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European Journal of Scientific Research
ISSN 1450-216X Vol.31 No.4 (2009), pp.553-565
© EuroJournals Publishing, Inc. 2009
http://www.eurojournals.com/ejsr.htm
Comparison on Cognitive Effects of Centella Asiatica in Healthy
Middle Age Female and Male Volunteers
Roxana Dev Omar Dev
Department of Sports Studies, Faculty of Educational Studies
Universiti Putra Malaysia, Malaysia
Suhaila Mohamed
Department of Food Service and Management, Faculty of Food and Science Technology
Universiti Putra Malaysia, Malaysia
Zarida Hambali
Department of Pathology, Faculty of Medicine and Health Sciences
Universiti Putra Malaysia, Malaysia
Bahaman Abu Samah
Department of Professional Development and Continuing Education
Universiti Putra Malaysia, Malaysia
Abstract
Aims of this study: Centella asiatica has a reputation to restore decline cognitive function in
traditional medicine and in animal model. However, little evidence regarding the efficacy
of Centella asiatica from clinical trials is available. Therefore, the present study
investigated the effect of Centella asiatica on cognitive function of healthy middle age
volunteer.
Materials and methods: Fourty one (22 females and 19 males) healthy middle age
participants received the Centella asiatica capsules at various doses ranging 3 g to 4 g
(according to body weight) once daily for 2 months. Cognitive performance was assessed
using the Woodcock-Johnson Cognitive Abilities Test III (WJ CAT III) prior to the trial
(baseline), 40 days, 60 days and 90 days (after treatment).
Results: The results showed that the Centella asiatica enhanced many of the cognitive test
measured at different time between males and females.
Conclusion: Therefore, the present findings suggest the potential Centella asiatica to
attenuate the age-related decline in cognitive function in healthy middle age and elderly
adults. However, the precise mechanism(s) underlying theses effects still require further
investigation.
Keywords: Centella asiatica; Cognitive function; Middle age adults
1. Introduction
As we age a gradual deficit is present with regard to cognitive functions which normally does not
severely disturb the daily life activities related to the physical, mental, or social functioning in elderly
Comparison on Cognitive Effects of Centella Asiatica in Healthy Middle
Age Female and Male Volunteers 554
adults (Wattanathorn et al., 2008). The cognitive decline has been characterized as a diminution of
attentional processes, episodic and working memory, and processing and psychomotor speed
(Salthouse, 1994; Christensen, 2001). However, for extreme cases this condition can eventually
progress to clinically recognizable dementia (Chen et al., 2005; Amieva et al., 2005). Mild cognitive
impairment (MCI), a more recent introduced concept, is characterized by memory complaints in a non-
demented and otherwise healthy upper middle aged and older persons (Shah et al., 2000). MCI can
actually progresses to Alzheimer’s disease (AD) in 10-15% of individuals per annum compared with 1-
2 % in appropriate controls (Petersen et al., 1999).
Numerous studies suggested that the age-related cognitive decline can be prevented (Solfrizzi et
al., 1999). Therefore, a new approach aimed at controlling the decrease in cognitive function was
focused (Wattanathorn et al., 2008). Numerous previous studies had demonstrated that fruits,
vegetables and medicinal plants could prevent the occurrence of the neurochemical and behavioral
changes occurred in aging (Veerendra Kumar and Gupta, 2002).
Centella asiatica is a small perennial herbaceous plant, belonging to the Umbelliferae family.
Both the leaves and the entire plant can be used therapeutically. The active ingredients of Centella
asiatica are claimed to posess would healing properties (EMEA, 1998). Madecassic asid, asiaticoside
and asiatic acid act on fibroblast cells and equilibrate collagen fiber synthesis, whenever it is modified
(EMEA, 1998).
In ancient Ayurvedic medicine, C. asiatica is reputed to restore youth, memory and longevity
(Kapoor, 1990). Cognitive enhancing effects have been observed in rats following oral administration
of an aqueous extract of C. asiatica; this effect was associated with an antioxidant mechanism in the
CNS (Veerendra Kumar & Gupta, 2002). For example, an Ayurvedic formulation composed of four
herbs, including C. asiatica, is used to retard age and prevent dementia, and the herb combined with
milk is given to improve memory (Manyam, 1999). Whereas in Tradional Chinese Medicine (TCM),
C. asiatica has been used for combating physical and mental exhaustion (Brinkaus et al., 2000; Duke
& Ayensu, 1985).
Alterations in other neurotransmitter systems have been associated with Alzheimer’s Disease
(AD) pathology (Advokat & Pellergrin, 1992; Reinikainen et al., 1988; Seidl et al., 2001; Storga et al.,
1996). Some drugs that modulate neurotransmitter systems have shown some benefits in AD-related
symptoms (e.g., trazodone improved behavioral problems associated with AD) ( Lake and Grossberg,
1987; Lebert et al., 1994). An aqueous extract of C.asiatica leaf had shown a modulation on
dopamine, 5-hydroxytrptamine (5-HT) and noradrenalin systems in rat brain and improved learning
and memory processes in vivo (Nalini et al., 1992). Glutamate may induce neuronal degeneration by
over stimulation of N-methyl-D-aspartate (NMDA) receptors. Memantine, an NMDA receptor
antagonist, is licensed for the treatment of moderately severe to severe AD and it is therapeutically
effective (Winbald & Poritis, 1999; Reisberg et al., 2002). The triterpene asiatic acid (in C. asiatica)
and its derivatives have been shown to protect cortical neurons from glutamate-induced excitotoxicity
in vitro (Lee et al., 2000); thus, further research regarding the clinical potential of these compounds
may be warranted.
Eventhough, Centella asiatica products are widely available in market as cognitive booster,
however, supported document with valid biological data for humans are still limited. Hence, this work
attempts to compare the cognitive effects of Centella asiatica in healthy middle-age female and male
volunteers.
2. Materials and Methods
2.1. Subjects
Twenty two female and nineteen male healthy middle age volunteers (age range: 35–50 years; mean
age: 43.3 years and 44.2 years respectively) were recruited from the university, primarily via university
555 Roxana Dev Omar Dev, Suhaila Mohamed, Zarida Hambali and Bahaman Abu Samah
bulletin and posters. Before participating, volunteers signed a written consent form describing the
details of the study. In the consent form, subjects were informed that the purpose of the experiment
was to study the effects of herbal medications on cognitive functions in healthy middle age volunteers.
Volunteers initially participated in a structured telephone interview (acquiring data on age, sex,
medical condition, and self-reported alcohol, cigarette, caffeine and other supplements used).
Individuals meeting criteria (35–50 years old, fluent in English and Bahasa Malaysia, high school
diploma or equivalent, within 20% of ideal body weight, and no current medical problems) were
invited for a group briefing with the researcher.
At the briefing, subjects’ medical history were assessed and were given a thorough explanation
on details of the study. Subjects were told that they will be given one of two different types of
treatment/supplement. Baseline medical status which include the pre data intake on biomedical
parameters (glucose, total cholesterol, high density lipoprotein, and triglycerides) were assessed, to
determine if there were contraindications to their participating in the study (Derogatis, 1994).
Volunteers also completed the “Health Questionnaire,” a locally developed questionnaire, detailing
their medical history. Exclusion criteria included past or current medical conditions that would
contraindicate study participation; history of or current substance use disorder, current emotional or
psychiatric problems and pregnancy or intention to become pregnant. One male subject withdrew from
the study after completing one session for reasons unrelated to the study. Volunteers received token for
their participation in the research study.
2.2. Design
A clinical, placebo controlled, consisting of four trials was conducted. Subjects were tested at
baseline, after 40 days and 60 days of treatment/supplement, and after 30 days of washout period. A
random list of numbers was generated by computer. Subjects were randomly assigned to treatment or
placebo group. Placebo and Centella asiatica capsules had the same colour, texture and size.
A series of cognitive test and filling-in questionnaire were done. This procedure usually took
about 1 ½ hours. Subjects were not allowed to take any caffeine beverages or products and sweetened
(with glucose) beverage, at least an hour before the cognitive tests. Besides that, a three-day diet recall
was also taken.
Rigorous protocol was taken to maintain the quality of the study. Subjects were called every
week to remind on their herbal administration and also asked about adverse events. Subjects were
asked to call the researcher if they experienced any medical problems during the 90-day study period.
At the end of the study, they were also asked about adverse events.
2.3. Supplements
The supplements, herbal (Centella asiatica) or placebo (cornstarch) were given according to the
subjects’ body weight, 500 mg for each 10 kg of body weight. So, there were a range of 5 to 8
capsules taken daily per person. However, the intake is consistent for each individual for two months.
These capsules were prepared by herbal manufacturer, Tokotenaga Sdn. Bhd. (GMP), Sekudai, Johor.
2.4. Cognitive tests
Woodcock-Johnson III Cognitive Abilities Test (WJ III COG) was used in this study. The WJ III COG
contains 20 tests, each measuring different aspect of cognitive ability. The tests combine to form
clusters for interpretive purposes. Eight clusters were used for this study. Cluster interpretation
minimizes the danger of generalizing from the score for a single, narrow ability to a broad,
multifaceted ability. Cluster interpretation results in higher validity because usually more than one
component of a broad ability comprises the score that serves as the basis for interpretation. The entire
selection of tasks or clusters took approximately 1 hour.
Comparison on Cognitive Effects of Centella Asiatica in Healthy Middle
Age Female and Male Volunteers 556
The eight clusters of cognitive test were as follows; long-term retrieval (glr), visual-spatial
thinking (gv), speed processing (gs), short-term memory (gsm), working memory (gwm), broad
attention (gba), executive processes (gep), and delayed recall (gdr). However, for better understanding
in the selected tested clusters, the following descriptions of the WJ III COG Tests are given.
Visual-Auditory Learning: This thinking ability test requires the subject to learn, store, and
retrieve a series of visual-auditory associations. On this test of associative and meaningful memory,
the subject was asked to learn and recall rebuses (pictographic representations of words).
Spatial Relations: This visualization-of-spatial-relationships task requires the subject to
identify the two or three pieces that form a complete target shape. The difficulty increases as the
drawings of the pieces are flipped, rotated, and become more similar in appearance.
Concept Formation: This controlled-learning task involves categorical reasoning based on
principles of inductive logic. This test also measures an aspect of executive processing-flexibility in
thinking when required to shift one’s mental set frequently. The subject was presented with a complete
stimulus set from which to derive the rule for each item. This test does not include a memory
component.
Visual Matching: More specifically, it is a measure of perceptual speed. This task measures an
aspect of speed at which an individual can make visual symbol discriminations. The subject was asked
to locate and circle the two identical numbers in a row of six numbers. This task proceeds in difficulty
from single-digit numbers to triple-digit numbers and has a 3-minute time limit.
Numbers Reversed: Although this test primarily measures short-term memory span, it can also
be classified as a measure of working memory or attentional capacity. The test requires the individual
to hold span of numbers in immediate awareness (memory) while performing a mental operation on it
(reversing the sequence).
Auditory Working Memory: Besides measuring for short-term auditory memory span, it can
also be classified as a measure of working memory or divided attention. The subject was asked to
listen to a series that contains digits and words, such as “elephant, 1 shoe, 8, 2, apple.” The subject
then attempts to reorder the information, repeating first the objects in sequential order and then the
digits in sequential order. This task requires the ability to hold information in immediate awareness,
divide the information into two groups and shift attentional resources to the two new ordered
sequences.
Visual-Auditory Learning-Delayed: The subject was asked to relearn the associations presented
in a test occurred 30 minutes before. The ease of relearning a previously learned task provides an
index of retention over time.
Retrieval Fluency: This test measures fluency of retrieval from stored knowledge. The subject
was required to name as many examples as possible from given category within a 1-minute time
period. The task consists of three different categories: things to eat or drink, first names of people, and
animals.
Picture Recognition: The subject’s task is to recognize a subset of previously presented
pictures within a field of distracting pictures. To eliminate verbal mediation as a memory strategy,
varieties of the same type of object were used as the stimuli and distracters for each item (e.g., several
different flowers or several different hats). The difficulty of the items increases as the number of
pictures in the stimulus set increases.
Decision Speed: It requires the ability to make correct conceptual decisions quickly. It is a
test of cognitive efficiency that measures the speed of processing simple concepts. In each row, the
subject’s task was to locate quickly the two pictures that were most similar conceptually. This test has
a 1-minute time limit.
Memory for Words: In this test, the subject was asked to repeat lists of unrelated words in the
correct sequence.
Planning: This test measures the mental control process involved in determining, selecting,
and applying solutions to problems using forethought. The Planning test is a complex task that draws
557 Roxana Dev Omar Dev, Suhaila Mohamed, Zarida Hambali and Bahaman Abu Samah
upon fluid reasoning (gf ) and visual processing (gv) abilities (in particular, spatial scanning). In this
test, the subject was asked to trace a pattern without removing the pencil from the paper or retracing
any lines.
Pair Cancellation: Paired Cancellation provides information about executive processing,
attention/ concentration, and processing speed abilities. In a 1-minute time period, the ubject was
asked to locate and mark a repeated pattern as quickly as possible.
The following are the 8 cognitive clusters chosen for this study:
Long-term retrieval (glr): Long-term retrieval (Glr) in this study is the ability to store
information and fluently retrieve it later in the process of thinking. Many narrow abilities are included
in this broad category. For example, associative memory, ideational fluency, meaningful memory,
associative fluency, expressional fluency, naming facility, and word fluency are all examples of narrow
glr abilities. The long-term storage process begins through a process of transfer of information from
immediate awareness to the stores of declarative and procedural knowledge. The amount of time that
lapses between the initial task performance and recall of information related to that task is not critically
important in defining glr, as long as the information is not held in immediate awareness. Examples of
tests are: Visual-Auditory Learning and Retrieval Fluency.
Visual-spatial thinking (gv): Visual-spatial thinking (gv) in this study is the ability to perceive,
analyze, synthesize, and think with visual patterns, including the ability to store and recall visual
representations. This broad thinking ability includes a number of specific, narrow, visual or spatial
abilities, including the ability to manipulate objects or patterns mentally, the ability to identify visual
representations that appear in obscure or vague circumstances, and visual memory. Typical gv tasks
include recognizing rotations and reversal of figures, finding hidden figures, identifying incomplete or
distorted figures, and comprehending spatial configurations. Examples of tests are: Spatial Relations
and Picture Recognition.
Processing speed (gs): Speed processing (gs) in this study is the ability to perform automatic
cognitive tasks, particularly when measured under pressure to maintain focused attention. Speed
processing is an aspect of cognitive efficiency. Tasks that define gs typically are easy and most people
would get all items correct if the test were not highly speed. Examples of tests are: Visual Matching
and Decision Speed.
Short-term memory (gsm): Short-term memory (gsm) in this study is an aspect of cognitive
efficiency. Specifically, it is the ability to apprehend and hold information in immediate awareness
and then use it within a few seconds. Although it is possible that gsm may include other processes, it is
most closely identified with memory span. Gsm is a limited capacity system where information is
typically retained for only a few seconds before it is lost. Once an individual uses what is being
retained in immediate awareness to perform a new task, the information held is subsequently either
stored or lost. Examples of tests are: Numbers Reversed and Memory for Words.
Working memory (gwm): Working memory (gwm) in this study refers to the ability to hold
information in immediate awareness while performing a mental operation on the information.
Examples of tests are: Numbers Reversed and Auditory.
Delayed recall (gdr): The Delayed Recall cluster measures the ability to both recall and relearn
associations that were previously learned. The cluster consists of only one delayed recall test. The
single test is Visual-Auditory Learning-Delayed. It provides information about the ability to recall and
relearn associations that were learned anywhere from 30 minutes to 8 days earlier.
Executive Processes (gep): The Executive Processes (gep) cluster in this study includes three
aspects of executive functioning: strategic planning, proactive interference control, and the ability to
shift repeatedly one’s mental set. Examples of tests are: Concept Formation, Planning and Pair
Cancellation.
Broad Attention (gba): Attention is a complex and multifaceted construct by which an
individual focuses on certain stimuli for information processing. These facets include focused or
selective attention, vigilance or sustained attention, divided attention, and attentional capacity or
working memory. The Broad Attention includes three tests, each measuring a different aspect of
Comparison on Cognitive Effects of Centella Asiatica in Healthy Middle
Age Female and Male Volunteers 558
attention. Examples of tests are: Numbers Reversed (attentional capacity), Auditory Working Memory
(divided attention) and Pair Cancellation (sustain attention).
2.5. Data Analysis
All collected data were analyzed by using the SPSS 14.0.1. Exploratory Data Analysis (EDA) was
used to investigate the data normality and to identify/determine the correct statistical design
(parametric or non-parametric). A one-way ANOVA was used to analyzed the mean differences
between treated/supplemented and control while Repeated Measures Analysia of variance (ANOVA)
were used to compare mean differences between Centella asiatica and control in relation to time: 0, 40
days, 60 days and 90 days of the study. Bonferoni post hoc testing was done on both sets of
ANOVA’s, comparing treatment to placebo and each groups at each time point. All statistical tests
were done at 0.05 level of significance (p < 0.05).
3. Results
3.1. Characteristics of subjects
The baseline data about characteristics of subjects in all groups were shown in Table 3.1. No
significant difference of all parameters among various groups was observed.
Table 3.1: Characteristics of subjects
Baseline data Placebo (male) Placebo (female) Centella asiatcia
(male) Centella asiatica
(female) Significant p
Age 40.11±4.62 44.20±4.80 43.3±3.56 44.17±5.94 p = 0.23
Education year 14.4±3.77 17.2±3.23 14.33±4.62 15.6±5.42 p = 0.44
Brief Intelligence
Ability 38.53±5.21 40.62±3.11 38.32±5.70 39.55±6.70 p = 0.37
3.2. The effects of Centella asiatica (CA) on cognitive
Prior to the determination of Centella asiatica on cognitive function, baseline data and mean pre-dose
baseline scores for all four conditions (PLM= male placebo, PLF= female placebo, CAM= male
Centella asiatica and CAF= female Centella asiatica) for each cognitive test scores were subjected to a
one-way ANOVA. The ANOVA test revealed that there were significant differences in the mean test
score on long-term retrieval (glr), visual-spatial thinking (gv) and speed processing (gs), between the
four condition groups; F(3,37)=8.32, p=0.00, F(3,37)=9.39, p=0.00, and F(3,37)=4.22, p=0.01
respectively. Bonferoni Post Hoc multiple comparisons test show that there was a statistically
significant difference in the mean test score for the following pair: CAF dan PLF for glr, CAF and
PLF; CAM and PLM for gv and CAF and PLF for gs. Eventhough there were significant differences
seen on the above conditions during the pre-dose baseline score, none were seen for all placebo groups
across time.
A set of Repeated Measures Analysis of Variance (ANOVA) were performed to investigate
group differences in mean score of the cognitive tests across time while a One-Way ANOVA were
performed to compare group differences in mean score of the cognitive tests among groups (treated
subjects with Centella asiatica and placebo). The summarized table for mean scores obtained by four
groups are depicted in Table 3.2.
Not much significant differences were seen for most cognitive tests across time among the male
subjects. Male subjects who consumed Centella asiatica (CAM) only showed significant increase
(p<0.05) in scores across time for three out of the eight cognitive tests which were long-term retrieval
(glr), visual spatial thinking (gv) and speed processing (gs). Meanwhile, female subjects who
559 Roxana Dev Omar Dev, Suhaila Mohamed, Zarida Hambali and Bahaman Abu Samah
consumed Centella asiatica (CAF) showed significant increase (p<0.05) in scores across time for five
out of the eight cognitive tests. The tests are: long-term retrieval (glr), short-term memory (gsm),
working memory (gwm), executive process (gep), and delayed recall (gdr). No significant differences
were seen on placebo subjects across time. For detailed findings, data obtained will be dealt
individually by each clusters of cognitive test performance.
Table 3.2: Mean pre-dose baseline raw scores and change from baseline scores for each condition at given
post-dose time point on selected cognitive performance
Post-dose Wash-out
Measure Pre-dose baseline score 40 days 60 days 90th day
Long term PLM 81.83 ± 9.74 88.22 ± 8.26 90.33 ± 9.3 91.56 ± 9.78 F(3,32) = 1.40, p = 0.26
retrieval PLF 89.00 ± 14.56 91.15 ± 6.83 94 ± 12.6 98.60 ± 7.39 F(3,36) = 2.06, p = 0.13
(glr) CAM 72.60 ± 12.81 78.45 ± 15.32 85.6 ± 15.7** 86.70 ± 15.13** F(3,36) = 3.98, p = 0.02
CAF 75.71 ± 13.50* 83.92 ± 13.52* 88.88 ± 12.57*/** 92.17 ± 13.4*/** F(3,44) = 3.49, p= 0.02
F(3,37) = 8.32, F(3,37) = 7.33, F(3,37) = 5.99, F(3,37) = 3.21,
p = 0.00 p = 0.00 p = 0.00 p = 0.03
visual PLM 56.50 ± 4.14 60.60 ± 2.14 59.90 ± 3.93 60.60 ± 2.63 F(3,32) = 2.27, p = 0.08
spatial PLF 59.80 ± 2.61 60.80 ± 1.61 62.05 ± 2.85 59.50 ± 3.5 F(3,36) = 1.38, p = 0.23
thinking CAM 50.33 ± 5.61 58.67 ± 3.43 60.33 ± 3.85 62.23 ± 3.35** F(3,36) = 4.99, p = 0.01
(gv) CAF 50.80 ± 5.89* 52.67 ± 5.49 53.33 ± 3.93 52.06 ± 4.15 F(3,44) = 0.26, p = 0.85
F(3,37) = 9.39, F(3,37) = 1.49, F(3,37) = 0.35, F(3,36) = 0.52,
p = 0.00 p = 0.23 p = 0.79 p = 0.67
Speed PLM 36.1 ± 4.77 36.70 ± 4.96 39.00 ± 3.07 39.75 ± 4.46 F(3,32) = 1.22, p = 0.33
processing PLF 42.9 ± 4.03 43.6 ± 3.80 44.45 ± 1.40 44.60 ± 4.18 F(3,36) = 1.49, p = 0.17
(gs) CAM 37.94 ± 3.67 39.17±3.42 40.61 ± 3.53 43.61 ± 4.7** F(3,36) = 4.86, p = 0.01
CAF 39.63 ± 4.95 42.00 ± 5.07* 42.59 ± 5.35 43.13 ± 4.36 F(3,44) = 4.72, p= 0.06
F(3,37) = 4.22, F(3,36) = 4.81, F(3,36) = 1.12, F(3,37) = 2.32,
p = 0.01 p = 0.01 p = 0.35 p = 0.09
Table 3.2: (continued)
Post-dose Wash-out
Measure Pre-dose baseline score 40 days 60 days 90th day
short-term PLM 17.67 ± 2.96 18.61 ± 4.0 18.78 ± 2.9 20.00 ± 2.96 F(3,32) = 0.82, p = 0.49
memory PLF 16.70 ± 4.41 18.65 ± 3.13 18.9 ± 3.04 20.10 ± 2.77 F(3,36) = 1.72, p = 0.18
(gsm) CAM 15.25 ± 2.32 16.8 ± 2.6 17.20 ± 2.36 18.20 ± 3.65 F(3,36) = 1.63, p = 0.19
CAF 15.64 ± 2.29 16.83 ± 2.14 19.67 ± 3.11** 19.79 ± 3.48** F(3,44) = 3.34, p = 0.02
F(3,37) = 1.18, F(3,37) = 0.94, F(3,37) = 1.16, F(3,37) = 0.83,
p = 0.33 p = 0.43 p = 0.34 p = 0.48
working PLM 18.3 ± 5.23 20.4 ± 5.66 20.20 ± 4.23 21.80 ± 6.5 F(3,32) = 1.95, p = 0.41
memory PLF 19.75 ± 6.37 22.50 ± 4.18 22.60 ± 5.31 22.75 ± 5.62 F(3,36) = 0.70, p = 0.56
(gwm) CAM 19.17 ± 3.04 21.56 ± 3.26 23.06 ± 3.76 22.28 ± 4.24 F(3,36) = 1.96, p = 0.33
CAF 18.59 ± 3.37 22.00 ± 2.86** 23.92 ± 4.2** 22.79 ± 5.13** F(3,44) = 3.17, p = 0.03
F(3,36) = 0.49, F(3,36) = 0.48, F(3,37) = 0.93, F(3,37) = 0.08,
p = 0.69 p = 0.70 p = 0.44 p = 0.97
executive PLM 61.53 ± 12.21 66.92 ± 5.84 67.48 ± 12.67 69.63 ± 6.07 F(3,32) = 2.38, p = 0.08
process PLF 56.88 ± 11.01 58.64 ± 6.72 59.58 ± 10.86 70.11 ± 7.34 F(3,36) = 2.94, p = 0.07
(gep) CAM 65.53 ± 13.77 71.71 ± 11.04 71.93 ± 15.44 77.95 ± 17.63 F(3,36) = 3.12, p = 0.06
CAF 54.97 ± 10.60 68.25 ± 13.52* 80.46 ± 9.43** 70.60 ± 18.72 F(3,44) =5.23, p = 0.01
F(3,37) = 1.44, F(3,36) = 3.77, F(3,37) = 1.89, F(3,37 ) =
2.42,
p = 0.25 p = 0.02 p = 0.15 p = 0.08
Comparison on Cognitive Effects of Centella Asiatica in Healthy Middle
Age Female and Male Volunteers 560
Table 3.2: (continued)
Post-dose Wash-out
Measure Pre-dose baseline score 40 days 60 days 90th day
delayed PLM 90.78 ± 27.81 96.67 ± 10.28 95.56 ± 10.51 95.11 ± 13.71 F(3,32) = 1.73, p = 0.18
recall PLF 94.7 ± 30.43 96.60 ± 16.30 97.50 ± 9.48 97.78 ± 9.39 F(3,35) = 1.37, p = 0.28
(gdr) CAM 82.80 ± 20.99 85.70 ± 26.92* 91.50 ± 24.72 95.70 ± 19.19 F(3,36) = 1.85, p = 0.15
CAF 87.73 ± 20.76 96.45 ± 21.05 103.42 ± 15.77*/** 109.45 ± 17.13*/** F(3,44) = 4.79, p = 0.01
F(3,36) = 2.68, F(3,36) = 5.19, F(3,37) = 4.38, F(3,37) = 3.32,
p = 0.06 p = 0.00 p = 0.01 p = 0.03
broad PLM 32.2 ± 5.92 35.10 ± 4.75 35.60 ± 4.03 36.70 ± 4.74 F(3,32) = 1.65, p = 0.14
attention PLF 35.75 ± 8.16 38.67 ± 9.08 37.00 ± 3.33 35.83 ± 7.20 F(3,36) = 0.47, p = 0.71
(gba) CAM 34.00 ± 1.73 36.22 ± 2.49 38.22 ± 9.32 36.78 ± 2.86 F(3,36) = 1.53, p = 0.22
CAF 34.50 ± 4.63 36.60 ±3.34 39.20 ± 6.27 37.40 ± 3.44 F(3,44) = 0.43, p = 0.74
F(3,37) = 0.68, F(3,37) = 0.73, F(3,37) = 1.68, F(3,37) = 0.18,
p = 0.57 p = 0.54 p = 0.09 p = 0.91
Shown are mean scores and S.E.M of cognitive test performance for each of the four conditions ((PLM = male placebo;
PLF = female placebo; CAM = male Centella asiatica, CAF = female Centella asiatica.
* p-value <0.05 when compared with placebo group (analysis between treatment), ** p-value<0.05 when compared with
baseline pre-dose score (analysis between trials).
4. Discussion
The present study investigated the effect of Centella asiatica on the cognitive performance in the
middle-age adults. The results indicate that the subjects who took Centella asiatica performed
significantly better in selected cognitive tests. This finding adds to the earlier findings that Centella
asiatica could have beneficial effects on the cognitive functions of subjects. Interestingly, females
showed more positive response to the ingestion of Centella asiatica as compared to male counterparts.
The results from this study also suggest that the ingestion of Centella asiatica can modulate differently
at different time period in males and females on cognitive test in the healthy middle-age adults.
Moreover, from this study ingestion of Centella asiatica can modulate differently on different
cognitive clusters in males and females.
There were three cognitive tests (that had significant differences across time) seen to increase
significantly for males who ingested Centella asiatica. Long term retrieval (glr) were seen
significantly different between trial period which began to modulate at 60th day of the trials and lasted
till the 90th day of the trial period. The other two which were speed processing (gs) and visual spatial
thinking (gv) were significantly different across time at the 90th day of the trial.
Earlier modulation was observed from female subjects who were supplemented with Centella
asiatica. Working memory (gwm) significantly increased at the 40th day of the trial. The other
cognitive tests such as long-term retrieval (glr), short-term memory (gsm), delayed recall (gdr) and
executive processes (gep) significantly increased at the 60th day of trial. Increment on glr, gsm and
gdr lasted till the 90th day of trial period, while mean scores for gwm and gep decrease at the 90th day
period. This marks the uniqueness of observation for female subjects.
Recently, it was found that the long-term memory retrieval process involved the function of
right prefrontal cortex (PFC) (Bukner and Petersen, 1996) whereas the visual-spatial thinking was
reported to involve the hippocampus (Moser and Moser, 1998). Previous studies demonstrated that the
speed processing involved the function of dorsal and ventral pre-frontal cortex (Rypma & D’Esposito,
1999; Crespo-Facorro et al., 1999). The flexible capacity to store and manipulate information, termed
short-term memory is extremely important to our effective cognitive functioning (Gathercole, 1999).
The regions that are involved are more complex than most cognitive abilities. Short-term memory are
mostly activated at the left prefrontal region, right frontal areas, biparietal areas and surprisingly the
left cerebellum (Andreasen et al., 1995).
The last two decades have witnessed a dramatic increase in research on working memory.
Performance of a new working memory task, one that has not previously been used in functional
561 Roxana Dev Omar Dev, Suhaila Mohamed, Zarida Hambali and Bahaman Abu Samah
neuroimaging study, produced a distributed network of cerebral activation (Garavan et al., 2000).
Regional activation was largely consistent with the circuitry thought to underlie the function of
working memory, incorporating dorsolateral prefrontal, premotor and parietal areas (Rypma &
D’Esposito, 1999; D’Esposito et al., 1998; Jonides et al., 1993).
The role of executive functioning/processes and working memory constructs in clinical and
individual differences research may, in part, have prompted interest in identifying the neuroanatomical
locations and mechanisms that subserve both (Garavan, 2000). A consensus implicating dorsolateral
prefrontal cortex as critical for executive functioning has emerged as this region has been observed in a
number of studies using a number of different tasks (D’Esposito et al., 1995; Owen et al., 1996;
Salmon et al., 1996; Collette et al., 1999). However, it would be a mistake to presume that executive
processes are located solely in prefrontal regions (Garavan et al., 2000). Those studies that have
localized executive functions to the dorsolateral prefrontal cortex have also observed extensive parietal,
premotor, cingulated, occipital and cerebellar activation (Garavan et al., 2000). Consistent with these
findings, recent functional imaging studies of ‘classic’ executive tasks such as the Tower of London
and Raven’s Progressive Matrices test reveal extensive activation in frontal, as well as temporal,
parietal and occipital lobes and in the cerebellum (Berman et al., 1995; Baker at al., 1996; Nagahama et
al., 1996; Prabhakaran et al., 1997).
It is known that the anterior angulate cortex, on the medial surface of the frontal lobes of the
brain is widely believed to be involved in the regulation of attention (D’Esposito et al., 1995). Beyond
this however, its specific contribution to cognition remains disputed by many studies. Selective visual
attention involves dynamic interplay between attentional control systems and sensory brain structures
(Hopfinger et al., 2000). Superior frontal, inferior parietal and superior temporal cortex were
selectively activated by cues, indicating that theses structures are part of a network for attentional
control (Hopfinger et al., 2000). In a study by Kastner & Ungerheinder (2000) visual attention
involves in the area of frontal and parietal cortex. While, Corbetta & Shulman (2002) reviewed
evidence for partially segregated networks of brain areas that carry out different attentional functions.
One system (top-down), which includes parts of the intraparietal cortex and superior frontal cortex, is
involved in preparing and applying goal-directed selection for stimuli and responses. The other
system, which includes the temporoparietal cortex and inferior frontal cortex, and is largely lateralized
to the right hemisphere, is not involved in top-down selection (Corbetta & Shulman, 2002).
In summary, the prefrontal cortex has been the focus of considerable scientific investigation in
recent years, owing in part to the growing recognition that dysfunction of this region and associated
circuitry probably underlies many of the cognitive and behavioral disturbances associated with major
neuropsychiatric disorders such as attention-deficit hyperactive disorder (ADHD) and schizophrenia
(Dalley et al., 2004). Recent findings in rodents and non-human primates suggest that divergent
cognitive processes may be carried out by anatomically distinct sub-regions of prefrontal cortex
(Aggleton et al., 1995; Walton et al., 2003), although the extent to which these processes can be
considered functionally 100% homologous in human remains controversial (Brown, 2003). The
prefrontal cortex also targets, in a reciprocal and topographical manner, the main nuclei of origin of the
major forebrain cholinergic and monoaminergic neutotransmitter systems, including noradrenaline
(NA), dopamine (DA), serotonin (5-HT) and acetylcholine (AcH) (Birrell & Brown, 2000). These
systems act in turn to neuro-modulate cortical networks by influencing inhibitory and excitatory
synaptic transmission as well as the other cortical processes (Arnsten, 1997).
Alterations in neurotransmitter systems have been associated with Alzheimer’s Disease (AD)
pathology. (Advokat & Pellegrin, 1992; Fowler et al., 1992; Reinikainen et al., 1988). Some drugs
that modulate neurotransmitter systems have shown some benefits in AD-related systems (Lebert at al.,
1994). A distinct role for norepinephrine was seen for long-term retrieval, when a study on rats
showed that role of norepinephrine (adrenergic signaling in the hippocampus) was critical in retrieval
(Murchinson et al., 2004). For visual-spatial task, both acetylcholine and serotonin in hippocampus
were simultaneously activated (Stancampiano et al., 1999). Previous studies demonstrated that
working memory could be modulated by dopamine, norepinephrine and other main neurotransmitters
Comparison on Cognitive Effects of Centella Asiatica in Healthy Middle
Age Female and Male Volunteers 562
(Goldman-Rakic et al., 2000; Arnsten & Robbins, 2002). Meanwhile, dopamine has been prominently
studied as a crucial neurotransmitter for tuning neuronal and circuit responses during executive
processes (Goldberg & Weinberger, 2004). Study by Robbins (1997) showed that acetylcholine has
important roles in attentional function, compared to dopamine and norepinephrine.
Further studies have showed the extract of C. asiatica leaf to be sedative, antidepressant and
potentially cholinomimetic in vivo (Sakina, & Dandiya, 1990). These findings suggest that C. asiatica
may be appropriate to treat symptoms of depression and anxiety in AD, and that it may also influence
cholinergic activity, and thus cognitive function. An aqueous extract of C.asiatica leaf modulated
dopamine, 5-HT and noradrenaline systems in rat brain and improved learning, short-term and working
memory in vivo (Nalini et al., 1992). Cognitive-enhancing effects have also been observed in rats
following oral administration of an aqueous extract of C. asiatica; which was associated with an
antioxidant mechanism in the central nervous system (Kumar and Gupta, 2002b). Most recent study
by Wattanathorn et al., 2008, showed that high dose of C. asiatica extract enhanced working memory,
increased mood and alertness in healthy elderly volunteers.
Therefore, the effects of Centella asiatica on working memory (gwm), short-term memory
(gsm) and executive processes (gep) might partly occur via the modulation of dopamine in prefrontal
cortex. Meanwhile, long-term retrieval (glr), and visual spatial thinking (gv) might partly occur via
the modulation of norepinephrine, serotonin and acetylcholine respectively in various parts of the
frontal cortex and hippocampus.
In conclusion, this study is the first study to demonstrate significant differences effects of
Centella asiatica on cognitive performances when gender is compared. Males seemed to respond more
to glr, gv and speed processing (gs) after consuming Centella asiatica, while females increased better
in their glr, gsm, gwm, gep and delayed recall (gdr). Another interesting finding was no significant
differences were seen on broad attention on both gender. However, precise mechanism underlying
these effects still require further investigation.
Acknowledgement
This study was supported by Faculty of Educational Studies and Research Management Center,
Universiti Putra Malaysia, Malaysia.
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