burk kinetics showed that piperine regulation of brain ACh and can be separated by
followed a competitive inhibition pattern for AChE selective inhibitors.24 In the absence of AChE,
and mixed-inhibition for BuChE. There was a BuChE can hydrolyse ACh and potentially
higher affinity for BuChE with the IC50 value over substitute for AChE without producing peripheral
50 fold that for AChE inhibition. This is in or central cholinergic side effects. Considering the
contrast to galanthamine which has a 50 fold more drastic decrease in AChE activity taking place in
selective inhibition for AChE over BuChE. 19 the brain and the large pool of BuChE still
available both in glia and neurons, it may not
The proportion of the two enzymes, AChE and institute an advantage for a cholinesterase inhibitor
BuChE, present in the human brain are strongly to be selective for AChE. In contrast, a good
altered during the course of Alzheimer’s disease. In balance between AChE and BuChE inhibition
the cortex AChE activity decreases progressively to should result in higher therapeutic efficacy.22
10-15% of normal values, while BuChE activity is
unchanged or even increased by 20%. This may be Compounds with preferential cholinergic activity
the consequence of a combination of an could potentially be used therapeutically according
accumulation of BuChE in neuritic plaques and of to the severity of Alzheimer’s disease. Dual-
reactive gliosis.20 Given the close spatial cholinergic inhibitors are appropriate for a mild
relationship between glial cell protoplasm and stage of the disease where the Km of ACh is low
synaptic gap, it is likely that extracellularly- enough to keep BuChE inactivated.26
diffusing ACh may come in contact with glial
BuChE and be effectively hydrolysed as a The present knowledge of the molecular
result.21An important feature distinguishing BuChE configuration of the two enzymes would allow
from AChE is the enzymes kinetics toward researchers to design compounds possessing well-
concentrations of ACh. An excess of this substrate balanced AChE-BuChE specificity, high central
(µM) will inhibit only AChE but not BuChE. nerve system (CNS) penetration and low peripheral
Consequently, because of the difference in Km of and central cholinergic toxicity. Some of the
the two enzymes, glial BuChE is less efficient in second generation cholinesterase inhibitors have
hydrolysing ACh at low substrate concentrations demonstrated some of the advantages of these
(sub-µM) than neuronal AChE.22 The mechanism characteristics.22 Comparing this study’s findings
of inhibition caused by the excess of substrate has with the current literature on approved
been clarified.23 cholinesterase inhibitors; piperine evidently inhibits
both cholinergic enzymes and has an added affinity
Comparing the synaptic function between the two for BuChE, which is seemingly a pertinent
enzymes has shown variations between studies. An characteristic to have for higher therapeutic
extensive investigation found that AChE inhibition efficiency.
was more efficient than BuChE in elevating
cortical ACh using a non-selective inhibitor Research findings have revealed piperine to exhibit
compound eptastigmine. 24 Interestingly when a range of pharmacological effects, particularly
comparing these results against a BuChE specific with neurodegenerative diseases like Alzheimer’s.
inhibitor MF 8622, a high elevation of ACh similar A study by Chonpathompikunlert et al.6 infused
to that of eptastigmine, without the typical piperine at doses 5, 10, 20 mg/kg/body weight for 3
cholinergic side effects was demonstrated.25 The weeks bilaterally via intracerebro ventricular route
results of these experiments support the concept of as a bypassing strategy into the CNS. The findings
two pools of functional cholinesterases in the brain, were significantly improved spatial memory and
one neuronal and AChE-dependent acting mainly neurodegeneration, however there was a lack of
within physiological conditions and one mainly dose response relationship of piperine and AChE,

International Journal of Pharmaceutical Sciences and Research 3730

Okello et al., IJPSR, 2015; Vol. 6(9): 3726-3732. E-ISSN: 0975-8232; P-ISSN: 2320-5148

indicating the dose range was too high, therefore a 3. Lleό A: Current therapeutic options for Alzheimer’s
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investigation into the antidepressant and cognitive butyrylcholinesterase knockout mice to (-)-huperzine A
effects of piperine-encapsulated liposomes (PL) and donepezil suggests humans with butyrylcholinesterase
deficiency may not tolerate these Alzheimer’s disease
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of 48 ng/kg/body weight in male Wister rats for 14 5. Xie WH, Stribley JA, Chatonnet A, Wilder PJ, Rizzino A,
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How to cite this article:

Okello EJ, Coleman A and Seal CJ: In-Vitro Anti-Cholinesterase Activities by Piperine, an Alkaloid from the Spice Family Piperaceae. Int
J Pharm Sci Res 2015; 6(9): 3726-32. doi: 10.13040/IJPSR.0975-8232.6(9).3726-32.

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